CN1914205A - Pyrazolo[3,4-b] pyridine compounds, and their use as phosphodiesterase inhibitors - Google Patents
Pyrazolo[3,4-b] pyridine compounds, and their use as phosphodiesterase inhibitors Download PDFInfo
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- CN1914205A CN1914205A CNA2004800416577A CN200480041657A CN1914205A CN 1914205 A CN1914205 A CN 1914205A CN A2004800416577 A CNA2004800416577 A CN A2004800416577A CN 200480041657 A CN200480041657 A CN 200480041657A CN 1914205 A CN1914205 A CN 1914205A
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Abstract
The invention provides a compound of formula (I) or a salt thereof, wherein Ar has the sub-formula (x) or (z) and wherein R<3> is optionally substituted C3-8cycloalkyl, optionally substituted C5-7 cycloalkenyl, an optionally substituted heterocyclic group (aa), (bb) or (cc), or a bicyclic group (ee); and wherein R<4> is H, C1-3 alkyl, C1-2fluoroalkyl, cyclopropyl, CH2OR<4a>, CH(Me)OR<4a>, or CH2CH2OR<4a>; and R<5> is inter alia H, C1-8alkyl, C1-8fluoroalkyl, C3-8 cycloalkyl, certain substituted alkyl groups, -(CH2)n<13>- Het, or optionally substituted phenyl or CH2-Ph; or R<4> and R<5> taken together are -(CH2)p<1>- or (CH2)p3 X<5> (CH2)p<4>- ; provided that at least one of R<4 >and R<5> is not a hydrogen atom (H). The invention also provides the use of the compounds as inhibitors of phosphodiesterase type IV (PDE4) and/or for the treatment and/or prophylaxis of inflammatory and/or allergic diseases such as chronic obstructive pulmonary disease (COPD), asthma, rheumatoid arthritis, allergic rhinitis or atopic dermatitis.
Description
The pharmaceutical composition that the present invention relates to pyrazolo [3,4-b] pyridine compounds, their preparation method, the intermediate that in the preparation method, uses and comprise described compound.The invention still further relates to described pyrazolo [3,4-b] therepic use of pyridine compounds, for example as the inhibitor of IV type phosphodiesterase (PDE4) and/or be used for the treatment of and/or prevent inflammatory diseases and/or allergic disease, for example chronic obstructive pulmonary disease (COPD), asthma, rheumatoid arthritis, rhinallergosis or atopic dermatitis.
Background of invention
US 3,979, and 399, US 3,840,546 and US 3,966,746 (E.R.Squibb ﹠amp; Sons) the 4-aminoderivative of pyrazolo [3,4-b] pyridine-5-methane amide is disclosed, wherein 4-amino N R
3R
4Can be acyclic amino, wherein R
3And R
4Can respectively do for oneself hydrogen, low alkyl group (for example butyl), phenyl etc.; Perhaps, NR
3R
4Can be 3-6 unit heterocyclic radical, for example pyrrolidino, piperidino-(1-position only) and Piperazino.Described compound is open as central nervous system depressant, can be used as tranquilizer, anodyne and depressor.
US 3,925, and 388, US 3,856,799, US 3,833,594 and US 3,755,340 (E.R.Squibb ﹠amp; Sons) the 4-aminoderivative of pyrazolo [3,4-b] pyridine-5-formic acid and methyl esters is disclosed.4-amino N R
3R
4Can be acyclic amino, wherein R
3And R
4Can respectively do for oneself hydrogen, low alkyl group (for example butyl), phenyl etc.; Perhaps, NR
3R
4Can be for also having 5-6 unit heterocyclic radical, for example pyrrolidino, piperidino-(1-position only), pyrazolyl, pyrimidyl, pyridazinyl or the piperazinyl of a nitrogen in addition.Described compound is open as central nervous system depressant, because anti-inflammatory and analgesic properties are arranged, so can be used as tranquilizer or tranquillizer.These compounds can improve adenosine-3 in the cell ', 5 '-ring one concentration of phosphoric acid, so can be used for relieving asthma symptoms.
H.Hoehn etc., J.Heterocycl.Chem., 1972,9 (2), 235-253 discloses amino substituent 1H-pyrazolo [3, the 4-b] pyridine of a series of 4-of containing hydroxyls, 4-chlorine, 4-alkoxyl group, 4-diazanyl and 4--5-carboxylic acid derivatives.
CA 1003419, CH 553 799 and T.Denzel, Archiv der Pharmazie, 1974,307 (3), 177-186 disclose do not have at 1 substituted 4, the dibasic 1H-pyrazolo of 5-[3,4-b] pyridine.
The following formula Pyrazolopyridine compound is disclosed at disclosure special permission communique JP-2002-20386-A in disclosed day of on January 23rd, 2002 (Ono Yakuhin Kogyo KK):
R wherein
1For: 1) group-OR
6, 2) and group-SR
7, 3) and the C2-8 alkynyl, 4) nitro, 5) cyano group, 6) the C1-8 alkyl that replaces of hydroxyl or C1-8 alkoxyl group, 7) phenyl, 8) group-C (O) R
8, 9) and group-SO
2NR
9R
10, 10) and group-NR
11SO
2R
12, 11) and group-NR
13C (O) R
14, or 12) group-CH=NR
15R
6And R
7For: i) hydrogen atom, ii) C1-8 alkyl, iii) the C1-8 alkyl of C1-8 alkoxyl group replacement, iv) trihalomethyl group, v) C3-7 cycloalkyl, the vi) C1-8 alkyl that replaces of phenyl, or vii) contain the first single, double or tricyclic heterocyclic of 3-15 of 1-4 nitrogen-atoms, a 1-3 Sauerstoffatom and/or 1-3 sulphur atom.R
2For: C1-8 alkoxyl group 1) hydrogen atom or 2).R
3For: C1-8 alkyl 1) hydrogen atom or 2).R
4For: 1) hydrogen atom, 2) C1-8 alkyl, 3) C3-7 cycloalkyl, 4) the C1-8 alkyl of C3-7 cycloalkyl substituted, 5) phenyl that can be replaced by 1-3 halogen atom, or 6) contain the first single, double or tricyclic heterocyclic of 3-15 of 1-4 nitrogen-atoms, a 1-3 Sauerstoffatom and/or 1-3 sulphur atom.R
5Be 1) hydrogen atom, 2) the C1-8 alkyl, 3) the C3-7 cycloalkyl, 4) the C1-8 alkyl of C3-7 cycloalkyl substituted, or 5) phenyl that can be replaced by 1-3 substituting group.R
3Be preferably hydrogen atom.R
4Be preferably methyl, ethyl, cyclopropyl, cyclobutyl or cyclopentyl.The compound of JP-2002-20386-A has PDE4 and suppresses active, so can be used for preventing and/or treating inflammatory diseases and many other diseases.
Contain 5-C (O) NH
2Substituent 1,3-dimethyl-4-(arylamino)-pyrazolo [3,4-b] pyridine and the disclosed compounds of JP-2002-20386-A like or identical, open as Orally active PDE4 inhibitor: H.Ochiai etc. by author from Ono Pharmaceutical Co., Bioorg.Med.Chem.Lett., published on January 5th, 2004, vol.14 (1), p.29-32 (on December 4th, 2003 or before can be from internet (article to be delivered) acquisition of this periodical).About being: H.Ochiai etc., Bioorg.Med.Chem., 2004,12,4089-4100 (can onlinely obtaining) on June 20th, 2004 as these compounds of Orally active PDE4 inhibitor and the complete paper of similar compounds; H.Ochiai etc., Chem.Pharm.Bull., 2004,52 (9), 1098-1104 (can onlinely obtaining) on June 15th, 2004.
EP 0 076 035 A1 (ICI Americas) disclose pyrazolo [3, the 4-b] pyridine derivate as central nervous system depressant, and can be used as tranquillizer or the tranquilizer of alleviating anxiety and Stress.
The compound cartazolate, promptly 4-(normal-butyl amino)-1-ethyl-1H-pyrazolo [3,4-b]-pyridine-5-ethyl formate is known.J.W.Daly etc., Med.Chem.Res., 1994,4,293-306 and D.Shi etc., Drug Development Research, 1997,42,41-56 discloses the 1H-pyrazolo [3 that a series of 4-(amino) replace, 4-b] pyridine-5-carboxylic acid derivatives (comprising 4-cyclopentyl amino-1-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-ethyl formate) and they are to A
1-Adenosine Receptors and A
2AThe affinity of-Adenosine Receptors and antagonistic activity, back one document discloses them to GABA
AThe affinity of the different binding sites of-receptor channel.S.Schenone etc., Bioorg.Med.Chem.Lett., 2001,11,2529-2531 and F.Bondavalli etc., J.Med.Chem., 2002, the 45 volume (the 22nd phases, on October 24th, 2002, claimed on September 24th, 2002 open on Web), the 4875-4887 page or leaf discloses a series of as A
14-amino-the 1-of-adenosine receptor ligands (2-chloro-2-phenylethyl)-1H-pyrazolo [3,4-b] pyridine-5-ethyl formate.
WO 02/060900 A2 discloses the MCP-1 antagonist that is used for the treatment of allergic disease, inflammatory diseases or autoimmune disorder, promptly a series of containing-C (O)-NR
4-C (O)-NR
5R
6Substituent bicyclic heterocyclic compounds comprises different azoles also [5,4-b] pyridine and 1H-pyrazolo [3,4-b] pyridine (called after pyrazolo [5,4-b] pyridine), and the 5-substituting group is-C (O)-NR
4-C (O)-NR
5R
6And choose wantonly at 1,3,4 and/or 6 and be substituted.The NH by substituting group-C (O) is disclosed among the WO 02/060900
2Substitute substituting group-C (O)-NR
4-C (O)-NR
5R
6Bicyclic heterocyclic compounds, they are at synthetic-C (O)-NR
4-C (O)-NR
5R
6Be used as intermediate in the compound that replaces.
5 of especially disclosing in loop systems of WO 00/15222 (Bristol-Myers Squibb) have C (O)-X
1Group and have E at 4
1The pyrazolo of group [3,4-b] pyridine.Wherein, X
1Can for for example-OR
9,-N (R
9) (R
10) or-N-(R
5) (A
2-R
2), E
1Can for for example-NH-A
1-cycloalkyl ,-NH-A
1-the cycloalkyl that replaces or-NH-A
1-heterocyclic radical; A wherein
1Be the alkylidene bridge of 1-10 carbon atom or the alkylidene bridge of replacement, A
2Can be the alkylidene bridge of for example chemical bond or 1-10 carbon atom or the alkylidene bridge of replacement.Disclosed compound can be used as the inhibitor of cGMP phosphodiesterase (especially V-type PDE), and can be used for treating the various diseases relevant with cGMP, for example erective dysfunction.WO 00/15222 openly do not comprise directly be connected 4 of pyrazolo [3,4-b] pyridine ring systems-cycloalkyl or the heterocyclic radical of NH-and/or have PDE4 and suppress active compound.
H.de Mello, A.Echevarria etc., 2004 J.Med.Chem., (believe on September 21st, 2004 or before publish soon) 3-methyl or 3-phenyl 4-anilino-1H-pyrazolo [3,4-b] pyridine 5-carboxylicesters as potential anti-Leishmania (Leishmania) medicine disclosed.
Patent application PCT/the EP2003/014867 of Glaxo Group Limited pending trial in application on December 19th, 2003 announced on July 8th, 2004; publication No. is WO2004/056823 A1 (being attached to this paper by reference), the openly also claimed 4-NR that contains of this application
3R
3aGroup (R
3aPreferred H) with at pyrazolo [3,4-b] pyridine compounds or its salt of 5 Het group of pyrazolo [3,4-b] pyridine, wherein Het is generally optional 5 yuan of heteroaryls that replace.PCT/EP2003/014867 also discloses these compounds as the purposes of PDE4 inhibitor and the purposes that is particularly useful for treating and/or preventing COPD, asthma or rhinallergosis.Among " the method F " that walks to the 59th page of the 18th row for the 58th page the 14th in PCT/EP2003/014867 (especially this section content is added all compounds, group and/or the substituting group mentioned in this section all definition in other place be attached to this paper by reference) in the text, the compound as the following general formula X XVIII of intermediate is disclosed:
Be used for the synthetic of claimed one group of 5-Het pyrazolo [3, the 4-b] pyridine compounds of PCT/EP2003/014867, wherein Het is 1 of optional replacement, 3- azoles-2-base.The intermediate 42,43 of PCT/EP2003/014867 (WO 2004/056823 A1) and 46 parts also disclose formula XXVIII compound is used as midbody compound in the embodiment of PCT/EP2003/014867 is synthetic embodiment.
Present patent application requires the right of priority of the PCT/EP2003/014867 of application on December 19th, 2003, depends on the above-mentioned paragraph that discloses formula XXVIII compound (the wherein preferred H of R3a) especially.
Please announce that on March 25th, 2004 publication No. is WO2004/024728 A2 (being attached to this paper by reference) by PCT/EP03/11814 in the patent of Glaxo Group Limited pending trial in application on September 12nd, 2003, this application discloses and has contained 4-NHR
3The pyrazolo of group and 5-C (O)-X group [3,4-b] pyridine compounds or its salt have following formula (I) structure:
Wherein:
R
1Be C
1-4Alkyl, C
1-3Fluoro-alkyl ,-CH
2CH
2OH or-CH
2CH
2CO
2C
1-2Alkyl;
R
2Be hydrogen atom (H), methyl or C
1Fluoro-alkyl;
R
3Be the optional C that replaces
3-8Cycloalkyl or the optional monounsaturated C that replaces
5-7Cycloalkenyl group or optional following formula (aa), (bb) or the heterocyclic radical (cc) that replaces;
N wherein
1And n
2Be 1 or 2 independently; Y is O, S, SO
2Or NR
10
Perhaps R
3Be two cyclic groups (dd) or (ee):
X is NR
4R
5Or OR
5a
In PCT/EP03/11814 (WO 2004/024728 A2), R
4Be hydrogen atom (H); C
1-6Alkyl; C
1-3Fluoro-alkyl; Or by a substituent R
11The C that replaces
2-6Alkyl.
In PCT/EP03/11814 (WO 2004/024728 A2), R
5Can be hydrogen atom (H); C
1-8Alkyl; C
1-8Fluoro-alkyl; Optional by C
1-2The C that alkyl replaces
3-8Cycloalkyl;-(CH
2)
n 4-part or C
3-8Cycloalkyl moiety is optional by C
1-2Alkyl replaces-(CH
2)
n 4-C
3-8Cycloalkyl, wherein n
4Be 1,2 or 3; By 1-2 independent substituent R
11The C that replaces
2-6Alkyl;-(CH
2)
n 11-C (O) R
16-(CH
2)
n 12-C (O) NR
12R
13-CHR
19-C (O) NR
12R
13-(CH
2)
n 12-C (O) OR
16-(CH
2)
n 12-C (O) OH;-CHR
19-C (O) OR
16-CHR
19-C (O) OH;-(CH
2)
n 12-SO
2-NR
12R
13-(CH
2)
n 12-SO
2R
16-(CH
2)
n 12-CN;-(CH
2)
n 13-Het; Or the optional phenyl that replaces.
Perhaps, in PCT/EP03/11814 (WO 2004/024728 A2), R
5Can have following formula (x), (y), (y1) or structure (z):
Wherein in formula (x), n=0,1 or 2; In formula (y) with (y1), m=1 or 2; In formula (z), r=0,1 or 2; Wherein in formula (x), (y) with (y1), 0,1 or 2 among A, B, D, E and the F is nitrogen or nitrogen-oxide compound (N independently
+-O
-), precondition be among A, B, D, E and the F at the most one for nitrogen-oxide compound; And remaining is CH or CR independently among A, B, D, E and the F
6Precondition is that then the 1-2 among A, B, D, E and the F is nitrogen or nitrogen-oxide compound (N independently when n is 0 in the formula (x)
+-O
-) and A, B, D, E and F at the most one be nitrogen-oxide compound;
In PCT/EP03/11814 (WO 2004/024728 A2), be independent of any other R
6Each R
6Be halogen atom; C
1-6Alkyl; C
1-4Fluoro-alkyl; C
1-4Alkoxyl group; C
1-2Fluoroalkyl; C
3-6Cycloalkyl oxy;-C (O) R
16a-C (O) OR
30-S (O)
2-R
16aR
16a-S (O)
2-NR
15a-; R
7R
8N-S (O)
2-; C
1-2Alkyl-C (O)-R
15aN-S (O)
2-; C
1-4Alkyl-S (O)-; Ph-S (O)-; R
7R
8N-CO-;-NR
15-C (O) R
16R
7R
8N; OH; C
1-4Alkoxy methyl; C
1-4Alkoxyethyl; C
1-2Alkyl-S (O)
2-CH
2-; R
7R
8N-S (O)
2-CH
2-; C
1-2Alkyl-S (O)
2-NR
15a-CH
2-;-CH
2-OH;-CH
2CH
2-OH;-CH
2-NR
7R
8-CH
2-CH
2-NR
7R
8-CH
2-C (O) OR
30-CH
2-C (O)-NR
7R
8-CH
2-NR
15a-C (O)-C
1-3Alkyl;-(CH
2)
n 14-Het
1, n wherein
14Be 0 or 1; Cyano group (CN); Ar
5bOr phenyl, pyridyl or pyrimidyl, wherein said phenyl, pyridyl or pyrimidyl are optional independently to be replaced by 1-2 following group: fluorine, chlorine, C
1-2Alkyl, C
1Fluoro-alkyl, C
1-2Alkoxyl group or C
1Fluoroalkyl;
Or two adjacent R
6Combine and to constitute-O-(CMe
2)-O-or-O-(CH
2)
n 14-O-, wherein n
14Be 1 or 2.
In PCT/EP03/11814 (WO 2004/024728 A2), in formula (z), G is O, S or NR
9, R wherein
9Be hydrogen atom (H), C
1-4Alkyl or C
1-4Fluoro-alkyl; 0,1,2 or 3 among J, L, M and the Q is nitrogen; Remaining is CH or CR independently among J, L, M and the Q
6, R wherein
6Be independent of the R of any other existence
6, as the definition in this article.
Disclosed formula (I) pyrazolo [3 among the PCT/EP03/11814 (WO 2004/024728 A2), 4-b] pyridine compounds or its salt is the inhibitor of IV type phosphodiesterase (PDE4), can be used for treating and/or preventing inflammatory diseases and/or allergic disease, for example chronic obstructive pulmonary disease (COPD), asthma, rheumatoid arthritis or rhinallergosis.
Summary of the invention
We have now found that new pyrazolo [3,4-b] pyridine compounds, and it has-C (O)-NH-C (R 5 of pyrazolo [3,4-b] pyridine ring system
4) (R
5)-aryl substituent, wherein R at least
4And R
5One of be not hydrogen atom (H), this compounds suppresses IV type phosphodiesterase (PDE4).
Therefore, the invention provides a kind of following formula (I) compound or its salt (particularly its pharmacy acceptable salt):
Wherein:
Ar has with following formula (x) or (z) structure:
R
1Be C
1-3Alkyl, C
1-3Fluoro-alkyl or-CH
2CH
2OH;
R
2Be hydrogen atom (H), methyl or C
1Fluoro-alkyl;
R
3Be the optional C that replaces
3-8Cycloalkyl or the optional monounsaturated C that replaces
5-7Cycloalkenyl group or optional following formula (aa), (bb) or the heterocyclic radical (cc) that replaces;
N wherein
1And n
2Be 1 or 2 independently; Y is O, S, SO
2Or NR
10R wherein
10Be hydrogen atom (H), C
1-2Alkyl, C
1-2Fluoro-alkyl, C (O) NH
2, C (O)-C
1-2Alkyl, C (O)-C
1Fluoro-alkyl or-C (O)-CH
2O-C
1Alkyl;
R wherein
3C
3-8Cycloalkyl or formula (aa), (bb) or heterocyclic radical (cc) are chosen wantonly on ring carbon atom and are replaced for following substituting group independently by 1-2: oxo (=O); OH; C
1-2Alkoxyl group; C
1-2Fluoroalkyl; NHR
21, R wherein
21Be hydrogen atom (H) or C
1-4Straight chained alkyl; C
1-2Alkyl; C
1-2Fluoro-alkyl;-CH
2OH;-CH
2CH
2OH;-CH
2NHR
22, R wherein
22Be H or C
1Alkyl;-C (O) OR
23, R wherein
23Be H;-C (O) NHR
24, R wherein
24Be H or C
1Alkyl;-C (O) R
25, R wherein
25Be C
1-2Alkyl; Fluorine; Oximido (=N-OH); Or (C
1-4Alkoxyl group) imino-(=N-OR
26, R wherein
26Be C
1-4Alkyl); Wherein any OH, alkoxyl group, fluoroalkyl or NHR
21Substituting group not with formula (I) in-R that the NH-group is connected
3Replace on the ring carbon atom, and not with heterocyclic radical (aa), (bb) or the R that Y group is connected (cc)
3Replace on the ring carbon atom;
Wherein work as R
3Be the optional monounsaturated C that replaces
5-7During cycloalkenyl group, then cycloalkenyl group is optional by 1 fluorine or C
1-2Alkyl substituent replace or by 2 be the substituting group replacement of fluorine or methyl independently, and with formula (I) in-R that the NH-group is connected
3Ring carbon atom does not participate in two keys of cycloalkenyl group;
Perhaps R
3Two cyclic groups for following formula (ee):
Y wherein
1, Y
2And Y
3Be CH independently
2Or oxygen (O), precondition is Y
1, Y
2And Y
3In maximum one be oxygen (O);
R
4Be hydrogen atom (H), methyl, ethyl, n-propyl, sec.-propyl, C
1-2Fluoro-alkyl, cyclopropyl ,-CH
2OR
4a,-CH (Me) OR
4aOr-CH
2CH
2OR
4aR wherein
4aBe hydrogen atom (H), methyl (Me) or C
1Fluoro-alkyl, for example CF
3Or CHF
2
R
5Be hydrogen atom (H); C
1-8Alkyl (C for example
1-6Alkyl or C
1-4Alkyl); C
1-3Fluoro-alkyl; Optional by C
1-2The C that alkyl replaces
3-8Cycloalkyl; Or-(CH
2)
n 4-part or C
3-8Cycloalkyl moiety is optional by C
1-2Alkyl replaces-(CH
2)
n 4-C
3-8Cycloalkyl, wherein n
4Be 1 or 2;
Perhaps R
5For by a R
11The C that substituting group replaces
1-4Alkyl; R wherein
11Be hydroxyl (OH); C
1-6Alkoxyl group; C
1-2Fluoroalkyl; Phenoxy group; (single fluoro-or two fluoro-phenyl) the oxygen base; (monomethyl-or dimethyl-phenyl) the oxygen base; Benzyloxy;-NR
12R
13-NR
15-C (O) R
16-NR
15-C (O)-NH-R
15Or-NR
15-S (O)
2R
16
Perhaps R
5Be the C that on different carbon atoms, is replaced by two hydroxyls (OH) substituting group
2-4Alkyl;
Perhaps R
5For-(CH
2)
n 11-C (O) R
16-(CH
2)
n 11-C (O) NR
12R
13-CHR
19-C (O) NR
12R
13-(CH
2)
n 11-C (O) OR
16-(CH
2)
n 11-C (O) OH;-CHR
19-C (O) OR
16-CHR
19-C (O) OH;-(CH
2)
n 11-S (O)
2-NR
12R
13-(CH
2)
n 11-S (O)
2R
16Or-(CH
2)
n 11-CN; N wherein
11(each R wherein that is 0,1,2 or 3
5N in the group
11Value be independent of other R
5N in the group
11Value); R
19Be C
1-2Alkyl;
Perhaps R
5For-(CH
2)
n 13-Het, wherein n
13Be 0,1 or 2, Het removes-NR
12R
13In addition 4 yuan, 5 yuan, 6 yuan or 7 yuan of saturated or undersaturated heterocycles, this heterocycle contains 1-2 ring hetero atom that independently is selected from O, S and N; Wherein work as n
13Be 0 o'clock, any ring hetero atom of existence can not connect-(CH
2)
n 13-part; Not any non-undersaturated (promptly not the participating in two keys) that wherein exists and be not that (promptly this nitrogen-atoms does not connect-(CH connectivity nitrogen
2)
n 13-part or do not connect R
5The carbon atom that connects) ring nitrogen is NR
17Wherein 1-2 ring carbon atom is optional independently by C
1-2Alkyl replaces;
Perhaps R
5For phenyl (Ph) ,-CH
2-Ph ,-CHMe-Ph ,-CHEt-Ph, CMe
2Ph or-CH
2CH
2-Ph, wherein phenyl ring Ph is optional is that following substituting group replaces: halogen atom by 1-2 independently; C
1-4Alkyl (C for example
1-2Alkyl); C
1-2Fluoro-alkyl (for example trifluoromethyl); C
1-4Alkoxyl group (C for example
1-2Alkoxyl group); C
1-2Fluoroalkyl (for example trifluoromethoxy or difluoro-methoxy); Cyclopropyl; Cyclopropyl oxygen base;-C (O)-C
1-4Alkyl;-C (O) OH;-C (O)-OC
1-4Alkyl; C
1-4Alkyl-S (O)
2-; C
1-4Alkyl-S (O)
2-NR
8a-; R
7aR
8aN-S (O)
2-; R
7aR
8aN-C (O)-;-NR
8a-C (O)-C
1-4Alkyl; R
7aR
8aN; OH; Nitro (NO
2); Or cyano group (CN);
Perhaps R
4And R
5Formation-(CH combines
2)
p 1-or-(CH
2)
p 3-X
5-(CH
2)
p 4-, X wherein
5Be O or NR
17ap
1=2,3,4,5 or 6, p
3And p
4Be 1,2 or 3 independently, precondition is if p
3Be 3, p then
4Be 1 or 2, if p
4Be 3, p then
3Be 1 or 2;
Precondition is R at least
4And R
5One of be not hydrogen atom (H);
Wherein, in formula (x):
A is C-R
6A, nitrogen (N) or nitrogen-oxide compound (N
+-O
-),
B is C-R
6B, nitrogen (N) or nitrogen-oxide compound (N
+-O
-),
D is C-R
6D, nitrogen (N) or nitrogen-oxide compound (N
+-O
-),
E is C-R
6E, nitrogen (N) or nitrogen-oxide compound (N
+-O
-),
F is C-R
6F, nitrogen (N) or nitrogen-oxide compound (N
+-O
-),
R wherein
6A, R
6B, R
6D, R
6EAnd R
6FBe hydrogen atom (H) independently; Halogen atom; C
1-6Alkyl (C for example
1-4Alkyl or C
1-2Alkyl); C
1-4Fluoro-alkyl (C for example
1-2Fluoro-alkyl); C
3-6Cycloalkyl; C
1-4Alkoxyl group (C for example
1-2Alkoxyl group); C
1-2Fluoroalkyl; C
3-6Cycloalkyl oxy;-C (O) R
16a-C (O) OR
30-S (O)
2-R
16a(C for example
1-2Alkyl-S (O)
2-); R
16a-S (O)
2-NR
15a-(C for example
1-2Alkyl-S (O)
2-NH-); R
7R
8N-S (O)
2-; C
1-2Alkyl-C (O)-R
15aN-S (O)
2-; C
1-4Alkyl-S (O)-, Ph-S (O)-, R
7R
8N-CO-;-NR
15a-C (O) R
16aR
7R
8N; Nitro (NO
2); OH (comprising its any tautomer); C
1-4Alkoxy methyl; C
1-4Alkoxyethyl; C
1-2Alkyl-S (O)
2-CH
2-; R
7R
8N-S (O)
2-CH
2-; C
1-2Alkyl-S (O)
2-NR
15a-CH
2-;-CH
2-OH;-CH
2CH
2-OH;-CH
2-NR
7R
8-CH
2-CH
2-NR
7R
8-CH
2-C (O) OR
30-CH
2-C (O)-NR
7R
8-CH
2-NR
15a-C (O)-C
1-3Alkyl;-(CH
2)
n 14-Het
1, n wherein
14Be 0 or 1; Cyano group (CN); Ar
5bPerhaps phenyl, pyridyl or pyrimidyl, wherein phenyl, pyridyl or pyrimidyl are optional independently by 1-2 following group replacement: fluorine, chlorine, C
1-2Alkyl, C
1Fluoro-alkyl, C
1-2Alkoxyl group or C
1Fluoroalkyl;
And/or two be selected from R
6A, R
6B, R
6D, R
6EAnd R
6FAdjacent group the formation :-CH=CH-CH=CH-that combines;-(CH
2)
n 14a-, n wherein
14aBe 3,4 or 5 (for example 3 or 4);-O-(CMe
2)-O-;-O-(CH
2)
n 14b-O-, wherein n
14bBe 1 or 2;-CH=CH-NR
15b-;-N=CH-NR
15b-;-CH=N-NR
15b-;-N=N-NR
15b-;-CH=CH-O-;-N=CH-O-;-CH=CH-S-; Or-N=CH-S-; R wherein
15bBe H or C
1-2Alkyl;
Precondition is:
Among A, B, D, E and the F is C-H (carbon-hydrogen), C-F (carbon-fluorine), nitrogen (N) or nitrogen-oxide compound (N independently more than two
+-O
-);
Be no more than two among A, B, D, E and the F and be nitrogen or nitrogen-oxide compound (N independently
+-O
-);
And be no more than one among A, B, D, E and the F and be nitrogen-oxide compound (N
+-O
-);
Wherein, in formula (z):
G is O, S or NR
9, R wherein
9Be hydrogen atom (H), C
1-4Alkyl or C
1-2Fluoro-alkyl;
J is C-R
6J, C-[and formula (I) tie point] or nitrogen (N),
L is C-R
6L, C-[and formula (I) tie point] or nitrogen (N),
M is C-R
6M, C-[and formula (I) tie point] or nitrogen (N),
Q is C-R
6Q, C-[and formula (I) tie point] or nitrogen (N),
R wherein
6J, R
6L, R
6MAnd R
6QBe hydrogen atom (H), halogen atom independently; C
1-4Alkyl (C for example
1-2Alkyl); C
1-3Fluoro-alkyl (C for example
1-2Fluoro-alkyl); C
3-6Cycloalkyl; C
1-4Alkoxyl group (C for example
1-2Alkoxyl group); C
1-2Fluoroalkyl; C
3-6Cycloalkyl oxy; OH (comprising its any tautomer); Or optional be the phenyl of following substituting group replacement independently by 1-2: fluorine, chlorine, C
1-2Alkyl, C
1Fluoro-alkyl, C
1-2Alkoxyl group or C
1Fluoroalkyl;
Precondition is:
Among J, L, M and the Q is C-H, C-F, C-C independently more than two
1-2The tie point of alkyl (for example C-Me), C-[bosom formula (I)] or nitrogen (N); With
Be no more than three among J, L, M and the Q and be nitrogen (N);
R
7And R
8Be hydrogen atom (H) independently; C
1-4Alkyl (C for example
1-2Alkyl, for example methyl); C
3-6Cycloalkyl; Or optional be the phenyl of following substituting group replacement independently by 1-2: fluorine, chlorine, C
1-2Alkyl, C
1Fluoro-alkyl, C
1-2Alkoxyl group or C
1Fluoroalkyl;
Perhaps R
7And R
8Formation-(CH together
2)
n 6,-C (O)-(CH
2)
n 7-,-C (O)-(CH
2)
n 10-C (O)-,-(CH
2)
n 8-X
7-(CH
2)
n 9-or-C (O)-X
7-(CH
2)
n 10-, n wherein
6Be 3,4,5 or 6, n
7Be 2,3,4 or 5, n
8, n
9And n
10Be 2 or 3 independently, X
7Be O or NR
14
R
7aBe hydrogen atom (H) or C
1-4Alkyl;
R
8aBe hydrogen atom (H) or methyl;
R
12And R
13Be H independently; C
1-4Alkyl (C for example
1-2Alkyl); C
3-6Cycloalkyl; Or optional be the phenyl of following substituting group replacement independently by 1-2: fluorine, chlorine, C
1-2Alkyl, C
1Fluoro-alkyl, C
1-2Alkoxyl group or C
1Fluoroalkyl;
Perhaps R
12And R
13Formation-(CH together
2)
n 6a-,-C (O)-(CH
2)
n 7a-,-C (O)-(CH
2)
n 10a-C (O)-,-(CH
2)
n 8a-X
12-(CH
2)
n 9a-or-C (O)-X
12-(CH
2)
n 10a-, n wherein
6aBe 3,4,5 or 6, n
7aBe 2,3,4 or 5, n
8a, n
9aAnd n
10aBe 2 or 3 independently, X
12Be O or NR
14a
R
14, R
14a, R
17And R
17aBe hydrogen atom (H) independently; C
1-4Alkyl (C for example
1-2Alkyl); C
1-2Fluoro-alkyl (CF for example
3); Cyclopropyl;-C (O)-C
1-4Alkyl (for example-C (O) Me);-C (O) NR
7aR
8a(for example-C (O) NH
2); Or-S (O)
2-C
1-4Alkyl (for example-S (O)
2Me);
Each R
15Be hydrogen atom (H) independently; C
1-4Alkyl (for example
tBu or C
1-2Alkyl, for example methyl); C
3-6Cycloalkyl; Or the optional phenyl that is replaced by 1-2 following group: halogen atom, C
1-2Alkyl, C
1Fluoro-alkyl, C
1-2Alkoxyl group or C
1Fluoroalkyl;
Each R
15aBe hydrogen atom (H) or C independently
1-4Alkyl;
R
16Be C
1-4Alkyl (C for example
1-2Alkyl); C
3-6Cycloalkyl (C for example
5-6Cycloalkyl); C
3-6Cycloalkyl-CH
2-(C for example
5-6Cycloalkyl-CH
2-); Phenyl; Or benzyl, wherein phenyl and benzyl are chosen wantonly independently on their ring and are replaced for following substituting group independently by 1-2: fluorine, chlorine, methyl, C
1Fluoro-alkyl, methoxyl group or C
1Fluoroalkyl;
R
16aBe C
1-6Alkyl (C for example
1-4Alkyl or C
1-2Alkyl); C
3-6Cycloalkyl (C for example
5-6Cycloalkyl), optional by an oxo (=O), OH or C
1-2Alkyl replaces (for example chooses the C 3 or 4 replacements wantonly
5-6Cycloalkyl ring; And/or preferred unsubstituted C
3-6Cycloalkyl); C
3-6Cycloalkyl-CH
2-(C for example
5-6Cycloalkyl-CH
2-); Pyridyl (for example pyridine-2-yl) is chosen wantonly on ring carbon atom by a following group and is replaced: halogen atom, C
1-2Alkyl, C
1Fluoro-alkyl, C
1-2Alkoxyl group or C
1Fluoroalkyl; Ar
5cPhenyl, optional is that following substituting group replaces: halogen atom, C by 1-2 independently
1-2Alkyl, C
1Fluoro-alkyl, C
1-2Alkoxyl group or C
1Fluoroalkyl; Benzyl is chosen wantonly on its ring and is replaced for following substituting group independently by 1-2: halogen atom, C
1-2Alkyl, C
1Fluoro-alkyl, C
1-2Alkoxyl group or C
1Fluoroalkyl; Or on ring carbon atom, connect, and contain 1-2 4 yuan, 5 yuan, 6 yuan or 7 yuan of saturated heterocyclics that independently are selected from the ring hetero atom of O, S and N, wherein the ring nitrogen of any existence is NR
27, R wherein
27Be H, C
1-2Alkyl or-C (O) Me, and described heterocycle is chosen wantonly at carbon atom by a C
1-2Alkyl or oxo (=O) substituting group replaces, precondition be any oxo (=O) substituting group replaces on the ring carbon atom of shack nitrogen-atoms;
Each R
30Be hydrogen atom (H), C independently
1-4Alkyl or C
3-6Cycloalkyl;
Ar
5bAnd Ar
5cIndependently in 5 yuan of rings, containing 1 O, S or NR
15a5 yuan of aromatic heterocycles, wherein said 5 yuan of rings also can be chosen wantonly and contain 1-2 extra nitrogen-atoms, and described heterocycle is chosen wantonly and replaced by the group below on the ring carbon atom: halogen atom, C
1-2Alkyl, C
1Fluoro-alkyl ,-CH
2OH ,-CH
2-OC
1-2Alkyl, OH (comprising its keto tautomer) or-CH2-NR
28R
29, R wherein
28And R
29Be H or methyl independently;
Het
1For on ring carbon atom, connecting, and contain 1-2 4 yuan, 5 yuan, 6 yuan or 7 yuan of saturated heterocyclics that independently are selected from the ring hetero atom of O, S and N; Wherein any ring nitrogen of Cun Zaiing is NR
31, R wherein
31Be H, C
1-2Alkyl or-C (O) Me; Described ring is chosen wantonly at carbon atom by a C
1-2Alkyl or oxo (=O) substituting group replaces, precondition be any oxo (=O) substituting group replaces on the ring carbon atom of shack nitrogen-atoms;
Precondition is:
Work as R
3Be formula (bb) heterocyclic radical, n
1Be 1, and Y is NR
10The time, R then
10Be not C
1-2Alkyl or C
1-2Fluoro-alkyl;
Work as R
3For formula (aa) heterocyclic radical and Y are NR
10The time, R then
10Be not C (O)-C
1-2Alkyl, C (O)-C
1Fluoro-alkyl or-C (O)-CH
2O-C
1Alkyl;
Work as R
3During for formula (cc) heterocyclic radical, then Y is O, S, SO
2Or NR
10, R wherein
10Be H;
Precondition is:
Work as R
3Be the optional C that replaces
3-8Cycloalkyl or the optional C that replaces
5-7During cycloalkenyl group, then any-C (O) OR
23,-C (O) NHR
24,-C (O) R
25,-CH
2OH or fluoro substituents are at R
33 of cyclobutyl ring; Or at R
3C
5Cycloalkyl (cyclopentyl) ring or cyclopentenes basic ring 3 or 4; Or at R
3C
6Cycloalkyl (cyclohexyl) ring or tetrahydrobenzene basic ring 4; Or at R
3Suberyl ring or suberene basic ring 3,4,5 or 6; Or at R
33,4,5,6 of ring octyl group ring or 7 (in this annexation, R
3Cycloalkyl ring or cyclenes basic ring 1 be considered to formula (I) in-tie point of NH-, promptly in the connection mode (I)-annular atoms of NH-);
Precondition is:
Work as R
3Be the optional C that replaces
3-8During cycloalkyl, then any OH, alkoxyl group, fluoroalkyl ,-CH
2CH
2OH or-CH
2NHR
22Substituting group is at R
33 of cyclobutyl ring; Or at R
3C
53 or 4 of cycloalkyl (cyclopentyl) ring; Or at R
3C
63,4 or 5 of cycloalkyl (cyclohexyl) ring; Or at R
33,4,5 or 6 of suberyl ring; Or at R
33,4,5,6 or 7 of ring octyl group ring;
Work as R
3During for formula (aa), (bb) or heterocyclic radical (cc), then any OH substituting group is at 6 yuan of R of formula (cc)
35 of heterocyclic radical, wherein n
2Be 1; Or at 7 yuan of R of formula (cc)
35 or 6 of heterocyclic radical, wherein n
2Be 2; Or at 7 yuan of R of formula (bb)
36 of heterocyclic radical, wherein n
1Be 2 (in this annexation, R
31 of heterocyclic be considered to formula (I) in-tie point of NH-, promptly in the connection mode (I)-annular atoms of NH-, then all the other positions of heterocyclic are numbered, make the possible lowest number of being numbered of ring hetero atom).
For example in the compound of formula (I) (or formula (IA) or formula (IB), see below), " alkyl " group or part can be straight or branched at compound.Operable alkyl (C for example
1-8Alkyl, C
1-6Alkyl, C
1-4Alkyl, C
1-3Alkyl or C
1-2Alkyl) comprises C
1-6Alkyl, C
1-4Alkyl, C
1-3Alkyl or C
1-2Alkyl, for example methyl, ethyl, n-propyl, normal-butyl, n-pentyl, n-hexyl or their any branched chain isomer, for example sec.-propyl, the tertiary butyl, sec-butyl, isobutyl-, 3-methyl fourth-2-base, 2-ethyl fourth-1-base etc.
Has corresponding implication derived from terms such as " alkoxyl group " of alkyl, " alkylidene groups ".For example " alkoxyl group " (C for example
1-6Alkoxyl group, C
1-4Alkoxyl group or C
1-2Alkoxyl group) comprises the oxygen radical derivative of methoxyl group, oxyethyl group, propoxy-and abovementioned alkyl." alkyl sulphonyl " (C for example
1-4Alkyl sulphonyl) comprises methyl sulphonyl (methylsulfonyl), ethylsulfonyl and derived from other group of abovementioned alkyl." alkylsulfonyloxy " (C for example
1-4Alkylsulfonyloxy) comprises mesyloxy (sulfonyloxy methyl oxygen base), ethanesulfonyloxy group etc.
" cycloalkyl " (C for example
3-8Cycloalkyl) comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group etc.Appropriate C
3-8Cycloalkyl can be C
3-6Cycloalkyl, C
5-6Cycloalkyl, C
4-7Cycloalkyl or C
6-7Cycloalkyl promptly comprises 3-6 unit, 5-6 unit, 4-7 unit, 6-7 unit carbocyclic ring respectively.
" fluoro-alkyl " comprises the alkyl that contains 1,2,3,4,5 or more a plurality of fluoro substituents (C for example
1-4Fluoro-alkyl, C
1-3Fluoro-alkyl or C
1-2Fluoro-alkyl), for example a methyl fluoride, difluoromethyl, trifluoromethyl, pentafluoroethyl group, 2,2,2-trifluoroethyl (CF
3CH
2-), 2,2-two fluoro ethyl (CHF
2-CH
2-) or 2-fluoro ethyl (CH
2F-CH
2-) etc." fluoroalkyl " comprises C
1-4Fluoroalkyl or C
1-2Fluoroalkyl, for example trifluoromethoxy, five fluorine oxyethyl groups, a fluorine methoxyl group, difluoro-methoxy etc." fluoro-alkyl alkylsulfonyl " (C for example
1-4The fluoro-alkyl alkylsulfonyl) comprises trifyl, five fluorine ethylsulfonyls etc.
Halogen atom (" halo ") in the compound (for example formula (I) compound) is meant fluorine atom, chlorine atom, bromine atoms or iodine atom (" fluoro ", " chloro ", " bromo " or " iodo "), for example fluoro, chloro or bromo.
When pointing out A atom or A part " bonding " or " connection " B atom or B part in the specification sheets, be other implication unless clearly demonstrate in the context, otherwise be meant that A atom/part directly connects B atom/part by one or two covalent linkage usually, do not comprise that A connects B (for example not comprising A-C-B) indirectly via atom in the middle of one or more/part.
Work as R
1Be C
1-3Alkyl or C
1-3During fluoro-alkyl, it can be a straight or branched.Work as R
1Be C
1-3During alkyl, it can be methyl, ethyl, n-propyl or sec.-propyl.Work as R
1Be C
1-3During fluoro-alkyl, R
1Can be for example C
1Fluoro-alkyl, for example a methyl fluoride, difluoromethyl, trifluoromethyl; Or R
1Can be C
2Fluoro-alkyl (for example pentafluoroethyl group), or more preferably C
1Fluoro-alkyl-CH
2-, for example 2,2,2-trifluoroethyl (CF
3CH
2-), 2,2-two fluoro ethyl (CHF
2CH
2-) or 2-fluoro ethyl (CH
2FCH
2-).
R
1Be C
1-3Alkyl (for example methyl, ethyl or n-propyl), C
1-3Fluoro-alkyl or-CH
2CH
2OH.R
1Be suitably for C
1-3Alkyl, C
1-2Fluoro-alkyl or-CH
2CH
2OH.Preferred R
1Be C
2-3Alkyl (for example ethyl or n-propyl), C
2Fluoro-alkyl (C for example
1Fluoro-alkyl-CH
2-, CF for example
3-CH
2-) or-CH
2CH
2OH; Particularly ethyl, n-propyl or-CH
2CH
2OH.More preferably R
1Be C
2Alkyl (ethyl) or C
2Fluoro-alkyl.R
1Ethyl most preferably.
Preferred R
2Be hydrogen atom (H) or methyl, for example hydrogen atom (H).
Preferred R
30-1 substituting group arranged.
In a preferred embodiment, R
3Be the optional C that replaces
3-8Cycloalkyl or the optional formula (aa) that replaces, (bb) or (cc) heterocyclic radical.
In an optional embodiment, work as R
3Be the optional C that replaces
3-8During cycloalkyl, R
3Be not unsubstituted C
5Cycloalkyl promptly is not unsubstituted cyclopentyl.In the case, preferred R
3Be the optional C that replaces
6-8Cycloalkyl or the optional cyclobutyl that replaces.
Work as R
3Be the optional C that replaces
3-8During cycloalkyl, more suitably be the optional C that replaces
6-7Cycloalkyl or the optional cyclobutyl that replaces, the preferred optional C that replaces
6Cycloalkyl (the promptly optional cyclohexyl that replaces).
Preferably, work as R
3Be the optional C that replaces
3-8During cycloalkyl, R
3For choosing wantonly by 1-2 is the C that following substituting group replaces independently
3-8Cycloalkyl (C for example
6-7Cycloalkyl or cyclobutyl): oxo (=O); OH; C
1Alkoxyl group; C
1Fluoroalkyl (for example trifluoromethoxy or difluoro-methoxy); NHR
21, R wherein
21Be hydrogen atom (H) or C
1-2Alkyl (more preferably R
21Be H); C
1-2Alkyl, for example methyl; C
1Fluoro-alkyl, for example-CH
2F or-CHF
2-CH
2OH;-CH
2NHR
22, R wherein
22Be H;-C (O) OR
23, R wherein
23Be H;-C (O) NHR
24, R wherein
24Be H or methyl;-C (O) R
25, R wherein
25Be methyl; Fluorine; Oximido (=N-OH); Or (C
1-4Alkoxyl group) imino-, for example (C
1-2Alkoxyl group) imino-(=N-OR
26, R wherein
26Be C
1-4Alkyl, for example C
1-2Alkyl); Wherein any OH, alkoxyl group, fluoroalkyl or NHR
21Substituting group not with formula (I) in-the NH-group is connected the R of (bonding)
3Replace on the ring carbon atom, and not with heterocyclic radical (aa), (bb) or the R that Y group is connected (cc)
3Replace on the ring carbon atom.
Preferably, work as R
3Be the optional C that replaces
3-8During cycloalkyl, R
3For choosing wantonly by 1-2 is the C that following substituting group replaces independently
3-8Cycloalkyl (C for example
6-7Cycloalkyl or cyclobutyl): oxo (=O); OH; NHR
21, R wherein
21Be hydrogen atom (H); C
1-2Alkyl, for example methyl; C
1Fluoro-alkyl, for example-CH
2F or-CHF
2-C (O) OR
23, R wherein
23Be H;-C (O) NHR
24, R wherein
24Be H or methyl (preferred H);-C (O) R
25, R wherein
25Be methyl; Fluorine; Oximido (=N-OH); Or (C
1-2Alkoxyl group) imino-(=N-OR
26, R wherein
26Be C
1-2Alkyl).
More preferably, work as R
3Be the optional C that replaces
3-8During cycloalkyl, R
3Independently be selected from the C that following substituting group (for example substituting group) replaces for optional by 1-2
3-8Cycloalkyl (C for example
6-7Cycloalkyl or cyclobutyl): oxo (=O); OH; NHR
21, R wherein
21Be hydrogen atom (H); Methyl;-CH
2F;-CHF
2-C (O) OR
23, R wherein
23Be H;-C (O) NHR
24, R wherein
24Be H or methyl (preferred H); Fluorine; Oximido (=N-OH); Or methoxyimino (=N-OR
26, R wherein
26Be methyl).
Again more preferably, work as R
3Be the optional C that replaces
3-8During cycloalkyl, R
3Independently be selected from the C that following substituting group (for example substituting group) replaces for optional by 1-2
3-8Cycloalkyl (C for example
6-7Cycloalkyl or cyclobutyl): oxo (=O); OH; Methyl;-C (O) NHR
24, R wherein
24Be H; Fluorine; Oximido (=N-OH); Or methoxyimino (=N-OR
26, R wherein
26Be methyl).
Also more more preferably, work as R
3Be the optional C that replaces
3-8During cycloalkyl, R
3Independently be selected from the C that following substituting group (for example substituting group) replaces for optional by 1-2
3-8Cycloalkyl (C for example
6-7Cycloalkyl or cyclobutyl): OH;-C (O) NHR
24, R wherein
24Be H; Oxo (=O) or oximido (=N-OH).
In an optional embodiment, R
3C
3-8Cycloalkyl can be unsubstituted.
Work as R
3Be the optional C that replaces
3-8Cycloalkyl or the optional C that replaces
5-7(for example optional C that replaces during cycloalkenyl group
5-8Cycloalkyl or C
5-7Cycloalkyl, for example optional C that replaces
6Cycloalkyl (the optional cyclohexyl that replaces) or the optional cyclohexenyl that replaces), if there be suitable 1-2 optional substituting group, then described substituting group (for example one or two substituting group) can be positioned at R
3Cycloalkyl ring or cyclenes basic ring 3,4 and/or 5 (for example at its 3 or 4).
(in this annexation, R
3Ring (R for example
3Cycloalkyl ring or cyclenes basic ring) 1 be considered to usually in this article with formula (I) in-tie point of NH-, promptly in the connection mode (I)-annular atoms of NH-);
For R
3Preferably, especially at R
3Be the optional C that replaces
3-8Cycloalkyl or the optional C that replaces
5-7During cycloalkenyl group, R
3Not with formula (I) in-replace on the annular atoms that NH-is connected (except optional replaced by alkyl or fluoro-alkyl), and R
3On two annular atomses that connect the atom both sides, do not replace (except choosing wantonly by alkyl, fluoro-alkyl or NHR
21Beyond replacing).For example, for R
3Preferably, working as R especially
3Be the optional C that replaces
3-8Cycloalkyl or the optional C that replaces
5-7During cycloalkenyl group, R
3Not with formula (I) in-replace and R on the annular atoms that NH-is connected
3On two annular atomses that connect the atom both sides, do not replace.
For R
3Preferably, especially at R
3Be the optional C that replaces
3-8Cycloalkyl or the optional C that replaces
5-7During cycloalkenyl group, if R
3When having the optional substituting group of 1-2, then described substituting group (for example one or two substituting group):
(a) at R
33 of cyclobutyl ring, or
(b) at R
3Cyclopentyl ring or cyclopentenes basic ring 3 and/or 4, or
(c) at R
3Cyclohexyl ring or tetrahydrobenzene basic ring 3,4 and/or 5, or
(d) at R
3Suberyl ring or suberene basic ring 3,4,5 and/or 6, or
(e) at R
33,4,5,6 and/or 7 of ring octyl group ring, and/or
(f) for substituting group alkyl or fluoro-alkyl, at R
31,2 and/or maximum numbered positions of cycloalkyl ring or cyclenes basic ring, and/or
(g) for substituting group NHR
21, at R
32 and/or maximum numbered positions of cycloalkyl ring or cyclenes basic ring.
Work as R
3Be the optional C that replaces
3-8During cycloalkyl, then any OH, alkoxyl group, fluoroalkyl ,-CH
2CH
2OH or-CH
2NHR
22Substituting group (particularly any OH substituting group) is preferably at R
3Cycloalkyl (C for example
6-8Cycloalkyl) ring 3,4 or 5 (for example 3 or 5).Optional any OH, alkoxyl group, fluoroalkyl ,-CH
2CH
2OH or-CH
2NHR
22Substituting group (particularly any OH substituting group) can be at R
33 of cyclobutyl ring; Or at R
3C
53 or 4 of cycloalkyl (cyclopentyl) ring; Or at R
3C
6(for example especially any OH substituting group can be at R for 3,4 or 5 of cycloalkyl (cyclohexyl) ring
33 or 5 of cyclohexyl ring); Or at R
33,4,5 or 6 of suberyl ring; Or at R
33,4,5,6 or 7 of ring octyl group ring.Preferably, any OH, alkoxyl group, fluoroalkyl ,-CH
2CH
2OH or-CH
2NHR
22Substituting group (particularly any OH substituting group) is at R
3C
53 or 4 of cycloalkyl (cyclopentyl) ring; Or more preferably at R
3C
63,4 or 5 of cycloalkyl (cyclohexyl) ring are more more preferably at its 3 or 5 a.
Work as R
3Be the optional C that replaces
3-8Cycloalkyl or the optional C that replaces
5-7During cycloalkenyl group, then any-C (O) OR
23,-C (O) NHR
24,-C (O) R
25,-CH
2OH or fluoro substituents are at R
33 of cyclobutyl ring; Or at R
3C
5Cycloalkyl (cyclopentyl) ring or cyclopentenes basic ring 3 or 4; Or at R
3C
6Cycloalkyl (cyclohexyl) ring or tetrahydrobenzene basic ring 4; Or at R
3Suberyl ring or suberene basic ring 3,4,5 or 6; Or at R
33,4,5,6 or 7 of ring octyl group ring.Any-C (O) OR
23,-C (O) NHR
24,-C (O) R
25,-CH
2OH or fluoro substituents (for example any-C (O) NHR
24Or fluoro substituents) preferably at R
3C
6Cycloalkyl (cyclohexyl) ring or tetrahydrobenzene basic ring 4.For any-C (O) NHR
24Substituting group is particularly preferably in R
34 of cyclohexyl ring.
Work as R
3Be the optional C that replaces
3-8During cycloalkyl, any NHR
21Substituting group except 1 (with in the formula (I)-annular atoms that NH-is connected) any position, for example 2,3,4,5,6,7 or 8.Preferably, any NHR
21Substituting group is at R
32,3,4,5 or 6 of cyclohexyl ring are for example at 3 or 5.
Work as R
3Be the optional C that replaces
3-8Cycloalkyl or the optional C that replaces
5-7During cycloalkenyl group, any alkyl or fluoro-alkyl substituting group can be at R
3The ring for example 1,2,3,4,5,6,7 or 8 (for example 1,2,3,5 or 6, for example 1).Preferred any alkyl or fluoro-alkyl substituting group are at R
3Cyclohexyl ring or tetrahydrobenzene basic ring 1,2,3,5 or 6, or more preferably at R
3Cyclohexyl ring or tetrahydrobenzene basic ring 1,3 or 5.
Work as R
3Be the optional C that replaces
3-8During cycloalkyl, any oxo (=O), oximido (=N-OH); Or (C
1-4Alkoxyl group) imino-(=N-OR
26) substituting group is preferably at R
3Cycloalkyl (C for example
6-8Cycloalkyl, for example cyclohexyl) ring 3,4 or 5, for example at 4.Preferred any such substituting group is at R
34 of cyclohexyl ring.
Work as R
3Be the optional C that replaces
3-8Cycloalkyl (C for example
6-7Cycloalkyl) time, R
3Preferred cyclohexyl (promptly unsubstituted); Or suberyl (promptly unsubstituted); Or the cyclohexyl that is replaced by the substituting group below: oxo (=O), OH, NHR
21, C
1-2Alkyl, C
1-2Fluoro-alkyl ,-CH
2OH ,-C (O) OR
23,-C (O) NHR
24,-C (O) R
25, fluorine, oximido (=N-OH) or (C
1-4Alkoxyl group) imino-(=N-OR
26); Or by the cyclohexyl of two fluoro substituents replacements.More preferably R
3Be cyclohexyl (promptly unsubstituted); Or suberyl (promptly unsubstituted); Or the cyclohexyl that is replaced by the substituting group below: oxo (=O), OH, NHR
21, C
1-2Alkyl, C
1-2Fluoro-alkyl ,-C (O) OR
23,-C (O) NHR
24, fluorine, oximido (=N-OH) or (C
1-2Alkoxyl group) imino-(=N-OR
26, R wherein
26Be C
1-2Alkyl); Or by the cyclohexyl of two fluoro substituents replacements.More preferably R again
3Be cyclohexyl (promptly unsubstituted) or the cyclohexyl that replaced by the substituting group below: oxo (=O), oximido (=N-OH) ,-C (O) NH
2, methyl or OH.Described optional substituting group can be at for example R
33 or 4 of cyclohexyl ring.Preferably, any OH substituting group is at R
33 of cyclohexyl ring, and/or any oxo (=O), oximido (=N-OH), (C
1-4Alkoxyl group) imino-(=N-OR
26) or-C (O) NH
2Substituting group is at R
34 of cyclohexyl ring, and/or any alkyl or fluoro-alkyl substituting group are at R
31,3 or 5 of cyclohexyl ring.
Perhaps, work as R
3Be the optional C that replaces
3-8During cycloalkyl, R
3Be preferably cyclobutyl, and optional replaced by the substituting group below: oxo (=O); OH; NHR
21, R wherein
21Be hydrogen atom (H); Methyl;-CH
2F;-CHF
2-C (O) OR
23-C (O) NHR
24, R wherein
24Be H or methyl (preferred H); Fluorine; Oximido (=N-OH); Or methoxyimino (=N-OR
26, R wherein
26Be methyl).In the case, preferred R
3For choosing wantonly by one-C (O) NHR
24(R wherein
24For H or methyl, be preferably H) cyclobutyl that replaces of substituting group.For example, R
3Can be cyclobutyl (promptly unsubstituted) or 3-(aminocarboxyl) cyclobutyl (being 3-(aminocarboxyl) ring fourth-1-yl) (for example being cis or transconfiguration, preferred cis-configuration).
Work as R
3Be the optional C that replaces
6-7During cycloalkyl, R
3Can be for example 4-hydroxyl-cyclohexyl (being 4-hydroxyl hexamethylene-1-yl), 4-methylcyclohexyl, 2-aminocyclohexyl or 3-oxo cyclohexyl, but R
3More preferably cyclohexyl (promptly unsubstituted), suberyl (promptly unsubstituted), 3-hydroxyl-cyclohexyl (being 3-hydroxyl hexamethylene-1-yl) (for example being cis or transconfiguration, preferred cis-configuration), 4-oxo-cyclohexyl (being 4-oxo hexamethylene-1-yl), 4-(oximido) cyclohexyl (being 4-(oximido) hexamethylene-1-yl), 4-(C
1-2Alkoximino) cyclohexyl, 4-(aminocarboxyl) cyclohexyl (being 4-(aminocarboxyl) hexamethylene-1-yl) (for example are cis or transconfiguration, preferred cis-configuration), 1-methylcyclohexyl, 3-methylcyclohexyl, 4,4-(difluoro) cyclohexyl or 3-aminocyclohexyl.Perhaps, R
3Can be preferably 4-ethanoyl cyclohexyl (for example being cis or transconfiguration, preferred cis-configuration).
Work as R
3Be the optional C that replaces
6-7During cycloalkyl, R
3Most preferably cyclohexyl (promptly unsubstituted), 3-hydroxyl-cyclohexyl (being 3-hydroxyl hexamethylene-1-yl) (being preferably cis-configuration), 4-oxo-cyclohexyl (being 4-oxo hexamethylene-1-yl), 4-(oximido) cyclohexyl (being 4-(oximido) hexamethylene-1-yl) or 4-(aminocarboxyl) cyclohexyl (being 4-(aminocarboxyl) hexamethylene-1-yl) (being preferably cis-configuration).
Work as R
3Be the optional C that replaces
5During cycloalkyl (the optional cyclopentyl that replaces), R
3Can be for example cyclopentyl (promptly unsubstituted), or more preferably 3-hydroxyl-cyclopentyl.
Work as R
3Be the optional monounsaturated C that replaces
5-7During cycloalkenyl group, preferred R
3Be the optional monounsaturated C that replaces
5-6Cycloalkenyl group, the more preferably optional monounsaturated C that replaces
6Cycloalkenyl group (the promptly optional monounsaturated cyclohexenyl that the replaces=optional cyclohexenyl that replaces).For example, R
3Cyclohexenyl can be the optional hexamethylene-3-alkene-1-base that replaces.
Work as R
3Be the optional monounsaturated C that replaces
5-7During cycloalkenyl group, in an optional embodiment, R
3Cycloalkenyl group is optional to be the substituting group replacement of fluorine or methyl by 1-2 independently.In this embodiment, if there are two substituting groups, then preferred these two substituting groups all are not methyl.
In another optional embodiment, R
3Cycloalkenyl group (for example cyclohexenyl) is optional by a fluorine or C
1-2Alkyl (preferred fluorine or methyl) replaces; Preferred R
3Cycloalkenyl group (for example cyclohexenyl) is replaced by a fluorine or is not substituted.For example, R
3The optional cycloalkenyl group that replaces can be hexamethylene-3-alkene-1-base (promptly unsubstituted) or 4-fluoro-hexamethylene-3-alkene-1-base.
For R
3Cycloalkenyl group, optional substituting group can be 1,2,3,4,5 or 6 of for example cyclenes basic ring.
Work as R
3During for formula (aa), (bb) or heterocyclic radical (cc), Y is preferably O or NR
10Work as R
3During for formula (aa) or heterocyclic radical (bb), Y is preferably O or N-C (O)-NH
2
Preferred R
10Be hydrogen atom (H), methyl, ethyl, C (O) NH
2, C (O)-C
1-2Alkyl or C (O)-C
1Fluoro-alkyl.Preferred R
10Be not C
1-2Alkyl or C
1-2Fluoro-alkyl.
More preferably R
10Be hydrogen atom (H), C (O) NH
2, C (O)-C
1-2Alkyl (for example C (O) methyl) or C (O)-C
1Fluoro-alkyl (C (O)-CF for example
3).More preferably R again
10Be H, C (O) NH
2Or C (O) methyl; C (O) NH for example
2
Work as R
3During for formula (aa), (bb) or heterocyclic radical (cc), preferred R
3Be formula (aa) or heterocyclic radical (bb), more preferably the heterocyclic radical of formula (bb).
In formula (bb), n
1Be preferably 1.In formula (cc), n
2Be preferably 1.Be R
3Heterocyclic radical is preferably 6 yuan of rings.
At R
3In, preferred formula (aa), (bb) or heterocyclic radical (cc) are not substituted on ring carbon atom.(in this annexation, when Y is NR
10The time, R
10Be not the substituting group of ring carbon atom).
At R
3Formula (aa), (bb) or (cc) in the heterocyclic radical, described 1-2 optional substituting group (being 1-2 optional ring carbon substituting group) preferably is OH independently; Oxo (=O); C
1-2Alkyl (for example methyl) or C
1-2Fluoro-alkyl (C for example
1Fluoro-alkyl, for example-CH
2F or-CHF
2).More preferably, at R
3Formula (aa), (bb) or (cc) in the heterocyclic radical, described 1-2 optional substituting group is C independently
1-2Alkyl (for example methyl) or oxo; The optional substituting group of most preferably described 1-2 be oxo (=O).
At R
3Formula (aa), (bb) or (cc) in the heterocyclic radical, any oxo (=O) substituting group on the carbon atom that connects Y (adjacent with Y), is O or NR at Y only for example preferably
10The time, oxo (=O) substituting group just on the carbon atom that connects Y (adjacent) with Y.
At R
3Formula (aa), (bb) or (cc) in the heterocyclic radical, any oxo (=O) substituting group can be preferably at R
32,3,4,5 or 6 of heterocyclic.For example, any oxo (=O) substituting group can be at formula (aa) R
32,4 of heterocyclic radical or 5 (for example at 2 or 4, perhaps two oxo substituting groups are at 2 and 4); 6 yuan of R in formula (cc)
32,4,5 or 6 (for example 4), wherein n of heterocyclic radical
2Be 1; 7 yuan of R in formula (bb)
32,3,5,6 or 7 (for example 5), wherein n of heterocyclic radical
1Be 2; Or at 7 yuan of R of formula (cc)
32,4,5,6 or 7 (for example 2), wherein n of heterocyclic radical
2Be 2.
(in this annexation, R
31 of heterocyclic be considered to usually in this article with formula (I) in-tie point of NH-, promptly in the connection mode (I)-annular atoms of NH-, then all the other positions of heterocyclic are numbered, make the possible lowest number of being numbered of ring hetero atom).
At R
3Formula (aa), (bb) or (cc) in the heterocyclic radical, any alkyl or fluoro-alkyl substituting group (ring carbon substituting group) can be at for example R
31,2,3,4,5 or 6 of heterocyclic (for example 1) are for example at R
31,3 or 5 of 6 yuan of heterocyclic.
At R
3Formula (aa), (bb) or (cc) in the heterocyclic radical, any OH substituting group is at 6 yuan of R of formula (cc)
35 of heterocyclic radical, wherein n
2Be 1; 7 yuan of R in formula (cc)
35 or 6 of heterocyclic radical, wherein n
2Be 2; Or at 7 yuan of R of formula (bb)
36 of heterocyclic radical, wherein n
1Be 2.
R
3Any other optional ring carbon substituting group of heterocyclic radical can be chosen wantonly and be positioned R
3Heterocycle numbered positions described herein is for R
3Be the optional C that replaces
5-7During cycloalkyl, only need on word, make some variations.
At R
3Formula (aa), (bb) or (cc) in the heterocyclic radical, preferably only allow C
1-2Alkyl, C
1-2Fluoro-alkyl, fluorine or oxo (=O) independently at R
32 of heterocyclic or the highest numbered positions are (for example respectively at R
32 and 6 of hexa-member heterocycle) go up and replace, or do not have substituting group, and/or only allow C in above-mentioned position
1-2Alkyl, C
1-2Fluoro-alkyl or fluorine are at R
31 of heterocyclic is gone up and is replaced, or does not have substituting group at 1.
Work as R
3For the heterocyclic radical and the Y of formula (aa) is NR
10The time, R then
10Be not C (O)-C
1-2Alkyl, C (O)-C
1Fluoro-alkyl or-C (O)-CH
2O-C
1Alkyl.
In a preferred embodiment, work as R
3During for the heterocyclic radical of formula (aa), then Y is O, S, SO
2, NH or NC (O) NH
2(for example O, S, SO
2Or NH).
Work as R
3Be formula (bb) heterocyclic radical, n
1Be 1, and Y is NR
10(NHR for example
3For
), R then
10Be not C
1-2Alkyl or C
1-2Fluoro-alkyl.Work as R
10Be formula (bb) heterocyclic radical, n
1Be 1 or 2 and Y be NR
10The time, then preferred R
10Be not C
1-2Alkyl or C
1-2Fluoro-alkyl.
In one embodiment, work as R
3During for formula (bb) heterocyclic radical, then preferred Y is O, S, SO
2Or NR
10, R wherein
10Be H, C (O) NH
2, C (O)-C
1-2Alkyl (for example C (O) methyl) or C (O)-C
1Fluoro-alkyl (C (O)-CF for example
3), or more preferably R
10Be H, C (O) NH
2Or C (O) Me (C (O) NH for example
2Or C (O) Me), C (O) NH most preferably
2
Work as R
3During for the heterocyclic radical of formula (cc), then Y is O, S, SO
2Or NR
10, R wherein
10Be H.
For formula (bb) and/or formula (cc), optional Y is O or NR
10
Work as R
3Be the optional C that replaces
3-8Cycloalkyl (C for example
6-7Cycloalkyl) or the optional monounsaturated C that replaces
5-7Cycloalkenyl group or the optional formula (aa) that replaces, (bb) or (cc) during heterocyclic radical, then substituting group is with respect to R
3The formula (I) that connects-the NH-group, can be cis or transconfiguration; This comprises the described mixture that is configured as the various configurations of main component.For example, with respect to R
3The formula (I) that connects-the NH-group, C
6-7OH on the cycloalkyl or-C (O) NHR
24Can be for example cis-configuration, and/or C
6-7NHR on the cycloalkyl
21Substituting group can comprise the described mixture that is configured as the various configurations of main component for being cis or transconfiguration for example.
Work as R
3During for two cyclic groups of formula (ee), then preferred Y
1, Y
2And Y
3All be CH
2
Preferred NHR
3Be formula (a), (a1), (b), (c), (c1), (c2), (c3), (c4), (c5), (c6), (c7), (d), (e), (f), (g), (g1), (g2), (g3), (g4), (h), (i), (j), (k), (k1), (k2), (L), (m), (m1), (m2), (m3), (n), (o), (o1), (o2), (o3), (p), (p1), (p2), (p3), (p4), (p5), (p6), (p9), (p10), (p11) or (q):
In with following formula (a) to (q) etc., NHR
3With 4 of formula (I) Pyrazolopyridines-the NH-tie point is the underscore part.
Preferred NHR
3 (c)、 (c1)、 (c2)、 (c3)、 (c4)、 (c5)、 (c6)、 (c7)、 (d)、 (e)、 (f)、 (g1)、 (g4)、 (h)、 (i)、 (j)、 (k)、 (k1)、 (k2)、 (L)、 (m)、 (m1)、 (m2)、 (m3)、 (n)、 (o)、 (o1)、 (o2)、 (o3)、 (p)、 (p2)、 (p5)、 (p6)、 (p9)、 (p10)、 (p11) (q); Or preferred NHR3 (a1)、 (c)、 (c1)、 (c2)、 (c3)、 (c4)、 (c5)、 (c6)、 (c7)、 (d)、 (e)、 (f)、 (g1)、 (g4)、 (h)、 (i)、 (j)、 (k)、 (k1)、 (k2)、 (L)、 (m)、 (m1)、 (m3)、 (n)、 (o)、 (o1)、 (o2)、 (o3)、 (p)、 (p1)、 (p2)、 (p5)、 (p6)、 (p9)、 (p10)、 (p11) (q)。
More preferably NHR
3For formula (c), (c1), (c4), (c5), (h), (i), (j), (k), (k2), (m1), (n), (o), (o2), (o3), (p2), (p5), (p6), (p9), (p11) or (q).NHR
3Can be for for example formula (c), (h), (k), (k2), (n), (o), (o2), (p9) or (p11); Or more more preferably (c), (h), (k2), (n), (o), (o2), (p9) or (p11).R most preferably
3Be tetrahydrochysene-2H-pyrans-4-base or 1-(aminocarboxyl)-4-piperidyl; Be NHR
3Most preferably be the formula (h) shown in above or (k2).
Work as NHR
3During for formula (n), it can be transconfiguration; But the cis-configuration of being preferably promptly is preferably suitable-(3-hydroxyl hexamethylene-1-yl) amino (comprising that cis-configuration is the mixture of the various configurations of main component), for example is any enantiomeric forms or various forms of mixture, for example racemic mixture.
Work as NHR
3During for formula (p9), it can be transconfiguration; But the cis-configuration of being preferably promptly is preferably suitable-[4-(aminocarboxyl) hexamethylene-1-yl] amino (comprising that cis-configuration is the mixture of the various configurations of main component).
In another kind of preferred embodiment, NHR
3For formula (p12) or (p13):
With following formula (p12) with (p13), NHR
3With 4 of formula (I) Pyrazolopyridines-the NH-tie point is the underscore part.
Work as NHR
3In the time of for formula (p12) or (p13), it can be transconfiguration; But the cis-configuration of being preferably, i.e. NHR
3Be preferably suitable-[4-ethanoyl hexamethylene-1-yl] amino or suitable-[3-(aminocarboxyl) encircles fourth-1-yl] amino (including the mixture that cis-configuration is the various configurations of main component) respectively.
Work as R
4Be C
1-2During fluoro-alkyl, R
4Can be C
1Fluoro-alkyl, for example a methyl fluoride, difluoromethyl or trifluoromethyl.
R
4aBe preferably hydrogen atom (H) or methyl (Me), more preferably H.
R
4Can be for example hydrogen atom (H); Methyl, ethyl, C
1Fluoro-alkyl ,-CH
2OH ,-CH (Me) OH ,-CH
2CH
2OH or-CH
2OMe; Or preferred hydrogen atom (H), methyl, ethyl, CF
3,-CH
2OH or-CH
2OMe.More preferably R
4Be methyl, ethyl, CF
3,-CH
2OH or-CH
2OMe; For example methyl, ethyl, CF
3Or-CH
2OH.More preferably R again
4Be methyl or ethyl.R most preferably
4Be ethyl.
Preferred R
4Be not hydrogen atom (H), more preferably R
5Be hydrogen atom (H).
Work as R
5For by a R
11The C that substituting group replaces
1-4Alkyl, perhaps R
5Be the C that on different carbon atoms, is replaced by 2 OH substituting groups
2-4During alkyl (for example ethyl or n-propyl), preferred R
5For by a R
11The C that substituting group replaces
1-4Alkyl.
Work as R
5For by a R
11The C that substituting group replaces
1-4Alkyl, preferred R
5For by a R
11The C that substituting group replaces
1-3Alkyl (C for example
1-2Alkyl).Preferably, R
5For-(CH
2)
n 5-R
11, n wherein
5Be 1,2,3 or 4, perhaps R
5For-CH (Me)-R
11Preferred n
5Be 1,2 or 3, more preferably 1 or 2, more more preferably 1.
Preferred R
11Be hydroxyl (OH); C
1-4Alkoxyl group or C
1-2Alkoxyl group (for example tert.-butoxy, oxyethyl group, or preferred methoxyl group); C
1Fluoroalkyl;-NR
12R
13-NR
15-C (O) R
16Or-NR
15-S (O)
2R
16More preferably R
11Be hydroxyl (OH), C
1-4Alkoxyl group (C for example
1-2Alkoxyl group) or-NR
12R
13More preferably OH, oxyethyl group, methoxyl group, NH again
2, NHMe, NHEt, NMe
2, tetramethyleneimine-1-base or piperidines-1-base; Preferred OH, methoxyl group, NH
2, NHMe or NMe
2
Work as R
5Be C
1-8During alkyl, preferred R
5Be C
1-6Alkyl, C
1-5Alkyl, C
1-4Alkyl or C
1-3Alkyl is worked as R
5Be C
1-3During fluoro-alkyl, preferred R
5Be C
1-2Fluoro-alkyl or C
1Fluoro-alkyl, for example a methyl fluoride, difluoromethyl or trifluoromethyl.Work as R
5For choosing wantonly by C
1-2The C that alkyl replaces
3-8During cycloalkyl, optional described C
3-8Cycloalkyl is not substituted on the connectivity ring carbon atom.Work as R
5Be the optional C that replaces
3-8During cycloalkyl, preferred R
5Be C
3-8Cycloalkyl (promptly unsubstituted) and/or the optional C that replaces
3-6Cycloalkyl, for example optional cyclopropyl that replaces or the optional cyclohexyl that replaces.
Work as R
5For optional replace-(CH
2)
n 4-C
3-8During cycloalkyl, n then
4Be preferably 1, and/or preferred R
5For optional replace-(CH
2)
n 4-C
3-6Cycloalkyl, for example optional replace-(CH
2)
n 4-cyclopropyl or optional replacement-(CH
2)
n 4-C
6Cycloalkyl.Work as R
5For optional replace-(CH
2)
n 4-C
3-8During cycloalkyl, preferred R
5Be unsubstituted.For example, R
5Can for (cyclohexyl) methyl-(promptly-CH
2-cyclohexyl) or-CH
2-cyclopropyl.
Work as R
19Be C
1-2During alkyl, optional R
19Can be methyl.
Work as R
5For-(CH
2)
n 11-C (O) R
16-(CH
2)
n 11-C (O) NR
12R
13-CHR
19-C (O) NR
12R
13-(CH
2)
n 11-C (O) OR
16-(CH
2)
n 11-C (O) OH;-CHR
19-C (O) OR
16-CHR
19-C (O) OH;-(CH
2)
n 11-S (O)
2-NR
12R
13-(CH
2)
n 11-S (O)
2R
16Or-(CH
2)
n 11-During CN; R then
5Be preferably-(CH
2)
n 11-C (O) NR
12R
13-(CH
2)
n 11-C (O) OR
16-(CH
2)
n 11-C (O) OH; Or-(CH
2)
n 11-CN; Or R
5Can be more preferably-(CH
2)
n 11-C (O) NR
12R
13-(CH
2)
n 11-C (O) OR
16Or-(CH
2)
n 11-CN; Or more more preferably-(CH
2)
n 11-C (O) NR
12R
13Or-(CH
2)
n 11-C (O) OR
16
Preferred n
11Be 0,1 or 2.In an optional embodiment, n
11Being 0 or 1, for example is 0.In a preferred embodiment, n
11Be 2.
Work as R
5For-(CH
2)
n 13During-Het, n
13Can be for example 0 or 1.
Preferred Het is saturated or undersaturated 5 yuan or 6 yuan of heterocycles, and/or preferred Het is 4 yuan, 5 yuan, 6 yuan or 7 yuan of saturated heterocyclics.Preferred heterocycle Het comprises a ring hetero atom that is selected from O, S and N.Carboatomic ring atom is unsubstituted among the preferred Het.Het can be for for example:
Work as R
5For phenyl (Ph) ,-CH
2-Ph ,-CHMe-Ph ,-CHEt-Ph, CMe
2Ph or-CH
2CH
2During-Ph (wherein phenyl ring Ph is optional is substituted), the optional substituting group by this paper definition of preferred Ph replaces.Preferred R
5For phenyl (Ph) or-CH
2-Ph, wherein the optional substituting group by 1-2 this paper definition of phenyl ring Ph replaces.
Work as R
5For phenyl (Ph) ,-CH
2-Ph ,-CHMe-Ph ,-CHEt-Ph, CMe
2Ph or-CH
2CH
2-Ph is when (wherein phenyl ring Ph is optional is replaced by 1-2 substituting group), and preferred phenyl ring Ph is optional to be that following substituting group replaces: fluorine by 1-2 (for example 1) independently; Chlorine; C
1-2Alkyl (for example methyl); C
1Fluoro-alkyl (for example trifluoromethyl); C
1-2Alkoxyl group (for example methoxyl group); Or C
1Fluoroalkyl (for example trifluoromethoxy or difluoro-methoxy).Ph can be unsubstituted.
Work as R
4And R
5Formation-(CH combines
2)
p 1-or-(CH
2)
p 3-X
5-(CH
2)
p 4-(X wherein
5Be O or NR
17a) time; Preferred R
4And R
5Formation-(CH combines
2)
p 1-.In one embodiment of the invention, R
4And R
5Formation-(CH can not combine
2)
p 1-or-(CH
2)
p 3-X
5-(CH
2)
p 4-.
Work as R
4And R
5Formation-(CH combines
2)
p 1-time, then p
1Can be for example 2,4,5 or 6.p
1Be preferably 2,4 or 5, more preferably 2 or 4.
Work as R
4And R
5Formation-(CH combines
2)
p 3-X
5-(CH
2)
p 4-(X wherein
5Be O or NR
17a) time; Then preferred: p
3Be 2, and/or p
4Be 2, and/or p
3And p
4One of be 1, and p
3And p
4In another is 2, and/or p
3And p
4Be 1.Preferred X
5Be O.-(CH
2)
p 3-X
5-(CH
2)
p 4-can for for example-(CH
2)
2-O-(CH
2)
2-.
In one embodiment of the invention, R
4And R
5Formation-(CH can not combine
2)
p 1-or-(CH
2)
p 3-X
5-(CH
2)
p 4-.
Preferred Ar has formula (x) structure.
Preferably in formula (x), among A, B, D, E and the F more than two (more preferably more than three) be C-H (carbon-hydrogen), C-F (carbon-fluorine) or nitrogen (N) independently.
Preferably in formula (x), among A, B, D, E and the F is C-H (carbon-hydrogen), C-F (carbon-fluorine), nitrogen (N) or nitrogen-oxide compound (N independently more than three
+-O
-).
Preferably in formula (x), among A, B, D, E and the F more than two (for example more than three) be C-H (carbon-hydrogen), C-F (carbon-fluorine) or nitrogen (N) independently; Among A, B, D, E and the F remaining more than one (for example more than two) be C-H (carbon-hydrogen), C-F (carbon-fluorine), C-Cl (carbon-chlorine), C-Me, C-OMe or nitrogen (N) independently.More preferably in formula (x), among A, B, D, E and the F more than two (for example more than three) be C-H (carbon-hydrogen); Among A, B, D, E and the F remaining more than one (for example more than two) be C-H (carbon-hydrogen), C-F (carbon-fluorine), C-Cl (carbon-chlorine), C-Me, C-OMe or nitrogen (N) independently.
Preferably in formula (x), among A, B, D, E and the F more than two (for example more than three, for example four or more) be C-H.
Preferably in formula (x), be no more than one (more preferably 0) among A, B, D, E and the F and be nitrogen or nitrogen-oxide compound (N independently
+-O
-).
Preferably in formula (x), A, B, D, E and F are not nitrogen-oxide compound (N
+-O
-).
Preferred Ar has formula (x) structure, and formula (x) is following formula (x1), (x2), (x3), (x4), (x5), (x6), (x7), (x8), (x9), (x10), (x11), (x12), (x12a), (x13), (x14), (x15) or (x16):
In a preferred embodiment, Ar has formula (x) structure, and formula (x) is formula (x1), (x2), (x3), (x4), (x5), (x6), (x7), (x8), (x9), (x10), (x11), (x12), (x13), (x14), (x15) or (x16).
More preferably Ar has formula (x) structure, and formula (x) is formula (x1), (x2), (x3), (x8), (x13) or (x14).More preferably Ar has formula (x) structure again, and formula (x) is formula (x1), (x8), (x13) or (x14).Most preferably Ar has formula (x) structure, and formula (x) is formula (x1).
In formula (x), preferred R
6A, R
6B, R
6D, R
6EAnd/or R
6FBe hydrogen atom (H), fluorine atom, chlorine atom, bromine atoms, iodine atom, methyl, ethyl, n-propyl, sec.-propyl, C independently of one another
4Alkyl, trifluoromethyl ,-CH
2OH, methoxyl group, oxyethyl group, positive propoxy, isopropoxy, C1
FluorineFor alkoxyl group (for example trifluoromethoxy or difluoro-methoxy), cyclohexyloxy; Cyclopentyloxy; Nitro (NO
2), OH, C
1-3Alkyl S (O)
2-(MeS (O) for example
2-), C
1-3Alkyl S (O)
2-NH-(Me-S (O) for example
2-NH-), Me
2N-S (O)
2-, H
2N-S (O)
2-,-CONH
2,-CONHMe ,-C (O) OH, cyano group (CN), NMe
2Or C
1-2Alkyl-S (O)
2-CH
2-(Me-S (O) for example
2-CH
2-).
More preferably R
6A, R
6B, R
6D, R
6EAnd/or R
6FBe independently of one another hydrogen atom (H), fluorine atom, chlorine atom, bromine atoms, iodine atom, methyl, ethyl, n-propyl, sec.-propyl, isobutyl-, trifluoromethyl ,-CH
2OH, methoxyl group, oxyethyl group, positive propoxy, isopropoxy, C
1Fluoroalkyl (for example trifluoromethoxy or difluoro-methoxy), nitro (NO
2), OH, C
1-3Alkyl S (O)
2-(MeS (O) for example
2-), C
1-2Alkyl S (O)
2-NH-(Me-S (O) for example
2-NH-) ,-CONH
2, cyano group (CN) or C
1-2Alkyl S (O)
2-CH
2-(Me-S (O) for example
2-CH
2).
More preferably R again
6A, R
6B, R
6D, R
6EAnd/or R
6FBe independently of one another hydrogen atom (H), fluorine atom, chlorine atom, bromine atoms, methyl, ethyl, n-propyl, sec.-propyl, trifluoromethyl ,-CH
2OH, methoxyl group, oxyethyl group, positive propoxy, difluoro-methoxy, OH or MeS (O)
2-.
Be selected from R when two
6A, R
6B, R
6D, R
6EAnd R
6FAdjacent group when combining, then preferably constitute :-CH=CH-CH=CH-;-(CH
2)
n 14a-, n wherein
14aBe 3,4 or 5 (for example 3 or 4);-O-(CMe
2)-O-;-O-(CH
2)
n 14b-O-, wherein n
14bBe 1 or 2;-CH=CH-NR
15b-;-N=CH-NR
15b-;-N=N-NR
15b, R wherein
15bBe H or C
1-2Alkyl (preferred R
15bBe H).In this embodiment, more preferably two be selected from R
6A, R
6B, R
6D, R
6EAnd R
6FAdjacent group the formation :-CH=CH-CH=CH that combines
2-or-(CH
2)
n 14a-, n wherein
14aBe 3,4 or 5 (for example 3 or 4).
In formula (x), for example in formula (x1), preferred 1,2 or 3 R
6B, R
6DAnd R
6EIn 1,2 or 3 be not hydrogen atom (H).
In formula (x), for example in formula (x1), preferred R
6AAnd R
6FOne of be or both are independently for hydrogen atom (H), fluorine atom (F) or methyl.For example, R
6AAnd R
6FOne of for or both be hydrogen atom (H).
In formula (x), for example in formula (x1), preferred described ring or member ring systems are unsubstituted, mono-substituted, dibasic or trisubstituted; Or preferred described ring or member ring systems are unsubstituted, mono-substituted or dibasic; Be more preferably mono-substituted or dibasic.In formula (x), for example in formula (x1), for mono-substituted described ring or member ring systems, this is selected from R
6A, R
6B, R
6D, R
6EAnd R
6FSubstituting group be preferably placed at respect to-(CR
4R
5(promptly for 4 bit substituents, D is CR to 3 or 4 of)-side chain
6D, R wherein
6DBe not H), perhaps be 2-methyl, 2-ethyl, 2-fluorine or 2-chlorine substituent.In formula (x), preferred 3 for dibasic described ring or member ring systems for example in formula (x1), 4-two replaces, 2, and 4-two replaces, 2, and 3-two replaces or 3, and 5-two replaces.In formula (x), also preferred 2,5-two replaces.
In a preferred embodiment, Ar has formula (x1) structure, and be phenyl, monoalkyl-phenyl-, single (fluoro-alkyl)-phenyl-, single halo-phenyl-, monoalkoxy-phenyl-, single (fluoroalkyl)-phenyl-, single (N, N-dimethylamino)-phenyl-, single (methyl-SO
2-NH-)-phenyl-, single (methyl-SO
2-)-phenyl-, dialkyl group-phenyl-, monoalkyl-single halo-phenyl-, single (fluoro-alkyl)-single halo-phenyl-, dihalo-phenyl-, dihalo-monoalkyl-phenyl-, dihalo-list (hydroxymethyl)-phenyl-(for example 2,3-two chloro-6-(hydroxymethyl)-phenyl-) or dialkoxy-phenyl-(for example 3,4-dimethoxy-phenyl-).The preferred further substituting group of definition of described substituting group is as defined substituting group in this paper preferred embodiment.
In a preferred embodiment, Ar is formula (x1), and is: monoalkyl-phenyl-, single (fluoro-alkyl)-phenyl-, single halo-phenyl-, monoalkoxy-phenyl-, single (fluoroalkyl)-phenyl-, dialkyl group-phenyl-, monoalkyl-single halo-phenyl-, dihalo-phenyl-or dihalo-monoalkyl-phenyl-.
In this embodiment, more preferably Ar is:
-single C
1-4Alkyl-phenyl-or single C
1-3Alkyl-phenyl-, 4-C for example
1-4Alkyl-phenyl-(4-C for example
1-3Alkyl-phenyl-) or 2-C
1-2Alkyl-phenyl-;
-single C
1Fluoro-alkyl-phenyl-, 4-C for example
1Fluoro-alkyl-phenyl-;
-single C
1-3Phenalkyloxy--, 4-C for example
1-3Phenalkyloxy--or 3-C
1-3Phenalkyloxy--;
-single (C
1Fluoroalkyl)-and phenyl-, 4-C for example
1Fluoroalkyl-phenyl-;
-two C
1-3Alkyl-phenyl-, two C
1-2Alkyl-phenyl-or dimethyl-phenyl-, for example 3,4-dimethyl-phenyl-, 2,4-dimethyl-phenyl-, 3,5-dimethyl-phenyl-, 2,3-dimethyl-phenyl-or 2,5-dimethyl-phenyl-; For example 3,4-dimethyl-phenyl-, 2,4-dimethyl-phenyl-, 2,3-dimethyl-phenyl-or 3,5-dimethyl-phenyl-;
-single C
1-3Alkyl-single halo-phenyl-, for example single C
1-2Alkyl-single halo-phenyl-and/or single C
1-3Alkyl-monochloro-phenyl-or single C
1-3Alkyl-single fluoro-phenyl-, for example 4-methyl-3-chloro-phenyl-, 3-methyl-4-chloro-phenyl-or 2-methyl-4-chloro-phenyl-;
-dihalo-phenyl-, for example 2-chloro-4-fluorophenyl-, 2,4-two fluoro-phenyl-, 4-bromo-2-fluorophenyl-or preferred 4-chloro-2-fluorophenyl-; For example two chloro-phenyl-, for example 3,4-two chloro-phenyl-, 2,4-two chloro-phenyl-, 2,6-two chloro-phenyl-or preferred 2,3-two chloro-phenyl-; Or
-dihalo-single C
1-2Alkyl-phenyl-, for example 2,4-two chloro-6-methyl-phenyl-.
In another kind of preferred embodiment, Ar has formula (x1) structure, and is three C
1-2Alkyl-phenyl-, trimethylphenyl-(for example 2,4,6-trimethylphenyl-) for example.
In another embodiment, Ar has formula (z) structure.
Preferably in formula (z), among J, L, M and the Q more than three (for example whole) be C-H, C-F, C-C independently
1-2The tie point of alkyl (for example C-Me), C-[and formula (I)] or nitrogen (N).
Preferably in formula (z), be no more than two (for example being no more than one) among J, L, M and the Q and be nitrogen (N).
Preferred Q is the tie point of C-[and formula (I)].
Preferred R
9Be hydrogen atom (H) or methyl.
Preferred R
6J, R
6L, R
6MAnd/or R
6QBe hydrogen atom (H) independently; Fluorine; Chlorine; C
1-2Alkyl (for example methyl); C
1Fluoro-alkyl (CF for example
3); C
1-2Alkoxyl group (methoxyl group); C
1Fluoroalkyl (CF for example
2HO-); OH (comprising its any tautomer); Or the optional phenyl that is replaced by the substituting group below: fluorine, methyl, C
1Fluoro-alkyl, methoxyl group or C
1Fluoroalkyl.More preferably R
6J, R
6L, R
6MAnd/or R
6QIndependently for H, OH (comprising its any keto tautomer), or more preferably C again
1-2Alkyl (for example methyl) or C
1Fluoro-alkyl.
When Ar had formula (z) structure, then formula (z) was preferably one of following group:
Preferred R
7aBe H or C
1-2Alkyl, more preferably H or methyl.Preferred R
8aBe H.
Preferred R
7And/or R
8Be hydrogen atom (H) independently; C
1-2Alkyl, for example methyl; C
3-6Cycloalkyl; Or phenyl, optional is that following substituting group replaces: fluorine, chlorine, C by 1-2 (for example 1) independently
1-2Alkyl, C
1Fluoro-alkyl, C
1-2Alkoxyl group or C
1Fluoroalkyl; Perhaps R
7And R
8Formation-(CH together
2)
n 6-or-(CH
2)
n 8-X
7-(CH
2)
n 9-, X wherein
7Be NR
14Or preferred O.
Work as R
7During for cycloalkyl or the optional phenyl that replaces, preferred R
8Be not cycloalkyl and the optional phenyl that replaces.In the case, R
8Can be for example H.
More preferably R
7And/or R
8Be hydrogen atom (H) or C independently
1-2Alkyl.Preferred R
8Be hydrogen atom (H).
Preferred n
6Be 4 or 5.Preferred n
7Be 3 or 4.Preferred n
8, n
9And/or n
10Be 2 independently.
Preferred R
12And/or R
13Be H independently; C
1-2Alkyl, for example methyl; C
3-6Cycloalkyl; Or phenyl, optional is that following substituting group replaces: fluorine, chlorine, C by 1-2 (for example 1) independently
1-2Alkyl, C
1Fluoro-alkyl, C
1-2Alkoxyl group or C
1Fluoroalkyl; Perhaps R
12And R
13Formation-(CH together
2)
n 6a-or-(CH
2)
n 8a-X
12-(CH
2)
n 9a-, wherein X is NR
14aOr preferred O.
Work as R
12During for cycloalkyl or the optional phenyl that replaces, preferred R
13Be not cycloalkyl and the optional phenyl that replaces.In the case, R
13Can be for example H.
More preferably R
12And/or R
13Be hydrogen atom (H) or C independently
1-2Alkyl.Preferred R
13Be hydrogen atom (H).
Preferred n
6aBe 4 or 5.Preferred n
7aBe 3 or 4.Preferred n
8a, n
9aAnd/or n
10aBe 2 independently.
In one embodiment of the invention, NR
7R
8And/or NR
12R
13Can be independently for for example
Or
Or
Or
Or
(be R
12And R
13Formation-(CH together
2)
2-N-(R
14)-(CH
2)
2-, or R
7And R
8Formation-(CH together
2)
2-N-(R
14a)-(CH
2)
2-), or
(be R
12With R
13Perhaps R
7With R
8Formation-(CH together
2)
2-O-(CH
2)
2-), or NMe
2
Preferred R
14, R
14a, R
17And/or R
17aBe hydrogen atom (H) independently; C
1-2Alkyl; C
1Fluoro-alkyl (CF for example
3);-C (O) Me;-C (O) NH
2Or-S (O)
2Me.More preferably R
14, p
14a, R
17And/or R
17aBe H, C independently
1-2Alkyl or-C (O) Me; Or for example H or C
1-2Alkyl.
Preferred R
15Be hydrogen atom (H) or C
1-4Alkyl (for example
tBu or C
1-2Alkyl, for example methyl); More preferably R
15Be hydrogen atom (H).
As each R
15aBe hydrogen atom (H) or C independently
1-4During alkyl, R
15aCan for H for example,
tBu or C
1-2Alkyl, for example methyl.Preferred each R
15aBe H or C independently
1-2Alkyl, more preferably H.
Preferred R
15bBe H.
Preferred R
16Be C
1-4Alkyl (C for example
1-2Alkyl) or C
3-6Cycloalkyl (C for example
5-6Cycloalkyl); More preferably R
16Be C
1-4Alkyl (C for example
1-2Alkyl).
Preferred R
16aFor:
C
1-4Alkyl (C for example
1-2Alkyl);
C
3-6Cycloalkyl (C for example
5-6Cycloalkyl), optionally replaced by the substituting group below: oxo (=O), OH or methyl substituents (for example choose wantonly at C
5-63 or 4 replacements of cycloalkyl ring; And/or preferred unsubstituted C
3-6Cycloalkyl);
C
3-6Cycloalkyl-CH
2-(C for example
5-6Cycloalkyl-CH
2-);
Pyridyl (for example pyridine-2-yl) is chosen wantonly and is being replaced by the group below on the ring carbon atom: halogen atom, C
1-2Alkyl, C
1Fluoro-alkyl, C
1-2Alkoxyl group or C
1Fluoroalkyl;
Ar
5c;
Phenyl, optional is that following substituting group replaces: halogen atom, C by 1-2 independently
1-2Alkyl, C
1Fluoro-alkyl, C
1-2Alkoxyl group or C
1Fluoroalkyl;
Benzyl is chosen wantonly on its ring and is replaced for following substituting group independently by 1-2: halogen atom, C
1-2Alkyl, C
1Fluoro-alkyl, C
1-2Alkoxyl group or C
1Fluoroalkyl; Or
Connect on ring carbon atom, and contain 1-2 5 yuan or 6 yuan of saturated heterocyclics that independently are selected from the ring hetero atom of O, S and N, wherein the ring nitrogen of any existence is NR
27, R wherein
27Be H, C
1-2Alkyl or-C (O) Me (preferred H or C
1-2Alkyl), and described heterocyclic carbon atom be not substituted.
Preferred R
16aBe C
1-4Alkyl (C for example
1-2Alkyl); Unsubstituted C
3-6Cycloalkyl (for example unsubstituted C
5-6Cycloalkyl); Phenyl, optional is that following substituting group replaces: halogen atom, C by 1-2 independently
1-2Alkyl, C
1Fluoro-alkyl, C
1-2Alkoxyl group or C
1Fluoroalkyl; Or benzyl, choose wantonly on its ring and replaced independently: halogen atom, C for following substituting group by 1-2
1-2Alkyl, C
1Fluoro-alkyl, C
1-2Alkoxyl group or C
1Fluoroalkyl.Preferred R
16aBe C
1-4Alkyl (C for example
1-2Alkyl).
Preferred each R
30Be hydrogen atom (H) or C independently
1-4Alkyl, for example H, the tertiary butyl or C
1-2Alkyl.
Preferred formula (I) compound or its salt is connecting R
4And R
5The carbon atom place be racemic, perhaps (more preferably) formula (I) compound or its salt is following formula (IA) compound or its salt:
Formula (IA) is meant that this compound or its salt more than 50% is connecting R
4And R
5The three-dimensional chemical configuration of carbon atom place shown in having.
In formula (IA), preferred more than 70% based on volumetric molar concentration, more preferably more than 75%, more more preferably more than 85%, also more more preferably more than 90% the compound or its salt of (for example more than 95%, for example more than 98%) connecting R
4And R
5The three-dimensional chemical configuration of carbon atom place shown in having.
Preferably in formula (IA), be with R
4And R
5The stereochemical structure at carbon atom place should to make it have enantiomer excessive (e.e.) be (not consider the stereochemical structure of any other carbon atom) more than 50%.More preferably, band R
4And R
5The enantiomer excessive (e.e.) at carbon atom place be more than 70% or more than 80%, more preferably more than 90%, also more preferably (do not consider the stereochemical structure of any other carbon atom) more than 95% more again.
The percentage ratio that " enantiomer is excessive " (e.e.) is defined as the main isomer of existence deducts the percentage ratio of the less important isomer of existence.For example, if having 95% main isomer and 5% less important isomer, then e.e. should be 90%.
In formula (IA), preferred R
4It is not hydrogen atom (H).In formula (IA), more preferably R
4Be methyl, ethyl, C
1Fluoro-alkyl (CF for example
3) ,-CH
2OH or-CH
2OMe; More preferably R again
4Be methyl, ethyl, CF
3Or-CH
2OH; More preferably R more also
4Be methyl or ethyl; R most preferably
4Be ethyl.
In formula (IA), preferred especially R
5Be hydrogen atom (H) and R
4It is not hydrogen atom (H).In formula (IA), more preferably R
5Be hydrogen atom (H); And R
4Be methyl, ethyl, C
1Fluoro-alkyl (CF for example
3) ,-CH
2OH or-CH
2OMe (for example methyl, ethyl, CF
3Or-CH
2OH).In formula (IA), R most preferably
5Be hydrogen atom (H); And R
4Be methyl or ethyl (preferred ethyl).
In formula (IA), work as R
4When not being hydrogen atom (H), and the optional R that works as
5During for hydrogen atom (H), preferred especially Ar (Ar that for example has formula (x1) structure) is a monocycle.Promptly in formula (IA), work as R
4When not being hydrogen atom (H), preferred especially two are selected from R
6A, R
6B, R
6D, R
6EAnd R
6FAdjacent group can not combine and constitute second loop section.
Have and/or believe (IA) structure that has formula (R wherein
5Be H, R
4For methyl, ethyl ,-CH
2OH or-CH
2OMe, Ar are monocycle) embodiment disclosed herein 1,8,24,28,63,127,129,174 and 178 usually have stronger PDE4B and suppress active than similar embodiment 6,7,29,26,64,126,124,170 and 177, and the latter is at CR
4R
5Have on (benzyl) carbon atom and/or believe and have the stereochemical structure opposite (comprising most of opposite stereochemical structures) with the former.
In an especially preferred embodiment, HN-CR
4R
5The HN-CR of-Ar for defining among any one embodiment among embodiment 1-314 and/or the embodiment 315-382
4R
5-Ar.
Preferred especially following formula (I) compound or its salt:
(1) 1-ethyl-N-[(1R)-1-phenyl propyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(2) 1-ethyl-N-(1-methyl isophthalic acid-phenylethyl)-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(3) 1-ethyl-N-{1-[4-(methyl sulphonyl) phenyl] ethyl }-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(4) N-(diphenyl methyl)-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(5) 1-ethyl-N-[1-(3-pyridyl) ethyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(6) 1-ethyl-N-[(1S)-1-phenyl propyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(7) 1-ethyl-N-[(1S)-1-phenylethyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(8) 1-ethyl-N-[(1R)-1-phenylethyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(9) 1-ethyl-N-[1-methyl isophthalic acid-(4-pyridyl) ethyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(10) 1-ethyl-N-[(1R)-1-phenylethyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(11) N-[1-(4-chloro-phenyl-) propyl group]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(12) 1-ethyl-N-{1-[4-(oxyethyl group) phenyl] ethyl }-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(13) 1-ethyl-N-(3-hydroxyl-1-phenyl propyl)-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(14) 1-ethyl-N-[1-(3-hydroxy phenyl) ethyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(15) N-[2-(dimethylamino)-1-phenylethyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(16) 1-ethyl-N-[1-phenyl-2-(1-pyrrolidyl) ethyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(17) 1-ethyl-N-[1-(hydroxymethyl)-1-phenyl propyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(18) 1-ethyl-N-{1-[4-(propoxy-) phenyl] ethyl }-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(19) 3-({ [1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-yl] carbonyl } amino)-3-phenylpropionic acid methyl esters
(20) 1-ethyl-N-[1-(4-fluorophenyl) ethyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(21) N-[1-(4-chloro-phenyl-) ethyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(22) ({ [1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-yl] carbonyl } amino) (phenyl) ethyl acetate
(23) 1-ethyl-N-{ (1R)-1-[3-(methoxyl group) phenyl] ethyl }-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(24) 1-ethyl-N-[(1S)-2-(methoxyl group)-1-phenylethyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(25) N-[(1R)-2-amino-2-oxo-1-phenylethyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(26) 1-ethyl-N-[(1R)-2-hydroxyl-1-phenylethyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(27) 1-ethyl-N-[(1R)-1-(4-nitrophenyl) ethyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(28) 1-ethyl-N-[(1S)-2-hydroxyl-1-phenylethyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(29) 1-ethyl-N-[(1R)-2-(methoxyl group)-1-phenylethyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(30) 1-ethyl-N-(2-hydroxyl-1,1-diphenyl-ethyl)-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(31) N-[1-(3-cyano-phenyl) ethyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(32) N-[cyano group (phenyl) methyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(33) N-{ cyclopropyl [4-(methoxyl group) phenyl] methyl }-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(34) 1-ethyl-N-[1-(1-naphthyl) ethyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(35) N-(1, the 2-diphenyl-ethyl)-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(36) 1-ethyl-N-{1-[4-(methoxyl group) phenyl] butyl }-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(37) 1-ethyl-N-[(1R)-1-(1-naphthyl) ethyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(38) 1-ethyl-N-[(1S)-1-(1-naphthyl) ethyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(39) N-[1-(aminocarboxyl)-1-phenyl propyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(40) 1-ethyl-N-(1-benzyl ring amyl group)-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(41) 1-ethyl-N-(4-phenyl tetrahydrochysene-2H-pyrans-4-yl)-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(42) 1-ethyl-N-(1-phenycyclopropyl)-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(43) N-{1-[4-(cyclohexyloxy)-3-aminomethyl phenyl] ethyl }-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(44) N-{1-[3-(cyclohexyloxy)-4-(methoxyl group) phenyl] ethyl }-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(45) N-[1-(2, the 3-dichlorophenyl) ethyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(46) N-{1-[4-(cyclohexyloxy)-3-hydroxy phenyl] ethyl }-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(47) N-{1-[4-(cyclopentyloxy) phenyl] ethyl }-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(48) 1-ethyl-N-[1-(4-aminomethyl phenyl) ethyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(49) N-{1-[4-(1, the 1-dimethyl ethyl) phenyl] suberyl }-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(50) N-[1-(4-bromophenyl) ethyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(51) 1-ethyl-N-[(1S)-1-(4-iodophenyl) ethyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(52) N-{1-[4-(amino-sulfonyl) phenyl] ethyl }-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(53) 1-ethyl-N-(1-methyl isophthalic acid-phenyl propyl)-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(54) N-[1-(1,3-benzodioxole-5-yl) cyclohexyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(55) 1-ethyl-N-{1-[4-(methoxyl group) phenyl] cyclohexyl }-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(56) 1-ethyl-N-[1-(4-fluorophenyl) cyclohexyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(57) N-[1-(3-chloro-phenyl-) cyclopentyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(58) N-[1-(2-chloro-phenyl-) cyclopentyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(59) N-{1-[4-(1, the 1-dimethyl ethyl) phenyl] cyclohexyl }-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(60) 1-ethyl-N-{1-[4-(1-methylethyl) phenyl] ethyl }-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(61) N-[1-(3, the 5-3,5-dimethylphenyl) ethyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(62) 1-ethyl-N-[(1S, 2R)-2-hydroxyl-1-phenyl propyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(63) 1-ethyl-N-{ (1R)-1-[4-(methoxyl group) phenyl] ethyl }-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(64) 1-ethyl-N-{ (1S)-1-[4-(methoxyl group) phenyl] ethyl }-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(65) 1-ethyl-N-(1-phenyl hexyl)-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(66) 1-ethyl-N-(1-phenylpentyl)-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(67) 1-ethyl-N-(2-methyl isophthalic acid-phenyl propyl)-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(68) 1-ethyl-N-(1-phenyl butyl)-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(69) 1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-N-(2,2,2-three fluoro-1-phenylethyls)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(70) N-[cyclopropyl (phenyl) methyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(71) 1-ethyl-N-[1-(4-fluorophenyl) propyl group]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(72) N-[1-(2, the 3-dichlorophenyl) propyl group]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(73) 1-ethyl-N-[(1R)-1-(4-aminomethyl phenyl) ethyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(74) 1-ethyl-N-(1-phenylethyl)-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(75) N-[(1R)-1-(4-bromophenyl) ethyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(76) N-[1-(4-chloro-phenyl-)-2-hydroxyethyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(77) N-[1-(3, the 4-dichlorophenyl)-2-hydroxyethyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(78) 1-ethyl-N-{1-[3-(methoxyl group) phenyl] propyl group }-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(79) 1-ethyl-N-{1-[4-(methoxyl group) phenyl] propyl group }-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(80) N-[1-(4-bromophenyl) propyl group]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(81) 1-ethyl-N-{1-[4-(propoxy-) phenyl] propyl group }-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(82) N-[1-(3, the 5-3,5-dimethylphenyl) propyl group]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(83) 1-ethyl-N-[1-(4-aminomethyl phenyl) propyl group]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(84) 1-ethyl-N-{1-[4-(1-methylethyl) phenyl] propyl group }-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(85) 1-ethyl-N-[1-(2-aminomethyl phenyl) ethyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(86) N-(1-{4-[(difluoromethyl) oxygen base] phenyl } ethyl)-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(87) 1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-N-{1-[4-(trifluoromethyl) phenyl] ethyl }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(88) 1-ethyl-N-[1-(2-aminomethyl phenyl) propyl group]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(89) 1-ethyl-N-{1-[4-(oxyethyl group) phenyl] propyl group }-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(90) N-(1-{4-[(difluoromethyl) oxygen base] phenyl } propyl group)-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(91) 1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-N-{1-[4-(trifluoromethyl) phenyl] propyl group }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(92) N-[1-(3, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(93) N-[1-(2, the 3-3,5-dimethylphenyl) ethyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(94) N-[1-(2, the 4-3,5-dimethylphenyl) ethyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(95) N-[1-(4-chloro-2-fluorophenyl) ethyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(96) N-[1-(3-chloro-4-aminomethyl phenyl) ethyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(97) N-[1-(2, the 3-3,5-dimethylphenyl) propyl group]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(98) N-[1-(2, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(99) N-[1-(4-chloro-2-fluorophenyl) propyl group]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(100) N-[1-(3-chloro-4-aminomethyl phenyl) propyl group]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(101) 1-ethyl-N-[1-(3-hydroxy phenyl) propyl group]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(102) N-[1-(2,3-dihydro-1H-indenes-5-yl) ethyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(103) 1-ethyl-N-[1-(5,6,7,8-tetrahydrochysene-2-naphthyl) ethyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(104) N-[1-(4-bromophenyl)-2,2, the 2-trifluoroethyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(105) 1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-N-{2,2,2-three fluoro-1-[3-(methoxyl group) phenyl] ethyl }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(106) 4-(cyclohexyl amino)-1-ethyl-N-{1-[4-(methyl sulphonyl) phenyl] ethyl }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(107) 4-(cyclohexyl amino)-1-ethyl-N-[(1R)-1-phenyl propyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(108) 4-(cyclohexyl amino)-N-(diphenyl methyl)-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(109) 4-(cyclohexyl amino)-1-ethyl-N-[(1R)-1-phenylethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(110) ({ [4-(cyclohexyl amino)-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-yl] carbonyl } amino) (phenyl) ethyl acetate
(111) N-[1-(4-chloro-phenyl-) ethyl]-4-(cyclohexyl amino)-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(112) 4-(cyclohexyl amino)-1-ethyl-N-(1-methyl isophthalic acid-phenylethyl)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(113) 4-(cyclohexyl amino)-1-ethyl-N-[1-(4-fluorophenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(114) N-[1-(4-chloro-phenyl-) propyl group]-4-(cyclohexyl amino)-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(115) 4-(cyclohexyl amino)-N-(1, the 2-diphenyl-ethyl)-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(116) 4-(cyclohexyl amino)-1-ethyl-N-{1-[4-(propoxy-) phenyl] ethyl }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(117) 3-({ [4-(cyclohexyl amino)-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-yl] carbonyl } amino)-3-phenylpropionic acid methyl esters
(118) 4-(cyclohexyl amino)-1-ethyl-N-[1-(hydroxymethyl)-1-phenyl propyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(119) 4-(cyclohexyl amino)-1-ethyl-N-(3-hydroxyl-1-phenyl propyl)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(120) 4-(cyclohexyl amino)-1-ethyl-N-{1-[4-(oxyethyl group) phenyl] ethyl }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(121) 4-(cyclohexyl amino)-1-ethyl-N-[1-(3-hydroxy phenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(122) 4-(cyclohexyl amino)-1-ethyl-N-[1-phenyl-2-(1-pyrrolidyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(123) 4-(cyclohexyl amino)-N-[2-(dimethylamino)-1-phenylethyl]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(124) 4-(cyclohexyl amino)-1-ethyl-N-[(1R)-2-(methoxyl group)-1-phenylethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(125) N-[(1R)-2-amino-2-oxo-1-phenylethyl]-4-(cyclohexyl amino)-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(126) 4-(cyclohexyl amino)-1-ethyl-N-[(1R)-2-hydroxyl-1-phenylethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(127) 4-(cyclohexyl amino)-1-ethyl-N-[(1S)-2-hydroxyl-1-phenylethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(128) 4-(cyclohexyl amino)-1-ethyl-N-{ (1R)-1-[3-(methoxyl group) phenyl] ethyl }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(129) 4-(cyclohexyl amino)-1-ethyl-N-[(1S)-2-(methoxyl group)-1-phenylethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(130) 4-(cyclohexyl amino)-1-ethyl-N-[(1R)-1-(4-nitrophenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(131) 4-(cyclohexyl amino)-1-ethyl-N-[(1S)-1-(1-naphthyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(132) 4-(cyclohexyl amino)-1-ethyl-N-[phenyl (4-phenyl-1,3-thiazoles-2-yl) methyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(133) N-[cyano group (phenyl) methyl]-4-(cyclohexyl amino)-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(134) 4-(cyclohexyl amino)-1-ethyl-N-[1-(1-naphthyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(135) 4-(cyclohexyl amino)-1-ethyl-N-(2-hydroxyl-1,1-diphenyl-ethyl)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(136) 4-(cyclohexyl amino)-1-ethyl-N-{ (1R)-1-[4-(methoxyl group) phenyl] ethyl }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(137) 4-(cyclohexyl amino)-1-ethyl-N-[1-(4-fluorophenyl) propyl group]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(138) 4-(cyclohexyl amino)-N-[1-(2, the 3-dichlorophenyl) propyl group]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(139) 4-(cyclohexyl amino)-1-ethyl-N-[(1R)-1-(4-aminomethyl phenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(140) 4-(cyclohexyl amino)-1-ethyl-N-(1-phenylethyl)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(141) N-[(1R)-1-(4-bromophenyl) ethyl]-4-(cyclohexyl amino)-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(142) 4-(cyclohexyl amino)-N-[1-(2, the 3-dichlorophenyl) ethyl]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(143) 4-(cyclohexyl amino)-1-ethyl-N-{1-[3-(methoxyl group) phenyl] propyl group }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(144) 4-(cyclohexyl amino)-1-ethyl-N-{1-[4-(methoxyl group) phenyl] propyl group }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(145) N-[1-(4-bromophenyl) propyl group]-4-(cyclohexyl amino)-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(146) 4-(cyclohexyl amino)-1-ethyl-N-{1-[4-(propoxy-) phenyl] propyl group }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(147) 4-(cyclohexyl amino)-N-[1-(3, the 5-3,5-dimethylphenyl) propyl group]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(148) 4-(cyclohexyl amino)-1-ethyl-N-[1-(4-aminomethyl phenyl) propyl group]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(149) 4-(cyclohexyl amino)-1-ethyl-N-{1-[4-(1-methylethyl) phenyl] propyl group }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(150) 4-(cyclohexyl amino)-1-ethyl-N-[1-(2-aminomethyl phenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(151) 4-(cyclohexyl amino)-N-(1-{4-[(difluoromethyl) oxygen base] phenyl } ethyl)-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(152) 4-(cyclohexyl amino)-1-ethyl-N-{1-[4-(trifluoromethyl) phenyl] ethyl }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(153) 4-(cyclohexyl amino)-1-ethyl-N-[1-(2-aminomethyl phenyl) propyl group]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(154) 4-(cyclohexyl amino)-1-ethyl-N-{1-[4-(oxyethyl group) phenyl] propyl group }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(155) 4-(cyclohexyl amino)-N-(1-{4-[(difluoromethyl) oxygen base] phenyl } propyl group)-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(156) 4-(cyclohexyl amino)-1-ethyl-N-{1-[4-(trifluoromethyl) phenyl] propyl group }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(157) 4-(cyclohexyl amino)-N-[1-(3, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(158) 4-(cyclohexyl amino)-N-[1-(2, the 3-3,5-dimethylphenyl) ethyl]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(159) 4-(cyclohexyl amino)-N-[1-(2, the 4-3,5-dimethylphenyl) ethyl]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(160) N-[1-(4-chloro-2-fluorophenyl) ethyl]-4-(cyclohexyl amino)-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(161) N-[1-(3-chloro-4-aminomethyl phenyl) ethyl]-4-(cyclohexyl amino)-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(162) 4-(cyclohexyl amino)-N-[1-(2, the 3-3,5-dimethylphenyl) propyl group]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(163) 4-(cyclohexyl amino)-N-[1-(2, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(164) N-[1-(4-chloro-2-fluorophenyl) propyl group]-4-(cyclohexyl amino)-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(165) N-[1-(3-chloro-4-aminomethyl phenyl) propyl group]-4-(cyclohexyl amino)-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(166) 4-(cyclohexyl amino)-1-ethyl-N-[1-(3-hydroxy phenyl) propyl group]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(167) N-[1-(4-chloro-phenyl-)-2-hydroxyethyl]-4-(cyclohexyl amino)-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(168) 4-(cyclohexyl amino)-N-[1-(2,3-dihydro-1H-indenes-5-yl) ethyl]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(169) 4-(cyclohexyl amino)-1-ethyl-N-[1-(5,6,7,8-tetrahydrochysene-2-naphthyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(170) amino 4-[(1-ethanoyl-4-piperidyl)]-the 1-ethyl-N-[(1S)-the 1-phenyl propyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(171) amino 4-[(1-ethanoyl-4-piperidyl)]-the 1-ethyl-N-[(1R)-the 1-phenylethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(172) amino 4-[(1-ethanoyl-4-piperidyl)]-N-(diphenyl methyl)-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(173) amino 4-[(1-ethanoyl-4-piperidyl)]-1-ethyl-N-{1-[4-(methyl sulphonyl) phenyl] ethyl }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(174) amino 4-[(1-ethanoyl-4-piperidyl)]-the 1-ethyl-N-[(1R)-the 1-phenyl propyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(175) N-[1-(4-chloro-phenyl-) ethyl]-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(176) N-[1-(4-chloro-phenyl-) propyl group]-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(177) 1-ethyl-N-[(1S)-1-(4-nitrophenyl) ethyl]-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(178) 1-ethyl-N-[(1R)-1-(4-nitrophenyl) ethyl]-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(179) 1-ethyl-N-{1-[4-(oxyethyl group) phenyl] ethyl }-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(180) amino 1-ethyl-4-[(4-oxo cyclohexyl)]-N-{1-[4-(propoxy-) phenyl] ethyl }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(181) 1-ethyl-N-[1-(4-fluorophenyl) ethyl]-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(182) 1-ethyl-N-[(1R)-2-hydroxyl-1-phenylethyl]-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(183) amino 1-ethyl-4-[(4-oxo cyclohexyl)]-N-(1-phenyl propyl)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(184) (2R)-[(1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-yl } carbonyl) amino] [3-(methoxyl group) phenyl] acetate
(185) 1-ethyl-N-{1-[4-(1-methylethyl) phenyl] ethyl }-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(186) 1-ethyl-N-[1-(2-aminomethyl phenyl) ethyl]-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(187) N-[1-(3, the 5-3,5-dimethylphenyl) ethyl]-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(188) 1-ethyl-N-{ (1R)-1-[4-(methoxyl group) phenyl] ethyl }-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(189) 1-ethyl-N-[1-(4-fluorophenyl) propyl group]-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(190) N-[1-(2, the 3-dichlorophenyl) propyl group]-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(191) 1-ethyl-N-[(1R)-1-(4-aminomethyl phenyl) ethyl]-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(192) amino 1-ethyl-4-[(4-oxo cyclohexyl)]-N-(1-phenylethyl)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(193) N-[(1R)-1-(4-bromophenyl) ethyl]-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(194) 1-ethyl-N-[(1S)-2-hydroxyl-1-phenylethyl]-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(195) N-[1-(4-chloro-phenyl-)-2-hydroxyethyl]-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(196) N-(1-{4-[(difluoromethyl) oxygen base] phenyl } ethyl)-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(197) amino 1-ethyl-4-[(4-oxo cyclohexyl)]-N-{1-[4-(trifluoromethyl) phenyl] ethyl }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(198) 1-ethyl-N-[1-(2-aminomethyl phenyl) propyl group]-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(199) 1-ethyl-N-{1-[4-(oxyethyl group) phenyl] propyl group }-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(200) N-(1-{4-[(difluoromethyl) oxygen base] phenyl } propyl group)-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(201) amino 1-ethyl-4-[(4-oxo cyclohexyl)]-N-{1-[4-(trifluoromethyl) phenyl] propyl group }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(202) N-[1-(3, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(203) amino 1-ethyl-4-[(4-oxo cyclohexyl)]-N-[(1R)-the 1-phenyl propyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(204) 1-ethyl-N-{ (1R)-1-[3-(methoxyl group) phenyl] ethyl }-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(205) N-[1-(2, the 3-3,5-dimethylphenyl) ethyl]-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(206) N-[1-(2, the 4-3,5-dimethylphenyl) ethyl]-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(207) N-[1-(4-chloro-2-fluorophenyl) ethyl]-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(208) N-[1-(3-chloro-4-aminomethyl phenyl) ethyl]-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(209) N-[1-(2, the 3-3,5-dimethylphenyl) propyl group]-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(210) N-[1-(2, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(211) N-[1-(4-chloro-2-fluorophenyl) propyl group]-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(212) N-[1-(3-chloro-4-aminomethyl phenyl) propyl group]-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(213) 1-ethyl-N-[1-(3-hydroxy phenyl) ethyl]-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(214) 1-ethyl-N-[1-(3-hydroxy phenyl) propyl group]-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(215) N-[1-(2, the 3-dichlorophenyl) ethyl]-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(216) 1-ethyl-N-{1-[3-(methoxyl group) phenyl] propyl group }-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(217) 1-ethyl-N-{1-[4-(methoxyl group) phenyl] propyl group }-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(218) N-[1-(4-bromophenyl) propyl group]-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(219) amino 1-ethyl-4-[(4-oxo cyclohexyl)]-N-{1-[4-(propoxy-) phenyl] propyl group }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(220) N-[1-(3, the 5-3,5-dimethylphenyl) propyl group]-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(221) 1-ethyl-N-[1-(4-aminomethyl phenyl) propyl group]-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(222) 1-ethyl-N-{1-[4-(1-methylethyl) phenyl] propyl group }-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(223) 1-ethyl-N-(1-{4-[(1-methylethyl) oxygen base] phenyl } ethyl)-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(224) amino 1-ethyl-4-[(4-oxo cyclohexyl)]-N-[1-(5,6,7,8-tetrahydrochysene-2-naphthyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(225) N-[1-(4-bromophenyl)-2,2, the 2-trifluoroethyl]-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(226) amino 1-ethyl-4-[(4-oxo cyclohexyl)]-N-{2,2,2-three fluoro-1-[3-(methoxyl group) phenyl] ethyl }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(227) 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-[1-(5,6,7,8-tetrahydrochysene-2-naphthyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(228) 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-[(1S)-2-hydroxyl-1-phenylethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(229) N-[1-(2,3-dihydro-1H-indenes-5-yl) ethyl]-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(230) N-[1-(4-chloro-phenyl-)-2-hydroxyethyl]-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(231) 1-ethyl-N-{1-[4-(oxyethyl group) phenyl] ethyl }-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(232) 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-{1-[4-(propoxy-) phenyl] ethyl }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(233) 1-ethyl-N-[1-(4-fluorophenyl) ethyl]-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(234) 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-[(1R)-2-hydroxyl-1-phenylethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(235) 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-(1-phenyl propyl)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(236) 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-{1-[4-(1-methylethyl) phenyl] ethyl }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(237) N-[1-(3, the 5-3,5-dimethylphenyl) ethyl]-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(238) 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-{ (1R)-1-[4-(methoxyl group) phenyl] ethyl }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(239) 1-ethyl-N-[1-(4-fluorophenyl) propyl group]-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(240) N-[1-(2, the 3-dichlorophenyl) propyl group]-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(241) 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-[(1R)-1-(4-aminomethyl phenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(242) 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-(1-phenylethyl)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(243) N-[(1R)-1-(4-bromophenyl) ethyl]-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(244) N-[1-(2, the 3-dichlorophenyl) ethyl]-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(245) N-[1-(4-chloro-phenyl-) propyl group]-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(246) N-[1-(4-chloro-phenyl-) ethyl]-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(247) 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-{1-[3-(methoxyl group) phenyl] propyl group }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(248) 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-{1-[4-(methoxyl group) phenyl] propyl group }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(249) N-[1-(4-bromophenyl) propyl group]-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(250) 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-{1-[4-(propoxy-) phenyl] propyl group }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(251) N-[1-(3, the 5-3,5-dimethylphenyl) propyl group]-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(252) 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-[1-(4-aminomethyl phenyl) propyl group]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(253) 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-{1-[4-(1-methylethyl) phenyl] propyl group }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(254) 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-[1-(2-aminomethyl phenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(255) N-(1-{4-[(difluoromethyl) oxygen base] phenyl } ethyl)-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(256) 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-{1-[4-(trifluoromethyl) phenyl] ethyl }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(257) 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-[1-(2-aminomethyl phenyl) propyl group]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(258) 1-ethyl-N-{1-[4-(oxyethyl group) phenyl] propyl group }-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(259) N-(1-{4-[(difluoromethyl) oxygen base] phenyl } propyl group)-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(260) 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-{1-[4-(trifluoromethyl) phenyl] propyl group }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(261) N-[1-(3, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(262) 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-[(1R)-the 1-phenyl propyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(263) 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-{ (1R)-1-[3-(methoxyl group) phenyl] ethyl }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(264) N-[1-(2, the 3-3,5-dimethylphenyl) ethyl]-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(265) N-[1-(2, the 4-3,5-dimethylphenyl) ethyl]-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(266) N-[1-(4-chloro-2-fluorophenyl) ethyl]-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(267) N-[1-(3-chloro-4-aminomethyl phenyl) ethyl]-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(268) N-[1-(2, the 3-3,5-dimethylphenyl) propyl group]-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(269) N-[1-(2, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(270) N-[1-(4-chloro-2-fluorophenyl) propyl group]-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(271) N-[1-(3-chloro-4-aminomethyl phenyl) propyl group]-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(272) 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-[1-(3-hydroxy phenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(273) 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-[1-(3-hydroxy phenyl) propyl group]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(274) N-[1-(2, the 4-3,5-dimethylphenyl) ethyl]-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(275) N-[1-(2, the 4-3,5-dimethylphenyl) ethyl]-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(276) N-[1-(3, the 5-3,5-dimethylphenyl) ethyl]-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(277) N-[1-(3, the 5-3,5-dimethylphenyl) ethyl]-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(278) 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-(1-{4-[(1-methylethyl) oxygen base] phenyl } ethyl)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(279) 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-(1-{4-[(1-methylethyl) oxygen base] phenyl } ethyl)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(280) 1-ethyl-N-[1-(4-fluorophenyl) ethyl]-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(281) 1-ethyl-N-[1-(4-fluorophenyl) ethyl]-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(282) N-[1-(4-chloro-phenyl-) propyl group]-1-ethyl-4-{[(1S, 3R)-and/or (1R, 3S)-the 3-hydroxy-cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(283) 1-ethyl-4-{[(1S, 3R)-and/or (1R, 3S)-the 3-hydroxy-cyclohexyl] amino }-N-[(1R)-1-(4-aminomethyl phenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(284) N-[1-(2, the 4-3,5-dimethylphenyl) ethyl]-1-ethyl-4-{[(1S, 3R)-and/or (1R, 3S)-the 3-hydroxy-cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide (isomer 1)
(285) N-[1-(2, the 4-3,5-dimethylphenyl) ethyl]-1-ethyl-4-{[(1S, 3R)-and/or (1R, 3S)-the 3-hydroxy-cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide (isomer 2)
(286) N-[1-(3, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-4-{[(1S, 3R)-and/or (1R, 3S)-the 3-hydroxy-cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(287) N-[1-(4-chloro-phenyl-) propyl group]-1-ethyl-6-methyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(288) N-[1-(4-chloro-phenyl-) ethyl]-1-ethyl-6-methyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(289) N-[1-(4-chloro-phenyl-) ethyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide (enantiomer 1)
(290) N-[1-(4-chloro-phenyl-) ethyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide (enantiomer 2)
(291) N-[1-(4-chloro-phenyl-) propyl group]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide (enantiomer 1)
(292) N-[1-(4-chloro-phenyl-) propyl group]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide (enantiomer 2)
(293) 1-ethyl-N-{1-[4-(oxyethyl group) phenyl] ethyl }-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide (enantiomer 1)
(294) 1-ethyl-N-{1-[4-(oxyethyl group) phenyl] ethyl }-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide (enantiomer 2)
(295) N-[1-(2, the 4-3,5-dimethylphenyl) ethyl]-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide (enantiomer 1)
(296) N-[1-(2, the 4-3,5-dimethylphenyl) ethyl]-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide (enantiomer 2)
(297) N-[1-(3, the 5-3,5-dimethylphenyl) ethyl]-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide (enantiomer 1)
(298) N-[1-(3, the 5-3,5-dimethylphenyl) ethyl]-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide (enantiomer 2)
(299) 1-ethyl-N-(1-{4-[(1-methylethyl) oxygen base] phenyl } ethyl)-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide (enantiomer 1)
(300) 1-ethyl-N-(1-{4-[(1-methylethyl) oxygen base] phenyl } ethyl)-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide (enantiomer 2)
(301) 1-ethyl-N-[1-(4-fluorophenyl) ethyl]-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide (enantiomer 1)
(302) 1-ethyl-N-[1-(4-fluorophenyl) ethyl]-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide (enantiomer 2)
(303) N-[1-(2, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide (enantiomer 1)
(304) N-[1-(2, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide (enantiomer 2)
(305) 1-ethyl-4-{[(1S, 3R)-and/or (1R, 3S)-the 3-hydroxy-cyclohexyl] amino }-N-[(1R)-1-(4-aminomethyl phenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide (diastereomer 1)
(306) 1-ethyl-4-{[(1S, 3R)-and/or (1R, 3S)-the 3-hydroxy-cyclohexyl] amino }-N-[(1R)-1-(4-aminomethyl phenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide (diastereomer 2)
(307) N-[1-(2, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide (enantiomer 2) hydrochloride
(308) 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-the 1-ethyl-N-[(1R)-1-(4-aminomethyl phenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(309) 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-the 1-ethyl-N-[(1R)-the 1-phenylethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(310) 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-N-[(1R)-1-(4-bromophenyl) ethyl]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(311) 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-N-[1-(2, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(312) 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-N-[1-(3-chloro-4-aminomethyl phenyl) propyl group]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(313) 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-N-[1-(4-chloro-2-fluorophenyl) propyl group]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide, or
(314) 4-{[4-(aminocarboxyl) cyclohexyl] amino }-the 1-ethyl-N-[(1R)-the 1-phenylethyl]-1H-pyrazolo [3,4-b] pyridine-the 5-methane amide is (for example, 4-{ is suitable-[4-(aminocarboxyl) cyclohexyl] amino }-the 1-ethyl-N-[(1R)-the 1-phenylethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide);
Be compound itself or its salt, for example its pharmacy acceptable salt.
Structure or its embodiment of above-mentioned particular compound have been provided among the embodiment 1-314A hereinafter.
Special preferred formula (I) compound or its salt is the compound or its salt (for example its pharmacy acceptable salt) of one of embodiment 1-314 or embodiment 314A.Provided structure or its embodiment of these particular compound among the embodiment 1-314 hereinafter, their name partly provides at embodiment.
In one embodiment, more preferably formula (I) compound or its salt is by structure described herein and/or the embodiment 73,98,283,304,306,307,310 of name definition or compound (or being the compound of embodiment 75) or its salt (for example its pharmacy acceptable salt) of 311.The structure of these compounds and name are partly introduced at embodiment.For example, these embodiment can be used for suction and give for example Mammals (for example people), and/or can be included in the pharmaceutical composition suitable and/or suitable inhalation after adjusting, and/or can be particulate form (for example particulate form, for example referring to following " reducing granularity " part) by maybe obtaining by micronization processes.
In another kind of preferred embodiment, formula (I) compound or its salt is:
(1) N-[(1S)-1-(2, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(2) N-[(1R)-1-(2, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(3) N-[(1R)-1-(2, the 5-3,5-dimethylphenyl) ethyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(4) 1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-N-[(1R)-1-(2,4, the 6-trimethylphenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(5) 1-ethyl-N-[(1R)-1-(2-ethylphenyl) ethyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(6) 1-ethyl-N-[(1R)-1-(4-ethylphenyl) ethyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(7) 1-ethyl-N-[(1R)-1-(4-aminomethyl phenyl) propyl group]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(8) 1-ethyl-N-[(1R)-1-(4-ethylphenyl) propyl group]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(9) 1-ethyl-N-{ (1R)-1-[4-(1-methylethyl) phenyl] propyl group }-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(10) N-[(1R)-1-(4-chloro-2-fluorophenyl) propyl group]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(11) N-[(1R)-1-(2, the 6-3,5-dimethylphenyl) propyl group]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(12) N-[(1R)-1-(2, the 5-3,5-dimethylphenyl) propyl group]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(13) 1-ethyl-N-[(1R)-1-(2-ethylphenyl) propyl group]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(14) 1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-N-[(1R)-1-(2,4, the 6-trimethylphenyl) propyl group]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(15) 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-N-[(1R)-1-(2, the 5-3,5-dimethylphenyl) ethyl]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(16) 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-the 1-ethyl-N-[(1R)-1-(4-ethylphenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(17) 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-the 1-ethyl-N-[(1R)-1-(2-ethylphenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(18) 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-the 1-ethyl-N-[(1R)-1-(2,4, the 6-trimethylphenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(19) 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-N-[(1R)-1-(2, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(20) 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-N-[1-(4-chloro-phenyl-) ethyl]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(21) 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-the 1-ethyl-N-[(1R)-the 1-phenyl propyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(22) 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-N-[1-(4-chloro-phenyl-) propyl group]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(23) 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-1-ethyl-N-[1-(4-fluorophenyl) propyl group]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(24) 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-the 1-ethyl-N-[(1R)-1-(4-aminomethyl phenyl) propyl group]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(25) 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-the 1-ethyl-N-[(1R)-1-(4-ethylphenyl) propyl group]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(26) 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-1-ethyl-N-{ (1R)-1-[4-(1-methylethyl) phenyl] propyl group }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(27) 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-N-[(1R)-1-(4-chloro-2-fluorophenyl) propyl group]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(28) 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-N-[(1R)-1-(2, the 6-3,5-dimethylphenyl) propyl group]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(29) 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-N-[(1R)-1-(2, the 5-3,5-dimethylphenyl) propyl group]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(30) 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-the 1-ethyl-N-[(1R)-1-(2-ethylphenyl) propyl group]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(31) 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-the 1-ethyl-N-[(1R)-1-(2,4, the 6-trimethylphenyl) propyl group]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(32) 4-{[4-(aminocarboxyl) cyclohexyl] amino }-N-[1-(4-chloro-phenyl-) propyl group]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(33) 4-{[4-(aminocarboxyl) cyclohexyl] amino }-the 1-ethyl-N-[(1R)-the 1-phenyl propyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(34) 4-{[4-(aminocarboxyl) cyclohexyl] amino }-N-(1-{4-[(difluoromethyl) oxygen base] phenyl } ethyl)-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(35) 4-{[4-(aminocarboxyl) cyclohexyl] amino }-N-[1-(4-chloro-phenyl-) ethyl]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(36) 4-{[4-(aminocarboxyl) cyclohexyl] amino }-1-ethyl-N-[1-(4-fluorophenyl) propyl group]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(37) 4-{[4-(aminocarboxyl) cyclohexyl] amino }-N-[(1R)-1-(4-bromophenyl) ethyl]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(38) 4-{[suitable-4-(aminocarboxyl) cyclohexyl] amino-N-[(1R)-1-(2, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(39) 4-{[suitable-4-(aminocarboxyl) cyclohexyl] amino-1-ethyl-N-[(1R)-1-(4-aminomethyl phenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(40) 4-{[suitable-4-(aminocarboxyl) cyclohexyl] amino-1-ethyl-N-[(1R)-1-phenylethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(41) 4-{[suitable-4-(aminocarboxyl) cyclohexyl] amino-N-[(1R)-1-(4-bromophenyl) ethyl]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(42) 4-{[anti--4-(aminocarboxyl) cyclohexyl] amino-N-[(1R)-1-(2, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(43) 4-{[anti--4-(aminocarboxyl) cyclohexyl] amino-1-ethyl-N-[(1R)-1-(4-aminomethyl phenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(44) 4-{[anti--4-(aminocarboxyl) cyclohexyl] amino-1-ethyl-N-[(1R)-1-phenylethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(45) 4-{[anti--4-(aminocarboxyl) cyclohexyl] amino-N-[(1R)-1-(4-bromophenyl) ethyl]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(46) 4-{[(3S)-and 1-(aminocarboxyl) tetramethyleneimine-3-yl] amino }-N-[1-(2, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(47) 4-{[(3S)-and 1-(aminocarboxyl) tetramethyleneimine-3-yl] amino }-the 1-ethyl-N-[(1R)-1-(4-aminomethyl phenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(48) 4-{[(3S)-and 1-(aminocarboxyl) tetramethyleneimine-3-yl] amino }-N-[1-(3, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(49) 4-{[(3S)-and 1-(aminocarboxyl) tetramethyleneimine-3-yl] amino }-N-[(1R)-1-(4-bromophenyl) ethyl]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(50) 4-{[(3R)-and 1-(aminocarboxyl) tetramethyleneimine-3-yl] amino }-N-[1-(2, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(51) 4-{[(3R)-and 1-(aminocarboxyl) tetramethyleneimine-3-yl] amino }-the 1-ethyl-N-[(1R)-1-(4-aminomethyl phenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(52) 4-{[(3R)-and 1-(aminocarboxyl) tetramethyleneimine-3-yl] amino }-N-[1-(3, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(53) 4-{[(3R)-and 1-(aminocarboxyl) tetramethyleneimine-3-yl] amino }-N-[(1R)-1-(4-bromophenyl) ethyl]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(54) 4-{[suitable-3-(aminocarboxyl) cyclobutyl] amino-1-ethyl-N-[(1R)-1-(4-aminomethyl phenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(55) 4-{[suitable-3-(aminocarboxyl) cyclobutyl] amino-N-[1-(2, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(56) 4-[(anti--4-ethanoyl cyclohexyl) amino]-1-ethyl-N-[(1R)-1-(4-aminomethyl phenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(57) amino 4-[(4-ethanoyl cyclohexyl)]-N-[(1R)-1-(2, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(58) 4-[(suitable-4-ethanoyl cyclohexyl) amino]-1-ethyl-N-[(1R)-1-(4-aminomethyl phenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(59) 1-ethyl-4-{[anti--the 3-hydroxy-cyclohexyl] amino-N-[(1R)-1-(4-aminomethyl phenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(60) N-[(1S)-1-(2, the 4-3,5-dimethylphenyl) ethyl]-1-ethyl-4-{[is anti--the 3-hydroxy-cyclohexyl] and amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(61) N-[(1R)-1-(2, the 4-3,5-dimethylphenyl) ethyl]-1-ethyl-4-{[is anti--the 3-hydroxy-cyclohexyl] and amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(62) N-[(1R)-1-(4-bromophenyl) ethyl]-1-ethyl-4-{[is anti--the 3-hydroxy-cyclohexyl] and amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(63) N-[1-(3, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-4-{[is anti--the 3-hydroxy-cyclohexyl] and amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(64) N-[4-(dimethylamino)-1-(3-aminomethyl phenyl)-4-oxo butyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(65) 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-N-[4-(dimethylamino)-1-(3-aminomethyl phenyl)-4-oxo butyl]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(66) 1-ethyl-N-[(1R)-1-(4-aminomethyl phenyl) ethyl]-4-(4-piperidyl amino)-1H-pyrazolo [3,4-b] pyridine-5-carboxamide hydrochloride, or
(67) N-[1-(2, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-4-(4-piperidyl amino)-1H-pyrazolo [3,4-b] pyridine-5-carboxamide hydrochloride;
Be compound itself or its salt, for example its pharmacy acceptable salt.
Provided structure or its embodiment of above-mentioned particular compound among embodiment 315-372 hereinafter and the embodiment 374-382, their name partly provides at embodiment.
In the preferred embodiment of above-claimed cpd (embodiment 315-372 and embodiment 374-382), more preferably formula (I) compound or its salt is by structure described herein and/or the embodiment 316,317,318,319,320,321,322,323,324,325,326,327,328,329,330,331,332,333,334,335,336,337,338,339,341,342,343,344,345,351,352 of name definition or 353 compound or its salt (for example its pharmacy acceptable salt).We think that in these embodiments, embodiment 316-333,335,338-345 and 351-353 are made up of a kind of enantiomer basically, and this enantiomer has (R) three-dimensional chemical configuration at the benzylic carbon atoms place.Further preferred formula (I) compound or its salt is by structure described herein and/or the embodiment 316,321,324,326,327,328,330,331,332,333,334,335,336,337,338,339,343,344 of name definition or 345 compound or its salt (for example its pharmacy acceptable salt).The structure of these embodiment and name are partly introduced at embodiment.
In the preferred embodiment of above-claimed cpd (embodiment 315-372 and embodiment 374-382), further preferred formula (I) compound or its salt is 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-N-[(1R)-1-(2, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide (embodiment 333) or its salt (for example its pharmacy acceptable salt).
Believe that embodiment 333 is made up of a kind of enantiomer basically, and this enantiomer has (R) three-dimensional chemical configuration at the benzylic carbon atoms place.About its structure referring to following embodiment 333.Embodiment 333 or its salt can be used for suction and give for example Mammals (for example people), and/or can be included in the pharmaceutical composition suitable and/or suitable inhalation after adjusting, and/or can be particulate form (for example particulate form, for example referring to following " reducing granularity " part) by maybe obtaining by micronization.
According to an optional embodiment of the present invention, formula (I) compound or its salt can be formula (XXVIII) compound or its salt:
Wherein:
R
X1Be hydrogen atom (H), C
1-2Alkyl or C
1Fluoro-alkyl (preferred H);
R
Y1Be hydrogen atom (H) or C
1-2Alkyl;
R
Y2Be hydrogen atom (H); C
1-3Alkyl (C for example
1-2Alkyl or methyl); Or-(CH
2)
n 7aa-OH; N wherein
7aaBe 1,2 or 3;
R
X2Be Ar
A, wherein:
(i) Ar
AFor choosing wantonly by 1-2 is the phenyl that following substituting group replaces independently: fluorine, chlorine, bromine, C
1-2Alkyl, C
1-2Fluoro-alkyl, C
1-2Alkoxyl group, C
1-2Fluoroalkyl; OH;-NR
11aaR
11bb(R wherein
11aaBe H or C
1-2Alkyl, R
11bbBe H, C
1-2Alkyl ,-C (O)-C
1-2Alkyl or-S (O)
2-C
1-2Alkyl); Cyano group;-C (O)-NR
11ccR
11dd(R wherein
11ccAnd R
11ddSolely be H or C
1-2Alkyl);-C (O)-OR
11ee, R wherein
11eeBe H or C
1-2Alkyl; Or-S (O)
2-R
11ff(R wherein
11ffBe C
1-2Alkyl, NH
2, NHMe or NMe
2); Perhaps described phenyl Ar
AChoose wantonly on two adjacent Ar annular atomses by the two ends of chain and replace, described chain is-(CH
2)
4-,-(CH
2)
3-or-CH=CH-CH=CH-; Perhaps
(ii) Ar
AFor containing 5 yuan of heteroaromatic rings of optional replacement that 1-4 is selected from the heteroatoms (for example 1-3 heteroatoms) of O, N or S; Wherein as described heteroaromatic rings Ar
AWhen containing 2-4 heteroatoms (for example 2 or 3 heteroatomss), then a heteroatoms is selected from O, N and S, and remaining heteroatoms is N; Wherein said heteroaromatic rings Ar
AOptional is C by 1-2 independently
1-4Alkyl (C for example
1-2Alkyl) or the group of OH (any keto tautomer that comprises the aromatic ring that OH replaces) replace.
Formula (XXVIII) compound can be preferably:
These three compounds are:
The 1-ethyl-N-[(1R)-2-hydroxyl-1-phenylethyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide,
The 1-ethyl-N-[(1S)-2-hydroxyl-1-phenylethyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide,
1-ethyl-N-[(1S, 2R)-2-hydroxyl-1-phenyl propyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide.
These three compounds at the same time International Patent Application PCT/the EP2003/014867 of pending trial (=PCT/EP03/14867) (Glaxo Group Limited applied on December 19th, 2003, announce on July 8th, 2004, publication No. is WO 2004/056823 A1) in be disclosed as intermediate 42,43 and 46 respectively, the content of this patent application is attached to this paper by reference.PCT/EP2003/014867 (for example referring to the 59th page) also discloses formula (XXVIII) compound, and this patent content is attached to this paper by reference.
Optional according to another preferred embodiment, formula (I) compound or its salt is not formula (XXVIII) compound or its salt.
The present invention provides the compound or its salt (particularly its pharmacy acceptable salt) of following formula (IB) on the other hand:
Wherein:
R
1aBe C
2-3Alkyl, C
2Fluoro-alkyl or-CH
2CH
2OH;
R
2aBe hydrogen atom (H) or methyl;
NHR
3aBe formula (p14), wherein NHR
3aIn group and the formula (IB) 4 of Pyrazolopyridine-the NH-tie point is following underscore part:
R
4aaBe methyl, ethyl, C
1Fluoro-alkyl (CF for example
3) ,-CH
2OH or-CH
2OMe;
R
6Aa, R
6Ba, R
6Da, R
6EaAnd R
6FaBe independently of one another hydrogen atom (H), fluorine atom, chlorine atom, bromine atoms, iodine atom, methyl, ethyl, n-propyl, sec.-propyl, isobutyl-, trifluoromethyl ,-CH
2OH, methoxyl group, oxyethyl group, positive propoxy, isopropoxy, C
1Fluoroalkyl (for example trifluoromethoxy or difluoro-methoxy), nitro (NO
2), OH, C
1-3Alkyl S (O)
2-(MeS (O) for example
2-), C
1-2Alkyl S (O)
2-NH-(Me-S (O) for example
2-NH-) ,-CONH
2, cyano group (CN) or C
1-2Alkyl S (O)
2-CH
2-(Me-S (O) for example
2-CH
2);
Precondition is R
6Aa, R
6Ba, R
6Da, R
6EaAnd R
6FaIn more than two (for example more than three) be hydrogen atom (H);
And in formula (IB), the described compound of 50% above volumetric molar concentration or salt are connecting R
4aaThree-dimensional chemical configuration shown in the carbon atom place of group has.
At R
1aIn, C
2-3Alkyl can be for example ethyl or n-propyl.At R
1aIn, C
2Fluoro-alkyl can be for example C
1Fluoro-alkyl-CH
2-, CF for example
3-CH
2-.Preferred R
1aFor ethyl, n-propyl or-CH
2CH
2OH.R
1aEthyl most preferably.
R
2aCan be for example H.
The NHR of formula (p14)
3aGroup is preferably cis-configuration, i.e. [suitable-4-(1-hydroxyethyl) cyclohexyl] amino (comprising that cis-configuration is the mixture of the various configurations of main component).
Preferred R
4aaBe methyl, ethyl, CF
3Or-CH
2OH; More preferably R
4aaBe methyl or ethyl; R most preferably
4aaBe ethyl.
Preferred R
6Aa, R
6Ba, R
6Da, R
6EaAnd/or R
6FaBe independently of one another hydrogen atom (H), fluorine atom, chlorine atom, bromine atoms, methyl, ethyl, n-propyl, sec.-propyl, trifluoromethyl ,-CH
2OH, methoxyl group, oxyethyl group, positive propoxy, difluoro-methoxy, OH or MeS (O)
2-.
Preferred R
6Aa, R
6Ba, R
6Da, R
6EaAnd R
6FaIn be hydrogen atom (H) more than three.
In formula (IB), connection-(CHR
4aa)-benzyl ring be preferably unsubstituted, mono-substituted, dibasic or trisubstituted; Or preferred described benzyl ring is unsubstituted, mono-substituted or dibasic; More preferably mono-substituted or dibasic.
In formula (IB), for mono-substituted benzyl ring, preferred R
6BaOr R
6DaFor fluorine atom, chlorine atom, bromine atoms, methyl, ethyl, n-propyl, sec.-propyl, trifluoromethyl ,-CH
2OH, methoxyl group, oxyethyl group, positive propoxy, difluoro-methoxy, OH or MeS (O)
2-(preferred fluorine atom, chlorine atom, bromine atoms, methyl, ethyl, n-propyl, sec.-propyl, trifluoromethyl, methoxyl group, oxyethyl group or difluoro-methoxy), R
6Aa, R
6Ba, R
6Da, R
6EaAnd R
6FaIn remaining is H.Perhaps, for mono-substituted benzyl ring in the formula (II), preferred R
6AaCan be fluorine atom, chlorine atom, methyl, ethyl, trifluoromethyl, methoxyl group or difluoro-methoxy, and R
6Ba, R
6Da, R
6EaAnd R
6FaBe H.
In formula (IB), preferred 3 for dibasic benzyl ring, 4-two replaces, 2, and 4-two replaces, 2, and 3-two replaces, 2, and 5-two replaces or 3, the dibasic benzyl ring of 5-.For example in formula (IB), benzyl ring can be 3,4-3,5-dimethylphenyl (R
6BaAnd R
6DaBe methyl, R
6Aa, R
6EaAnd R
6FaBe H) or 2,4-3,5-dimethylphenyl (R
6AaAnd R
6DaBe methyl, R
6Ba, R
6EaAnd R
6FaBe H) or 2,5-3,5-dimethylphenyl (R
6AaAnd R
6EaBe methyl, R
6Ba, R
6DaAnd R
6FaBe H) or 3,5-3,5-dimethylphenyl (R
6BaAnd R
6EaBe methyl, R
6Aa, R
6DaAnd R
6FaBe H) or 2-fluoro-4-chloro-phenyl-(R
6AaBe fluorine atom, R
6DaBe chlorine atom, R
6Ba, R
6EaAnd R
6FaBe H) or 3-chloro-4-aminomethyl phenyl (R
6BaBe chlorine atom, R
6DaBe methyl, R
6Aa, R
6EaAnd R
6FaBe H).
In formula (IB), preferred more than 70% based on volumetric molar concentration, more preferably more than 75%, more more preferably more than 85%, also more more preferably more than 90% the compound or its salt of (for example more than 95%, for example more than 98%) at band R
4aaThree-dimensional chemical configuration shown in the carbon atom place of group has.
Preferably in formula (IB), be with R
4aaIt is (not consider the stereochemical structure of any other carbon atom) more than 50% that the stereochemical structure of the carbon atom of group should make it have enantiomer excessive (e.e.).More preferably, band R
4aaThe enantiomer of the carbon atom of group excessive (e.e.) is more than 70% or more than 80%, more preferably more than 90%, more preferably (does not consider the stereochemical structure of any other carbon atom) more than 95% again.As mentioned before, " enantiomer is excessive " percentage ratio of (e.e.) being defined as the main isomer of existence deducts the percentage ratio of the less important isomer of existence.For example, if having 95% main isomer and 5% less important isomer, then e.e. should be 90%.
Formula (IB) compound or its salt is preferably 4-{[suitable-4-(1-hydroxyethyl) cyclohexyl] amino }-N-[1-(2, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide or its salt (for example its pharmacy acceptable salt), and the described compound of 50% above volumetric molar concentration or salt are (R) three-dimensional chemical configuration at the benzylic carbon atoms place.Referring to for example hereinafter embodiment 373.
Mention hereinafter under all situations of salt, solvate, isomer, tautomer, molecular weight, synthetic method approach, medicinal use, pharmaceutical composition, dosage and combination medicine etc., also relate to/comprise formula (IB) compound or its salt of alternative formula (I) compound or its salt.
Salt, solvate, isomer, tautomer, molecular weight etc.
Because the potential medicinal use of the salt of formula (I) compound, so the salt of formula (I) compound is preferably pharmaceutically acceptable.Suitable pharmacy acceptable salt can comprise acid salt or base addition salt.
Pharmaceutically-acceptable acid addition can be prepared as follows: make formula (I) compound and suitable mineral acid or organic acid (for example Hydrogen bromide, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, succsinic acid, toxilic acid, formic acid, acetate, propionic acid, fumaric acid, citric acid, tartrate, lactic acid, phenylformic acid, Whitfield's ointment, L-glutamic acid, aspartic acid, tosic acid, Phenylsulfonic acid, methylsulfonic acid, ethyl sulfonic acid, naphthene sulfonic acid for example 2-naphthene sulfonic acid or caproic acid) choose that reaction obtains salt in suitable solvent (for example organic solvent) wantonly, generally separate with filtration by for example crystallization.The pharmaceutically-acceptable acid addition of formula (I) compound can for hydrobromate for example, hydrochloride, vitriol, nitrate, phosphoric acid salt, succinate, maleate, formate, acetate, propionic salt, fumarate, Citrate trianion, tartrate, lactic acid salt, benzoate, salicylate, glutaminate, aspartate, tosilate, benzene sulfonate, mesylate, esilate, naphthalenesulfonate (for example 2-naphthalenesulfonate) or hexanoate.
Pharmaceutically acceptable base addition salt can be prepared as follows: make formula (I) compound and suitable mineral alkali or organic bases (for example triethylamine, thanomin, trolamine, choline, arginine, Methionin or Histidine) choose reaction in suitable solvent (for example organic solvent) wantonly, obtain base addition salt, generally separate with filtration by for example crystallization.
Other suitable pharmacy acceptable salt comprises pharmaceutically acceptable metal-salt, for example pharmaceutically acceptable an alkali metal salt or alkaline earth salt, for example sodium salt, sylvite, calcium salt or magnesium salts; Especially the pharmaceutically acceptable metal-salt of one or more carboxylic moiety that may exist in formula (I) compound.
Other non-pharmacy acceptable salt (for example oxalate) can be used for for example separating The compounds of this invention, and is included in the scope of the present invention.
The scope of the invention comprises all possible stoichiometric form and the non-stoichiometric forms of the salt of formula (I) compound.
Be included in all solvates, hydrate and the complex compound that also have The compounds of this invention and salt thereof of the scope of the invention.
May there be isomer in some group of the present invention, substituting group, compound or salt.The scope of the invention comprises the isomer that all are such, comprises racemic modification, enantiomer and composition thereof.
In compound or its salt according to the present invention, pharmaceutical composition, purposes, treatment/prevention method, preparation method's etc. explanation, describe or during the isomer configuration (for example three-dimensional chemical configuration) of claimed regulation; the present invention includes mixture; described mixture comprises (a) a kind of main component; be describe or the compound or its salt of claimed configuration; and (b) one or more submembers, be not describe or the compound or its salt of the configuration of failed call protection.Preferably in such mixture; describe or the compound or its salt of claimed configuration as main component; its molecular fraction accounts for compound or more than 70% or more than 75% of salt total content in the mixture; more preferably more than 85%; again more preferably more than 90%; also more more preferably more than 95%, most preferably more than 98%.
Utilize technology known in the art can measure the percentage composition of a kind of isomer/stereochemistry component in the mixture of different isomerization body/stereochemistry component, in case of necessity, also can measure enantiomer and/or diastereomer is excessive.These methods comprise:
(1) NMR of employing chiral reagent (for example
1H NMR) method of masurement of spectrography.Can be in the presence of suitable chiral reagent, nucleus magnetic resonance (NMR) spectrum of measuring compound/salt mixture is (preferred
1H NMR spectrum, and/or solution phase NMR spectrum are for example at solvent C DCl
3Or among the D6-DMSO), chiral reagent makes the NMR peak " division " of the specific atoms in the different isomerization body be different peak positions.Chiral reagent can be i) the optically-active pure reagent, it and compound/reactant salt form for example mixture of diastereomer, ii) chiral solvent, iii) chiral molecules, it and compound/salt formation transition material (for example diastereomer), or iv) chiral shift reagent.Referring to for example J.March, " Advanced Organic Chemistry ", the 4th edition, 1992, the 125-126 pages or leaves and the reference 138-146 that wherein quotes.Chiral shift reagent can be the chirality lanthanide shift reagent; for example three [3-trifluoroacetyl group-d-camphoryl] europium-(III) or Morrill, " Lanthanide Shift Reagents in Stereochemical Analysis ", VCH; New York, 1986 other reagent of introducing.No matter use which type of chiral reagent, usually, the relative integral (intensity) at the NMR peak of specific atoms or group can be used as the measuring of relative quantity of each isomer of existence in the different isomerization body.
(2) method of masurement of employing chiral chromatography (especially analysis mode chromatogram).The suitable chiral column that separates different isomerization body component can be used for realizing separating, and for example adopts gas phase or liquid chromatography (for example HPLC) and/or analysis mode chromatogram for example.Can carry out integration (area under each peak) to the peak of each isomer; The percentage ratio that the integration contrast of the different isomerization body that exists or ratio can be measured each isomer of existence.Referring to for example: " Chiral Chromatography ", Separation Science Series Author:T.E.Beesley and R.P.W.Scott, JohnWiley ﹠amp; Sons, Ltd., Chichester, UK, 1998, e-book ISBN:0585352690, books ISBN:0471974277.
(3) adopt isolation technique such as gas-chromatography or liquid chromatography, can separate original non-enantiomer mixture (directly separate usually, need not derivatization) of The compounds of this invention/salt.Therefore, diastereomer ratio and/or excessive can obtaining according to relative peak area or isolating relative mass.
(4) use chirality/optically-active reagent to transform separating obtained subsequently isomer, for example diastereomer.Can followingly transform: but with deriveding group on compound/salt (for example-OH ,-NHR) transform with optically-active deriveding group (for example optically-active acyl chlorides or acid anhydrides); Perhaps compound is handled with optically-active acid or optically-active alkali (for example+or-two-toluoyl base tartrate), formed acid salt or base addition salt.After deriving, gained isomer (for example diastereomer) is separated with gas phase or liquid chromatography (normally achiral); Perhaps (especially containing isomer salt) can separate by a kind of isomer salt of selective crystallization (for example diastereomeric salt).The quality that can utilize peak area or measure isolating various isomer is determined isomer proportion and/or excessive.
Referring to for example J.March, " Advanced Organic Chemistry ", the 4th edition, 1992, the 120-121 pages or leaves and the 126th page, and the reference 105-115 and the 147-149 that wherein quote.
(5) opticity [α] of measurement mixture is with pure isomer [α]
MaxIf the opticity of (available) compares (for example referring to J.March, " Advanced Organic Chemistry ", the 4th edition, 1992, the 125 pages and the reference 138-139 that wherein quotes).Between this measuring method hypothesis [α] and the concentration is linear relationship basically.
May there be one or more tautomeric forms in some group of formula (I) compound or its salt (for example heteroaromatic ring system).The scope of the invention comprises the tautomeric forms that all are such, comprises mixture.
During in particular for the oral pharmaceutical purposes, the molecular weight of formula (I) compound may optionally be below 1000, for example below 800, particularly below 650, perhaps below 600.The molecular weight of this paper is meant non-solventization " free alkali " compound, does not promptly comprise the molecular weight of any additive salt, solvent (for example water) molecule etc.
The synthetic method route
Following method can be used for preparing formula of the present invention (I) compound:
Following partial synthesis method can be used R
2Formula (I) compound example explanation for hydrogen atom (H).Yet some or all these methods also can be done to be used to prepare R after the suitable modification (for example changing raw material and reagent)
2Formula (I) compound for methyl.
Method A
For preparation formula (I) compound, the carboxylic acid of formula (II) can be converted into the active compound of formula (III), wherein X
1Be the leavings group that can be replaced by amine (as giving a definition), subsequently active compound can with amine ArCR
4R
5NH
2Reaction:
For example, active compound (formula (III) compound) can be acyl chlorides (X
1=Cl).The carboxylic acid of formula (II) by for example with thionyl chloride at organic solvent (for example chloroform) or there is not under the solvent reaction, can obtain above-mentioned active compound.Perhaps, active compound (formula (III) compound) can be active ester, wherein leavings group X
1For:
Back a kind of active compound of formula (III) can be prepared as follows with the carboxylic acid of formula (II):
(a) make the reaction of carboxylic acid and carbodiimide (for example EDC) or its salt (for example hydrochloride), EDC is 1-ethyl-3-(3 '-dimethylamino-propyl) carbodiimide, also be 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide, preferably with products therefrom and I-hydroxybenzotriazole (HOBT) reaction; Solvent (preferred anhydrous solvent) for example dimethyl formamide (DMF) or acetonitrile are used in reaction (a) usually, and/or preferably adopt anhydrous condition, and/or usually at room temperature (for example about 20 ℃ to about 25 ℃) carry out; Or
(b) with Tetrafluoroboric acid 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyl-urea (TBTU) or phosphofluoric acid O-(7-azepine benzo triazol-1-yl)-N, N, N ', N '-tetramethyl-urea (HATU) reaction, alkali for example diisopropylethylamine (
iPr
2NEt=DIPEA) exist down, usually at solvent for example in the presence of dimethyl formamide (DMF) or the acetonitrile, and/or preferably at anhydrous condition and/or usually at room temperature (for example about 20 ℃ to about 25 ℃) react.
The compound of formula (II) can prepare by the ester cpds of hydrolyzing type (IV):
This method preferably makes the following reaction of compound of formula (IV):
(a) with alkali (for example sodium hydroxide or potassium hydroxide) reaction in solvent (for example aqueous solvent, for example aqueous ethanolic solution or the two alkane aqueous solution), perhaps
(b) with acid (for example hydrochloric acid) reaction in solvent (for example aqueous solvent, for example two alkane aqueous solution).
The compound of formula (IV) can according to for example Yu etc. (J.Med Chem., 2001,44, the 1025-1027) method of Jie Shaoing is by the compound and the amine R of formula V
3NH
2Prepared in reaction.The present invention preferably exists down at alkali (for example triethylamine or N, N-diisopropylethylamine), and/or (for example ethanol, two alkane or acetonitriles) carry out in organic solvent.Reactant may need to be heated to for example about 60-100 ℃ (for example about 80-90 ℃):
The compound of formula V also has introduction in above reference.They can be prepared as follows: the compound and (R that make formula (VI)
2) (OEt) C=C (CO
2R
e)
2Reaction under heating, (R
2) (OEt) C=C (CO
2R
e)
2Can be for example (oxyethyl group methylene radical) diethyl malonate (R wherein
2Be H, Re is Et) or 2-(1-oxyethyl group ethylidene) diethyl malonate (R wherein
2Be Me, Re is Et), then with phosphoryl chloride reaction under heating:
About preparing the example of the method for compound (V) by compound (VI), referring to for example: (i) the synthetic and G.Yu of mesosome 1 etc. hereinafter, J.Med Chem., 2001,44,1025-1027, wherein R
2=H, R
1=ethyl; Referring to (ii) hereinafter mesosome 10 synthetic, wherein R
2=Me, R
1=ethyl: referring to the (iii) hereinafter synthetic intermediate of mesosome 182, wherein R
2=H, R
1=methyl (being the reaction of 5-amino-1-methylpyrazole and ethoxy methylene diethyl malonate).
At required formula (VI) amino-pyrazol is not under the situation of commercially available prod, for example, adopts Dorgan etc., J.Chem.Soc., Perkin Trans.1, (4), 938-42, the method of introducing in 1980 can prepare amino-pyrazol (VI), and described method comprises makes cyano ethyl hydrazine and suitable aldehyde R
40CHO for example reacts in the ethanol at solvent, heating simultaneously, and reduction is for example for example reduced in the trimethyl carbinol at solvent with sodium then.R
40Should select to compare R
1The group of a few carbon atom, for example R
40=methyl will obtain R
1=ethyl.
Perhaps, for example, not under the situation of commercially available prod at required formula (VI) amino-pyrazol, use shown in the intermediate 170 and general reaction process shown below, can be by (different R
1) (for example intermediate 1, wherein R for the 4-chlorine 5-ester cpds of formula V
1=ethyl) the amino 5-ester/acid compound of preparation formula (IV) and 4-(II).In the method:
-optional 4-chlorine 5-ester Pyrazolopyridine (for example intermediate 1) with formula V is converted into 4-alkoxyl group (C for example
1-4Alkoxyl group, for example oxyethyl group) Pyrazolopyridine;
-slough R
1Group (is for example used N-bromo-succinimide (NBS), is preferably also used alkali, for example Na
2CO
3) (for example obtain intermediate 1A-and in following " intermediate 1A ", provided the alternate synthesis method);
-by with R
3NH
2Reaction, 4-chlorine or 4-alkoxyl group are fallen in displacement, thereby insert 4-amino N HR
3Group;
-make gained Pyrazolopyridine and R
1-X
41Reaction and in the alkylation of N-1 place, X wherein
41For can be by the N-1 nitrogen metathetical group of Pyrazolopyridine, so that insert needed R again
1Group [being the amino 5-ester cpds of 4-of preparation formula (IV)].X
41Can be for example halogen, for example Cl, Br or I; Or X
41Can be-O-S (O)
2-R
41, R wherein
41Be C
1-4Alkyl, C
1-2Fluoro-alkyl or optional by C
1-2The phenyl that alkyl replaces.With R
1-X
41The N-1 alkylated reaction be preferably in alkali and carry out under existing, about the example of appropriate base, be converted into the reaction of (IV) referring to following (IX).
Following flow process (intermediate 170 flow processs) has shown about sloughing R
1Again the suitable exemplary route and the condition of insertion reaction route are inserted R
1=n-propyl, R
3=tetrahydrochysene-2H-pyrans-4-base:
In a kind of alternate embodiment of method A, the 4-chlorine substituent of the compound of formula V can be replaced by another halogen atom (for example bromine atoms) or can be by amine R by another
3NH
2The suitable leavings group displacement of metathetical.Can be the R in for example formula (Va) compound by amine metathetical leavings group
LA, R wherein
LABe alkoxyl group OR
35(OC for example
1-4Alkyl, particularly OEt) or-O-S (O)
2-R
37Here, R
37Be C
1-8Alkyl (C for example
1-4Alkyl or C
1-2Alkyl, for example methyl), C
1-6Fluoro-alkyl (C for example
1-4Fluoro-alkyl or C
1-2Fluoro-alkyl, for example CF
3Or C
4F
9) or phenyl, wherein said phenyl is optional to be that following group replaces: C by 1-2 independently
1-2Alkyl, halogen or C
1-2Alkoxyl group (for example phenyl or 4-methyl-phenyl).Formula (Va) compound and amine R
3NH
2Reaction in can use or not use solvent, and may need the heating:
In the another kind of alternate embodiment of method A, the compound of above-mentioned formula (IV) can be prepared as follows: the compound and the alkylating agent R that make formula (IX)
1-X
3Reaction, wherein X
3For can be by 1 nitrogen-atoms metathetical leavings group of Pyrazolopyridine in formula (IX) compound:
Can use suitable R
1-X
3Alkylating agent.For example, X
3Can be halogen atom, for example chlorine atom or preferred bromine atoms or iodine atom, perhaps X
3Can be-O-S (O)
2-R
36, R wherein
36Be C
1-8Alkyl (C for example
1-4Alkyl or C
1-2Alkyl, for example methyl), C
1-6Fluoro-alkyl (C for example
1-4Fluoro-alkyl or C
1-2Fluoro-alkyl, for example CF
3Or C
4F
9) or phenyl, wherein said phenyl is optional to be that following group replaces: C by 1-2 independently
1-2Alkyl, halogen or C
1-2Alkoxyl group (for example phenyl or 4-methyl-phenyl).This reaction is preferably under the alkali existence to be carried out, described alkali can comprise or be for example salt of wormwood, yellow soda ash, sodium hydride, potassium hydride KH, basic resin or alkaline polymer, the 2-of conjugated polymer tertbutylimido-2-diethylin-1 for example, 3-dimethyl-1,3-diaza-2-phospha cyclohexane.This reaction is preferably in solvent and for example carries out under organic solvent (for example DMF) existence; Preferred anhydrous solvent.
The compound of formula (IX) can prepare according to the similar approach by formula V compound formula (IV) compound: make formula (X) compound (except R
1Outside=the H, identical with the formula V compound) and amine R
3NH
2Reaction.This reaction is preferably in alkali (for example triethylamine or N, N-diisopropylethylamine) and exists down and/or carry out in organic solvent (for example ethanol, two alkane or acetonitriles).This reaction may need to be heated to for example about 60-100 ℃, for example about 80-90 ℃:
Perhaps, in formula (X), 4-chlorine can be by 4-C
1-4Alkoxyl group (for example 4-oxyethyl group) displacement; Formula (Xa) compound after these are modified can be chosen preparation according to the method described above wantonly, for example referring to intermediate 170 flow processs of above demonstration, description or intermediate 1A hereinafter.
Method B
The compound of formula (I) can through type (VII) compound and amine R
3NH
2Prepared in reaction.In formula (VII) compound, R
LBFor can be by amine R
3NH
2Metathetical leavings group metathetical leavings group.R
LBCan be bromine atoms (Br) or more preferably chlorine atom (Cl), perhaps R
LBCan be alkoxyl group OR
35(OC for example
1-4Alkyl, particularly OEt) or-O-S (O)
2-R
37Here, R
37Be C
1-8Alkyl (C for example
1-4Alkyl or C
1-2Alkyl, for example methyl), C
1-6Fluoro-alkyl (C for example
1-4Fluoro-alkyl or C
1-2Fluoro-alkyl, for example CF
3Or C
4F
9) or phenyl, wherein said phenyl is optional to be that following group replaces: C by 1-2 independently
1-2Alkyl, halogen or C
1-2Alkoxyl group (for example phenyl or 4-methyl-phenyl).Preferably (VII) reaction of being converted into (I) is preferably in alkali (for example triethylamine or N, N-diisopropylethylamine) and exists down and/or carry out in organic solvent (for example ethanol, THF, two alkane or acetonitriles).This reaction may need to be heated to for example about 60-100 ℃, and for example about 80-90 ℃, and need for example 8-48 hour or 12-24 hour:
R
LBFor formula (VII) compound (being formula (VIIa) compound) of chlorine atom can according to Bare etc. (J.Med.Chem., 1989,32,2561-2573) method of Jie Shaoing prepares in two steps.This method comprises 2 steps.In a first step, make formula (VIII) compound and thionyl chloride (the perhaps another kind of reagent that is fit to generate acyl chlorides) reaction, be reflected in the organic solvent (for example chloroform or THF) or and carry out with purified solution by carboxylic acid.This reaction may need heating, the intermediate that forms thus can be separated or do not separate.Second step related to and amine ArCR
4R
5NH
2Reaction in organic solvent (for example THF or chloroform), also can use alkali, for example triethylamine or diisopropylethylamine:
Can be according to (J.Med Chem., 2001,44, the 1025-1027) method of Jie Shaoing, preparation formula (VIII) compounds such as Yu by the ester of hydrolysis formula V.This step is preferably reacted in solvent (for example aqueous solvent, for example aqueous ethanolic solution or the two alkane aqueous solution) with alkali (for example sodium hydroxide or potassium hydroxide):
The A preparation according to the method described above of formula V compound.
Method C
Formula (I) compound can be prepared as follows: make formula (IXa) compound and alkylating agent R
1-X
3Reaction, wherein X
3For can be by 1 nitrogen-atoms metathetical leavings group of Pyrazolopyridine in formula (IXa) compound:
Can use suitable R
1-X
3Alkylating agent.For example, X
3Can be halogen atom, for example chlorine atom or preferred bromine atoms or iodine atom, perhaps X
3Can be-O-S (O)
2-R
36, R wherein
36Be C
1-8Alkyl (C for example
1-4Alkyl or C
1-2Alkyl, for example methyl), C
1-6Fluoro-alkyl (C for example
1-4Fluoro-alkyl or C
1-2Fluoro-alkyl, for example CF
3Or C
4F
9) or phenyl, wherein said phenyl is optional to be that following gene replaces: C by 1-2 independently
1-2Alkyl, halogen or C
1-2Alkoxyl group (for example phenyl or 4-methyl-phenyl).This reaction is preferably under the alkali existence to be carried out, described alkali can comprise or be for example salt of wormwood, yellow soda ash, sodium hydride, potassium hydride KH, basic resin or alkaline polymer, the 2-of conjugated polymer tertbutylimido-2-diethylin-1 for example, 3-dimethyl-1,3-diaza-2-phospha cyclohexane.This reaction is preferably in solvent and for example carries out under organic solvent (for example DMF) existence; Preferred anhydrous solvent.
Formula (IXa) compound can be by formula (IX) compound:
The elder generation ester hydrolysis (IX), then by the activation gained carboxylic acid and with amine ArCR
4R
5NH
2Reaction, thus be converted into acid amides (IXa).Can suitably use among the aforesaid method A by the conversion of (IV) → (II) → (III) → (I) mentioned reagent and reaction conditions by the conversion of ester (IX) → acid → acid amides (IXa).
The method preparation that the ester cpds of formula (IX) is described in the alternate embodiment of A according to the method described above.
Method D: the method that a kind of formula (I), (II) or compound or its salt (IV) is converted into another kind of formula (I), (II) or compound or its salt (IV)
A kind of formula (I), (II) or compound or its salt (IV) (or its protected compound, for example compound of N protection, for example compound of BOC-N-protection) can be converted into another kind of formula (I), (II) or compound or its salt (IV).This conversion preferably include or following D1-D7 in one or more methods:
D1. ketone is converted into the method (for example embodiment 231-281) of corresponding oxime.
D2. method for oxidation, for example method for oxidation can comprise or: alcohol is oxidized to ketone (for example using Jones reagent) or alcohol or oxidation of ketones is carboxylic acid.Described method for oxidation can comprise or nitrogenous formula (I) compound or its salt is converted into corresponding N-oxide compound (for example using metachloroperbenzoic acid), the compound that for example will contain pyridine is converted into corresponding pyridine N-oxide compound (about the detailed introduction of appropriate method, referring to for example embodiment 210-212 of the PCT/EP03/11814 (WO 2004/024728 A2) of application on September 12nd, 2003, be attached to this paper by reference).
D3. method of reducing for example is reduced to alcohol with ketone or carboxylic acid.
D4. process for acylating; for example acylated amine is (about the detailed introduction of appropriate method; embodiment 329-349 and embodiment 353 referring to the PCT/EP03/11814 (WO 2004/024728 A2) of application on September 12nd, 2003 for example are attached to this paper by reference), perhaps acidylate hydroxyl.
D5. alkylation, for example alkylated amines or hydroxyl.
D6. method for hydrolysis, for example ester is hydrolyzed to corresponding carboxylic acid or its salt (about the detailed introduction of appropriate method, referring to for example embodiment 351,488,489,650,651 of the PCT/EP03/11814 (WO 2004/024728 A2) of application on September 12nd, 2003, be attached to this paper by reference).
D7. deprotection method, for example protection of deaminize (for example de-acyl reaction or slough tertbutyloxycarbonyl (BOC)).Slough BOC and can (for example use hydrogenchloride) under acidic conditions and carry out in organic solvent (for example two alkane), the embodiment 381 and 382 of this paper is examples of such BOC removal methods.
D8. generate ester or acid amides method, for example adopt corresponding carboxylic acid.
D9. Sulphonylation method; for example generate sulphonamide (about the detailed introduction of appropriate method by amine and sulfonic acid halide (for example SULPHURYL CHLORIDE) reaction; referring to for example embodiment 322-328 of the PCT/EP03/11814 (WO 2004/024728 A2) of application on September 12nd, 2003, be attached to this paper by reference).
And/or
D10. a formula (I) compound is reset through Beckmann and is another kind of formula (I) compound, for example use cyanuryl chloride (2,4,6-three chloro-1,3,5-triazine) and methane amide (for example DMF) reaction under room temperature for example (referring to L.D.Luca, J.Org.Chem., 2002,67,6272-6274).Beckmann resets and can comprise for example with NHR
3Be formula (o2)
Formula (I) compound be converted into NHR
3Be formula (m3)
Formula (I) compound, suitable concrete grammar is the example explanation in the embodiment 658 and 659 of the PCT/EP03/11814 (WO 2004/024728 A2) of on September 12nd, 2003 application, the document is attached to this paper by reference.
Therefore, the present invention also provides the method for a kind of preparation formula (I) compound or its salt:
R wherein
1, R
2, R
3, R
4, R
5With Ar as herein definition, described method comprises:
(a) make the active compound of formula (III),
X wherein
1For can be by amine metathetical leavings group, with amine ArCR
4R
5NH
2Reaction;
(b) make formula (VII) compound:
R wherein
LBFor can be by amine R
3NH
2The metathetical leavings group is with amine R
3NH
2Reaction;
(c) make formula (IXa) compound and alkylating agent R
1-X
3Reaction, wherein X
3For can be by 1 nitrogen-atoms metathetical leavings group of Pyrazolopyridine in formula (IXa) compound:
Perhaps
(d) a kind of formula (I) compound or its salt (or its protected compound, for example compound of N protection, for example compound of BOC-N-protection) is converted into another kind of formula (I) compound or its salt;
Choose wantonly formula (I) compound is converted into salt, for example pharmacy acceptable salt.
Method (a) and (b), (c) and preferred or optional feature (d) are the feature that aforesaid method A, B, C and D describe independently of one another, can do the change that is necessary simultaneously.
The present invention also provides: (e) method of the pharmacy acceptable salt of a kind of preparation formula (I) compound, this method comprise formula (I) compound or its salt are converted into its required pharmacy acceptable salt (referring to the embodiment 307 of for example this paper).
The present invention also provides the method that is provided by this paper prepared formula (I) compound or its salt.
Medicinal use
The present invention also provides formula (I) compound or its pharmacy acceptable salt to be used as the active treatment material of Mammals (for example people).Described compound or salt can be used for the treatment of and/or prevent any disease/illness described herein (for example to be used for the treatment of and/or to prevent Mammals for example people's inflammatory diseases and/or allergic disease; Or for example be used for the treatment of and/or prevent Mammals for example people's cognitive decline or dysthymia disorders) and/or as phosphodiesterase inhibitor (for example as phosphodiesterase 4 (PDE4) inhibitor)." treatment " can comprise and treating and/or preventing.
Formula (I) compound or its pharmacy acceptable salt purposes in preparation medicine (for example pharmaceutical composition) also is provided, described medicine is used for the treatment of and/or prevents any Mammals described herein (for example people) disease/illness, for example be used for the treatment of and/or prevent Mammals for example the people inflammatory diseases and/or allergic disease or be used for the treatment of and/or prevent mammiferous cognitive decline or dysthymia disorders.
A kind of method that treats and/or prevents any disease/illness described herein that needs this Mammals that treats and/or prevents (for example people) also is provided, the for example a kind of inflammatory diseases of this Mammalss that treat and/or prevent of needs (for example people) and/or method of allergic disease, cognitive decline or dysthymia disorders for the treatment of and/or preventing, this method comprise formula (I) compound or its pharmacy acceptable salt of this paper definition that gives described Mammals (for example people) treatment significant quantity.
Phosphodiesterase 4 inhibitors is considered to can be used for treating and/or preventing multiple disease/illness of Mammals (for example people), especially inflammatory diseases and/or allergic disease, for example asthma, chronic obstructive pulmonary disease (COPD) (for example chronic bronchitis and/or pulmonary emphysema), atopic dermatitis, urticaria, rhinallergosis, allergic conjunctivitis, vernal conjunctivitis, eosinophilic granuloma, psoriasis, rheumatoid arthritis, septic shock, ulcerative colitis, Crohn disease (Crohn ' s disease), the reperfusion injury of cardiac muscle and brain, chronic glomerulonephritis, endotoxin shock, adult respiratory distress syndrome, multiple sclerosis, cognitive decline (for example neurology department's disorders such as alzheimer s disease (Alzheimer ' s disease) cause cognitive decline), dysthymia disorders or pain (for example inflammatory pain).Ulcerative colitis and/or Crohn disease are referred to as inflammatory bowel usually.
In treating and/or preventing, described inflammatory diseases and/or allergic disease are preferably chronic obstructive pulmonary disease (COPD), asthma, rheumatoid arthritis, rhinallergosis or the atopic dermatitis of Mammals (for example people).In treating and/or preventing, described inflammatory diseases and/or allergic disease are preferably chronic obstructive pulmonary disease (COPD), asthma, rheumatoid arthritis or the rhinallergosis of Mammals (for example people).More preferably treat and/or prevent Mammals (for example people's) COPD or asthma.
The PDE4 inhibitor be considered to effectively to treat asthma (for example referring to M.A.Giembycz, Drugs, in February, 2000,59 (2), 193-212; Z.Huang etc., Current Opinionin Chemical Biology, 2001,5:432-438; H.J.Dyke etc., Expert Opinionon Investigational Drugs, in January, 2002,11 (1), 1-13; C.Burnouf etc., Current Pharmaceutical Design, 2002,8 (14), 1255-1296; A.M.Doherty, Current Opinion Chem.Biol., 1999,3 (4), 466-473; P.J.Barnes, Naure Reviews-Drug Discovery, in October, 2004,831-844; And the reference of wherein quoting).
PDE4 inhibitor (for example cilomilast and roflumilast) be considered to effectively to treat COPD (for example referring to S.L.Wolda, Emerging Drugs, 2000,5 (3), 309-319; Z.Huang etc., Current Opinion in Chemical Biology, 2001,5:432-438; H.J.Dyke etc., Expert Opinion on Investigational Drugs, in January, 2002,11 (1), 1-13; C.Burnouf etc., Current Pharmaceutical Design, 2002,8 (14), 1255-1296; A.M.Doherty, Current Opinion Chem.Biol., 1999,3 (4), 466-473; A.M.Vignola, Respiratory Medicine, 2004,98,495-503; D.Spina, Drugs, 2003,63 (23), 2575-2594; And the reference of wherein quoting; G.Krishna etc., Expert Opinion on Investigational Drugs, 2004,13 (3), 255-267 (especially referring to 259-261 page or leaf and reference 102-111 and 201 wherein).The feature of COPD be usually owing to chronic bronchitis and/or pulmonary emphysema exist airflow obstruction (for example referring to S.L.Wolda, Emerging Drugs, 2000,5 (3), 309-319).
The PDE4 inhibitor is considered to effectively to treat rhinallergosis (for example referring to B.M.Schmidt etc., J.Allergy ﹠amp; Clinical Immunology, 108 (4), 2001,530-536).
The PDE4 inhibitor is considered to effectively to treat rheumatoid arthritis and multiple sclerosis (for example referring to H.J.Dyke etc., Expert Opinion on Investigational Drugs, in January, 2002,11 (1), 1-13; C.Burnouf etc., Current Pharmaceutical Design, 2002,8 (14), 1255-1296; A.M.Doherty, Current Opinion Chem.Biol., 1999,3 (4), 466-473; And the reference of wherein quoting).
To the application of atopic dermatitis referring to for example A.M.Doherty, Current OpinionChem.Biol., 1999,3 (4), 466-473; And the reference of wherein quoting.
For treating and/or preventing atopic dermatitis, can adopt topical administration mode (for example topical administration skin (skin of for example getting involved)).
The PDE4 inhibitor is considered to have the pain relieving characteristic, can effectively treat thus pain (A.Kumar etc., Indian J.Exp.Biol., 2000,38 (1), 26-30).
In the present invention, can treat and/or prevent cognitive decline, for example the cognitive decline that causes of neurology department's disease (for example alzheimer's disease).For example described treating and/or preventing can comprise the cognitive ability that improves the neuropath.Referring to for example H.T.Zhang etc., Psychopharmacology, in June, 2000,150 (3), 311-316; And Neuropsychopharmacology, 2000,23 (2), 198-204; T.Egawa etc., JapaneseJ.Pharmacol., 1997,75 (3), 275-81.
PDE4 inhibitor (for example rolipram) is considered to have antidepressant characteristic (J.Zhu etc. for example, CNS Drug Reviews, 2001,7 (4), 387-398; O ' Donnell, Expert Opinionon Investigational Drugs, 2000,9 (3), 621-625; H.T.Zhang etc., Neuropsychopharmacology, in October, 2002,27 (4), 587-595; J.M.O ' Donnell and H.-T.Zhang, Trends Pharmacol.Sci., in March, 2004,25 (3), 158-163; T.E.Renau, Curr.Opinion Invest.Drugs, 2004,5 (1), 34-39).
The PDE4 inhibitor is proposed to be used in treatment inflammatory bowel (for example ulcerative colitis and/or Crohn disease), referring to K.H.Banner and M.A.Trevethick, and Trends Pharmacol.Sci., in August, 2004,25 (8), 430-436.
Pharmaceutical composition and administration
For medicinal use, The compounds of this invention is usually with the pharmaceutical composition administration.
Therefore, the present invention provides a kind of pharmaceutical composition on the other hand, and described composition comprises formula (I) compound or its pharmacy acceptable salt and one or more pharmaceutically acceptable carrier and/or vehicle.
Described pharmaceutical composition can be used for treating and/or preventing any disease described herein.
The present invention also provides a kind of method of pharmaceutical compositions, described composition comprises formula (I) compound or its pharmacy acceptable salt and one or more the pharmaceutically acceptable carrier and/or the vehicle of this paper definition, and described method comprises with described compound or its salt and one or more pharmaceutically acceptable carriers and/or mixed with excipients together.
The present invention also provides the pharmaceutical composition by described method preparation.
Formula (I) compound and/or pharmaceutical composition can be by for example oral, parenteral (for example intravenously, subcutaneous or intramuscular), suctions, part (for example local skin) or intranasal administrations.Therefore, described pharmaceutical composition preferably is fit to oral, parenteral (for example intravenously, subcutaneous or intramuscular), suctions, part (for example local skin) or intranasal administration.
More preferably, described pharmaceutical composition be fit to suck or orally give Mammals (for example people) for example.Inhalation comprises by for example aerosol or dry powder composite topical administration lung.
Suitable pharmaceutical composition for oral administration can be liquid or solid; For example it can be syrup, suspensoid, emulsion, tablet, capsule or lozenge.
Suspension or solution that liquid preparation (for example oral preparations) is made of in suitable pharmaceutically acceptable liquid vehicle described compound or its pharmacy acceptable salt usually, described carrier is for example aqueous solvent (for example water, ethanol or glycerine) or non-aqueous solvent (for example polyoxyethylene glycol or oil).Described preparation also can comprise suspension agent, sanitas, correctives and/or tinting material.
In one embodiment, described pharmaceutical composition is unit dosage, for example is used for the oral administration tablet or the capsule of (for example being used for the orally give people).
Be fit to carrier and/or vehicle that the pharmaceutical composition for oral administration tablet can comprise one or more pharmaceutically acceptable suitable preparation tablets.For example, such carrier can be or comprise lactose, Mierocrystalline cellulose (for example Microcrystalline Cellulose) or N.F,USP MANNITOL.Described tablet can also contain or alternative one or more pharmaceutically acceptable vehicle that contains, tackiness agent (for example Vltra tears or polyvidone (Povidone)) for example, lubricant is stearic acid alkaline earth salt (for example Magnesium Stearate) for example, and/or tablet disintegrant for example sodium starch glycolate, croscarmellose sodium or Crospovidone (cross-linked pvp).When described pharmaceutical composition was tablet, its preparation method comprised the steps: that (i) mixes formula (I) compound or its pharmacy acceptable salt of this paper definition with one or more pharmaceutically acceptable carriers and/or vehicle; (ii) gained mixture (it is powder type usually) is pressed into tablet and (iii) optional usefulness tablet coated fertilizer to described tablet coating.
Being fit to the pharmaceutical composition for oral administration capsule can prepare with the encapsulated method.For example can comprise the particle or the powder of activeconstituents with suitable pharmaceutically acceptable preparing carriers, be filled into hard gelatine capsule then.Perhaps, can then dispersion or suspension be filled into soft gelatin capsule with any suitable pharmaceutically acceptable carrier (for example water-based natural gum or oil) preparation dispersion or suspension.
The parenteral composition can comprise described compound or solution or the suspensoid of pharmacy acceptable salt in sterile aqueous carrier or the acceptable oil of parenteral.Perhaps, can be with described solution lyophilize; Cold dried parenteral pharmaceutical composition can be rebuild with suitable solvent before administration.
Local medicine composition (for example skin local medicine composition) can or contain the solution of DMSO, for example DMSO/ acetone soln agent (DMSO=methyl-sulphoxide) for for example ointment, ointment (being the oil-in-water pharmaceutical composition), aqueous gel.Local medicine composition (for example oil-in-water composition) can be chosen wantonly and comprise skin penetration toughener (for example propylene glycol), and/or (for example being used for the oil-in-water composition) emulsifying agent (for example tensio-active agent) sodium lauryl sulphate (SDS) for example.Topical ointments can comprise for example polyoxyethylene glycol and/or propylene glycol.In local medicine composition (for example ointment or oil-in-water composition), formula (I) compound or its salt accounts for composition total weight and may optionally be 0.25-5%, for example 0.5-2.5%.In local medicine composition, formula (I) compound or its salt may optionally be compound or its pharmacy acceptable salt of embodiment 73,75,98,283,304,306,307,310,311,316,321,324,326,327,328,330,331,332,333,334,335,336,337,338,339,343,344 or 345.For example, local medicine composition (for example skin local medicine composition) can be used for the treatment of and/or prevent for example atopic dermatitis of Mammals (for example people).
Nose composition interior or inhalation can be formulated as aerosol, drops, gelifying agent or dry powder doses easily.
Aerosol (aerosol that for example is used for inhalation) can comprise solution or the fine suspension of active substance at pharmaceutically acceptable water-based or non-aqueous solvent.Aerosol can single dose or the sterile form of multidose be loaded on closed container, described container can be for cartridge case or is loaded form again, preparation is for atomisation unit or sucker use.Perhaps, described closed container can be the single assigned device, and the aerosol injector (metered-dose inhaler) of sucker or outfit metering valve just abandons this device in case container contents exhausts in for example disposable nose.
When described formulation comprises the aerosol injector, preferably comprise suitable pressure propellent for example pressurized air, carbonic acid gas or organic propellent such as Chlorofluorocarbons (CFCs) (CFC) or hydrogen fluorohydrocarbon (HFC).Appropriate C FC propellent comprises Refrigerant 12, trichlorofluoromethane and dichloro tetrafluoro ethane.Appropriate H FC propellent comprises 1,1,1,2,3,3,3-heptafluoro-propane and 1,1,1,2-Tetrafluoroethane.Aerosol also can adopt pump spraying gun form.
Make the particle size reduction of formula (I) compound or its salt
For the pharmaceutical composition that is fit to and/or is fit to inhalation after adjusting, preferred formula (I) compound or its salt is a particulate form, and more preferably particulate form is obtained by micronization processes, perhaps can be obtained by micronization processes.Micronization processes normally makes compound/salt produce collision and/or friction in the circulation of quick travel or spiral/spiral type air-flow, generally includes cyclone separator.The preferred size of particulate (for example micronized) compound or salt (for example D50 value) is about 0.5 micron to about 10 microns, for example about 1 micron to about 7 microns or about 1 micron to about 5 microns (for example using laser diffraction measurement).For example preferred formula (I) compound or salt have with undefined granularity: D10, about 0.3 micron to about 3 microns (for example about 0.5 micron to about 2 microns, perhaps about 1 micron), and/or D50, about 0.5 micron to about 10 microns or about 1 micron to about 7 microns (for example about 1 micron to about 5 microns or about 2 microns to about 5 microns or about 2 microns to about 4 microns), and/or D90, about 1 micron to about 30 microns, perhaps about 2 microns to about 20 microns, perhaps about 2 microns to about 15 microns, perhaps about 3 microns to about 15 microns (for example about 5 microns to about 15 microns or about 5 microns to about 10 microns or about 2 microns to about 10 microns); For example use determination of laser diffraction.
In granulometry, D90, D50 and D10 are meant that respectively 90%, 50% and 10% described material is less than the micron granularity of stipulating.D50 is a median particle size.DV90, DV50 and DV10 are meant that respectively the described material that accounts for cubic capacity 90%, 50% and 10% is less than the micron granularity of stipulating.DM90, DM50 and DM10 are meant that respectively the described material that accounts for gross weight 90%, 50% and 10% is less than the micron granularity of stipulating.
The laser diffraction of granularity detects can adopt dry method (compound/salt that is suspended in air-flow passes laser beam) or wet method [compound/salt that is suspended in liquid dispersion medium (for example octane-iso (for example when compound dissolves in octane-iso) or 0.1% tween 80/water) passes laser beam].When detecting, preferably adopt Fraunhofer arithmetic calculation granularity with laser diffraction; And/or preferably use MalvernMastersizer or Sympatec device to detect.For example, during by laser diffraction detection and/or analysis granularity, can adopt following any or all of (preferably whole) condition: MalvernMastersizer longbed version, dispersion medium 0.1% tween 80/water, the about 1500rpm of stir speed (S.S.), about 3 minutes of first supersound process is disperseed at last and is analyzed, 300RF (inverse-Fourier) lens, and/or carry out Fraunhofer with Malvern software and calculate.
Provide the non-limiting example of micronization technology on a small scale below:
Micronization embodiment: embodiment 73,75,98,283,304,306,307,308,309,310,311,312,313,314,314A or 333 micronization
● purpose: use Jetpharma MC1 micronizer, the about 600-1000mg embodiment 73,75,98,283,304,306,307,308,309,310,311,312,313,314 of micronization, 314A or 333 (seeing below).
● by the granularity of laser diffraction analysis starting raw material (not micronized) and micronized raw material, analyze degree of crystallinity with PXRD.
Equipment and material
Equipment/raw material explanation and specification
Jetpharma MC1 micronizer nitrogenous source: the gas tank of band 275psi pipe
Analytical balance Sartorius Analytical
Top material loading balance Mettler PM400
Digital display calliper VWR electronic caliper
Treat micronization raw material embodiment 307
(schedule of operation 1-implements)
Treat micronization raw material embodiment 73, embodiment 75, embodiment 283
(substituting or embodiment 333 of schedule of operation 1
Embodiment-implement)
Treat micronization raw material embodiment 73,98,283,304,306,307,
308、309、310、311、312、313、
314 or 314A
(schedule of operation 2-does not implement)
Jetpharma MC1 micronizer comprises horizontal plate-like pulverizer body, and pulverizer is equipped with: be used to import tubulose compound inlet (for example the angle with horizontal plane is about 30 degree), the input gas of not micronized formula (I) compound that is suspended in air-flow or salt the separate gas inlet, discharge the pneumatic outlet of gas and collect the collection container of micronization raw material (micronizer container).Pulverize body two chambers are arranged: (a) outer annular chamber that communicates with the gas inlet is used to receive pressurized gas (for example air or nitrogen); (b) the inner crushiing chamber of disc is coaxial with the mistress, is used for compound/salt that micronization is imported, and two chambers are spaced apart by annular wall.Annular wall (ring R) has hole, many small-bores to connect inside and outside two Room, along the annular wall circumferentially-spaced.Open to inner room in each hole (blowing angle along between radial direction and the tangential direction) at a certain angle, and as nozzle, the guiding pressurized gas to be entering inner room from the mistress at a high speed, and along inner room (cyclone) to center convolution motion (vortex).The compound inlet transmits with air-flow through nozzle and inner room, and nozzle is towards the tangent direction of inner room, in the annular wall the inside and near annular wall/ring R.The upper and lower major diameter outlet of inner crushiing chamber central shaft is connected to (a) (lower part outlet) collection container, and it does not have air, (b) (top outlet) pneumatic outlet.Be used for the Venturi tube (V) that gas is imported inner placement of tubulose compound inlet, and can vertically moving.The compound inlet also has a branch connection feed(raw material)inlet up, is used for charging.
In use, below the narrow end of Venturi tube (V) preferably is placed on, and a bit in end front, feed(raw material)inlet, like this when Venturi tube (V) transporting compressed gas body (for example air or nitrogen), the raw material that adds is sucked into air-flow by the compound inlet, quickens to make raw material enter inner crushiing chamber with subsonic speed in tangential direction.In crushiing chamber, raw material is further quickened to reach supersonic speed by crushiing chamber annular wall (R) aperture/nozzle system on every side.Slightly the inching nozzle angle makes the raw material that quickens with center vortex or the motion of cyclone form.Raw material in the crushiing chamber rotates rapidly, and particle collides mutually in this process, makes to be broken for than small-particle than macroparticle." centrifugal " booster action of vortex is feasible to be positioned at the outer peripheral portion of inner room than macroparticle, and shifts to the center gradually up to discharging crushiing chamber than small-particle, discharges with low pressure, low speed by lower part outlet usually.The particle of discharging crushiing chamber is heavier than air, and enters collection container (micronizer container) by lower part outlet after the sedimentation, and waste gas rises (comprise minority pulverize the subparticle of raw material), with low pressure, low velocity discharge in atmosphere.
Schedule of operation:
Micronizer is installed.The narrow end of Venturi tube is placed on below the end of feed(raw material)inlet and more forward, with the measurement of microcaloire chi to guarantee correct insertion.The pressure of described ring (R) and Venturi tube (V) is adjusted to experimental design part (referring to following experimental section) specified value, regulate by the valve on the micronizer pressure warning unit.Whether whether observing the pressure warning unit reading has any fluctuation, leak with inspection units.
Note keeping Venturi tube (V) pressure ratio annular wall (R) pressure at least 2 crust greatly, reflux, for example emerge from the feed(raw material)inlet to prevent raw material.
Check the balance performance with standard weights.The feed containers that the raw material (referring to the experimental implementation part, being used for the schedule of operation 1 of embodiment 307) of specified amount is added micronizer with spoon.Feed containers and raw material are weighed.Monitoring equipment pressure in micronization process.
After finishing micronization, close nitrogenous source, the raw material after the micronization is deposited to the micronizer container then.With the micronised powder of micronizer container (collection container) and cyclone (on returnable) collect together weighed and the collection vial of mark in.The weight of record micronization raw material.In order to calculate and import the difference of material quantity, weighing feed containers once more.Take micronizer apart,, collect in the flask with the residual PDE4 compound of 70/30 isopropanol flushing micronizer internal surface.Clean micronizer up hill and dale with the Lancer cleaning machine then, after drying, carry out later operation again.
Optional experiment parameter
The experiment parameter of schedule of operation 1: embodiment 307 and result
This experiment (schedule of operation 1) adopts the compound of embodiment 307 to carry out micronization, schedule of operation and device or its similar operation program and the device of the above general introduction of general employing, and the experiment parameter below main the use has obtained following experimental result:
Operation | Raw material add-on (g) | The pressure (crust) of Venturi tube (V)/ring (R) | Granularity data (micron) (not micronized raw material) | Granularity data (micron) (micronized raw material) | The rate of recovery of micronized raw material * |
1 | About 0.9g | V=5-7 crust R=3-4 crust | D10=2.48 D50=8.98 D90=24.14 | D10=0.84 D50=1.56 D90=2.74 | 58% |
Raw material in raw material+cyclone in the yield %=[(collection container)/raw material that adds] * 100
Usually, use this method yield can reach about 50-75%, comprise from the raw material of collection container and cyclone inwall.
Those of skill in the art use the knowledge of grasp can change above-mentioned optional parameter.
In another embodiment of schedule of operation 1, adopt the schedule of operation 1 of conditions of similarity and variation program also to be used for following embodiment usually:
Embodiment 73
Embodiment 75
Embodiment 283
Embodiment 333.
Schedule of operation 2: optional experiment parameter
Starting raw material (not micronized) (schedule of operation 2): embodiment 73,98,283,304,306,307,308,309,310,311,312,313,314 or 314A (noting-do not implement)
Balance Sartorius analytical balance
Operation | Raw material add-on (g) | The pressure (crust) of Venturi tube (V)/ring (R) | The feeding rate of expection | Note |
2 | About 0.9g | V=8-10 crust R=5.5-6 crust | 180-200mg/min | Note not enforcement of schedule of operation 2 |
Those of skill in the art use the knowledge of grasp can change above-mentioned optional parameter.
Schedule of operation 2 comprises possible parameter and condition and the micronized embodiment of possibility, but does not implement.
Other embodiment: any embodiment of compound or its salt disclosed by the invention chooses micronization according to the method described above wantonly.
Dry powder inhalation composition
For the pharmaceutical composition that is fit to and/or is fit to inhalation after adjusting, preferred pharmaceutical compositions is a dry powder inhalation composition.Such composition can comprise powder base for example lactose or starch, formula (I) compound or its salt (preferred particulate form, for example micronization form) and optional performance modifier such as L-leucine, N.F,USP MANNITOL, trehalose and/or Magnesium Stearate.Preferred dry powder inhalation composition comprises the powder mixture of lactose and formula (I) compound or its salt.Preferred lactose hydrate of lactose (for example lactose monohydrate) and/or preferred level and/or the purified grade lactose of sucking.Preferred lactose size definition is as follows: the lactose granule diameter of (in weight or meausurement) is less than 1000 microns (for example 10-1000 micron such as 30-1000 microns) 90% or more, and/or the lactose granule diameter more than 50% is less than 500 microns (for example 10-500 microns).Preferred lactose size definition is as follows: the lactose granule diameter more than 90% is less than 300 microns (for example 10-300 micron such as 50-300 microns), and/or the lactose granule diameter more than 50% is less than 100 microns.The optionally lactose granularity is defined as follows: the lactose granule diameter more than 90% is less than the 100-200 micron, and/or the lactose granule diameter more than 50% is less than the 40-70 micron.The most important thing is, preferred about 3% to the lactose granule diameter of about 30% (for example about 10%) (in weight or meausurement) less than 50 microns or less than 20 microns.For example, suitable suction level lactose has E9334 lactose (10% fines) (Borculo Domo Ingredients, Hanzeplein 25,8017 JDZwolle Netherlands), but is not limited thereto.
In dry powder inhalation composition, preferred formula (I) compound or its salt account for composition weight about 0.1% to about 70% (for example about 1% to about 50%, for example about 5% to about 40%, for example about 20 to about 30%).
Be the limiting examples of dry powder inhalation composition below:
Dry powder formulations embodiment-dry powder lactose mixed preparation
Use formula (I) compound or its salt (for example above micronization embodiment preparation) of for example micronization form of particulate, be prepared as follows powder mixture: with the compound/salt of institute's expense (10mg for example, 1%w/w) (990mg for example, each concentration mixture 99%w/w) is at the Teflon of Mikro-dismembrator ball mill (but not having spot contact bearing) with the suction level lactose that contains 10% fines
TMMixed about 4 hours with 3/4 speed (about 2000-2500rpm) in (tetrafluoroethylene) jar.Mikro-dismembrator (B.Braun Biotech International, Schwarzenberger Weg 73-79, D-34212 Melsungen, Germany; Www.bbraunbiotech.com) comprise the pedestal that has the lateral vibration arm that projects upwards, shaker arm is connected Teflon
TMOn the jar.Realize married operation by shaker arm.
Other mixture: 10%w/w compound/salt (50mg)+90%w/w lactose (450mg contains the suction level lactose of 10% fines).
The serial dilution of 1%w/w mixture for example can be obtained 0.1% and the mixture of 0.3%w/w.
Powder inhaler
Especially for dry powder inhalation composition, can choose wantonly the pharmaceutical composition of inhalation is joined in the dose container (for example comprising dry powder composite) of many sealings, sealed vessel is vertically installed in the suitable suction apparatus with strip or band shape.Described container can be broken or peel-to-open as required, and for example the dry powder composite of described dosage can pass through such as DISKUS
TM(GlaxoSmithKline) device inhalation.Usually, DISKUS
TMSuction apparatus comes down to GB 2,242, the device that 134 A introduce, in such device, at least one is used for the container of powder type pharmaceutical composition, and (described at least one container is preferably many sealed dose containers, these containers are with longitudinal strip or banded the installation) be limited between two unit, two unit are fixed to one another with peelable form; Described device comprises: the instrument that limits the open site of described at least one container; Peel off each unit in the open site to open the instrument of container; And be communicated with and open outlet of container, the user can be by the pharmaceutical composition of this outlet from the container suction powder type opened.
Unit dosage and dosage regimen
Preferred described composition is unit dosage, and for example tablet of usefulness for oral administration or capsule for example are used for the tablet or the capsule of administration of human.
In described pharmaceutical composition, one of oral or parenteral admin or each dosage device preferably comprise 0.01-3000mg, more preferably 0.5-1000mg formula (I) compound or its pharmacy acceptable salt, calculate with free alkali.In the nose or one of inhalation or each dosage device preferably comprise 0.001-50mg, more preferably 0.01-5mg formula (I) compound or its pharmacy acceptable salt again, calculate with free alkali.
Pharmaceutically acceptable The compounds of this invention or its salt give Mammals (for example people) with oral or parenteral mode preferred every day, the dosage of formula (I) compound or its pharmacy acceptable salt is 0.001mg-50mg/kg body weight/day (mg/kg/ days), for example 0.01-20mg/kg/ days or 0.03-10mg/kg/ days or 0.1-2mg/kg/ days, calculate with free alkali.
Pharmaceutically acceptable The compounds of this invention or its salt preferred every day with in the nose or suction give Mammals (for example people), the dosage of formula (I) compound or its pharmacy acceptable salt is 0.0001-5mg/kg/ days or 0.0001-1mg/kg/ days, for example 0.001-1mg/kg/ days or 0.001-0.3mg/kg/ days or 0.001-0.1mg/kg/ days or 0.005-0.3mg/kg/ days, calculate with free alkali.
Formula (I) compound that pharmaceutically acceptable The compounds of this invention or its salt give preferred every day or the dosage (for adult patients) of its pharmacy acceptable salt are as follows: for example oral or parenteral gives 0.01mg/ days-and 3000mg/ days or 0.5-1000mg/ days, for example 2-500mg/ days; Or nose is interior or suction gives 0.001-300mg/ days or 0.001-50mg/ days or 0.01-30mg/ days or 0.01-5mg/ days or 0.02-2mg/ days, calculates with free alkali.
Combination medicine
The compounds of this invention, salt and/or pharmaceutical composition also can with other therapeutic activity medicine, for example β
2Adrenoceptor agonists, antihistaminic, anti-allergic drug or antiphlogiston combined utilization.
Therefore, the present invention provides combination medicine on the other hand, and it comprises formula (I) compound or its pharmacy acceptable salt and other therapeutic activity medicine, for example β
2-adrenoceptor agonists, antihistaminic, anti-allergic drug, antiphlogiston or anti-infective.
Preferred β
2-adrenoceptor agonists is Salmeterol (for example racemic modification or single enantiomer for example R-enantiomer), salbutamol, formoterol, Salmefamol, Partusisten or terbutaline or its salt (for example its pharmacy acceptable salt), for example vitriol of Salmeterol xinafoate, salbutamol or free alkali or formoterol fumarate.Preferred long-acting beta-2-adrenoreceptor agonists, especially curative effect are at 12-24 hour medicine, for example Salmeterol or formoterol.Preferred β
2-adrenoceptor agonists is used for inhalation, for example once a day, and/or is used for inhalation simultaneously; More preferably β
2-adrenoceptor agonists is the particulate form of for example this paper definition.Preferred β
2-adrenoceptor agonists combination medicine is used for the treatment of and/or prevents COPD or asthma.Salmeterol or its pharmacy acceptable salt (for example Salmeterol xinafoate) are preferably with the suction administration of human, and inhalation dose is 25-50 microgram (in a free alkali), twice of every day.Contain β
2The combination medicine of-adrenoceptor agonists can be the combination medicine of being introduced as WO 00/12078.
Preferred long-acting beta
2-adrenoceptor agonists comprises the β that WO 02/066422A, WO03/024439, WO 02/070490 and WO 02/076933 are introduced
2-adrenoceptor agonists.
Especially preferred long-acting beta
2-adrenoceptor agonists comprises formula (XX) compound or its salt or solvate (referring to WO 02/066422):
Wherein, in formula (XX):
m
xInteger for 2-8;
n
xBe the integer of 3-11, precondition is m
x+ n
xBe 5-19,
R
11xFor-XSO
2NR
16xR
17x, wherein X is-(CH
2)
p x-or C
2-6Alkenylene;
R
16xAnd R
17xIndependently be selected from hydrogen, C
1-6Alkyl, C
3-7Cycloalkyl, C (O) NR
18xR
19x, phenyl and phenyl (C
1-4Alkyl)-,
Perhaps R
16xAnd R
17xConstitute 5 yuan, 6 yuan or 7 yuan with the nitrogen that they connected and contain azo-cycle, R
16xAnd R
17xOptional separately by 1-2 following group replacement: halogen, C
1-6Alkyl, C
1-6Haloalkyl, C
1-6The C of alkoxyl group, hydroxyl-replacement
1-6Alkoxyl group ,-CO
2R
18x,-SO
2NR
18xR
19x,-CONR
18xR
19x,-NR
18xC (O) R
19xOr 5 yuan, 6 yuan or 7 yuan of heterocycles;
R
18xAnd R
19xIndependently be selected from hydrogen, C
1-6Alkyl, C
3-6Cycloalkyl, phenyl and phenyl (C
1-4Alkyl)-;
p
xBe the integer of 0-6, the integer of preferred 0-4;
R
12xAnd R
13xIndependently be selected from hydrogen, C
1-6Alkyl, C
1-6Alkoxyl group, halogen, phenyl and C
1-6Haloalkyl;
R
14xAnd R
15xIndependently be selected from hydrogen and C
1-4Alkyl, precondition are R
14xAnd R
15xThe total number of carbon atoms be no more than 4.
WO 02/066422 disclosed preferred β
2-adrenoceptor agonists comprises:
3-(4-{[6-({ (2R)-2-hydroxyl-2-[4-hydroxyl-3-(methylol) phenyl] ethyl } amino) hexyl] oxygen base } butyl) benzsulfamide and
3-(3-{[7-((2R)-and 2-hydroxyl-2-[4-hydroxyl-3-(methylol) phenyl] ethyl } amino) heptyl] the oxygen base } propyl group) benzsulfamide.
WO 03/024439 disclosed preferred beta-2-adrenoreceptor agonists comprises:
4-{ (1R)-2-[(6-{2-[(2, the 6-dichloro benzyl) the oxygen base] oxyethyl group } hexyl) amino]-the 1-hydroxyethyl }-2-(methylol) phenol.
The combination medicine preferred oral administration of formula (I) compound or its salt and antihistaminic (for example for example uniting tablet) as the associating composition, and can be used for treating and/or preventing rhinallergosis.The example of antihistaminic comprises methapyrilene, perhaps H1 antagonist cetirizine, Loratadine (Clarityn for example for example
TM), Desloratadine (Clarinex for example
TM) or fexofenadine (Allegra for example
TM).
The present invention also provides combination medicine on the other hand, and it comprises formula (I) compound or its pharmacy acceptable salt and anticholinergic compound, for example muscarine (M) receptor antagonist, especially M
1, M
2, M
1/ M
2Or M
3Receptor antagonist, more preferably M
3Receptor antagonist, more preferably so again M
3Receptor antagonist: relative M
1And/or M
2Acceptor, its selectivity antagonism (for example having the antagonistic action more than 10 times or 10 times) M
3Acceptor.Combination medicine for anticholinergic compound/muscarine (M) receptor antagonist and PDE4 inhibitor, referring to for example WO 03/011274 A2, WO 02/069945 A2/US, 2002/0193393 A1 and US2002/052312 A1, and part or all of relevant publication, described publication has provided the example that can unite anticholinergic compound/muscarine (M) receptor antagonist of use with formula (I) compound or its salt and/or suitable pharmaceutical compositions.For example muscarinic receptor antagonist can comprise or be Ipratropium Bromured salt (for example ipratropium bromide), oxitropine salt (for example oxitropium bromide) or more preferably thiophene tropine salt (for example tiotropium bromide); Relevant thiophene tropine is referring to for example EP 418 716A1.
Anticholinergic compound or muscarine (M) receptor antagonist, for example M
3The preferred inhalation of receptor antagonist, the more preferably particulate form of this paper definition for example.More preferably muscarine (M) receptor antagonist and formula (I) compound or its pharmacy acceptable salt are inhalation again.Preferably give anticholinergic compound or muscarinic receptor antagonist and formula (I) compound or its salt simultaneously.The muscarinic receptor antagonist combination medicine is preferred for treating and/or preventing COPD.
Other suitable combination medicine for example comprises combination medicine like this, and it comprises for example anti-inflammatory corticosteroid of formula (I) compound or its pharmacy acceptable salt and other anti-inflammatory drug; Or nonsteroidal anti-inflammatory drug (NSAID) for example leukotriene antagonist (for example Singulair), iNOS inhibitor, tryptase inhibitors, elastase inhibitor, Beta 2 integrin antagonist, adenosine 2a agonist, CCR3 antagonist or 5-lipoxidase inhibitor; Or anti-infective (for example microbiotic or antiviral drug).The administration of iNOS inhibitor preferred oral.Suitable iNOS inhibitor (inducible nitric oxide synthase inhibitor) comprises WO 93/13055, WO 98/30537, WO 02/50021, WO 95/34534 and WO 99/62875 disclosed iNOS inhibitor.Appropriate C CR3 inhibitor comprises WO 02/26722 disclosed CCR3 inhibitor.
Combination medicine comprises formula (I) compound or its pharmacy acceptable salt and anti-inflammatory corticosteroid, and (it is preferred for treating and/or preventing asthma; COPD or rhinallergosis) time; the preferably anti-inflammatory reflunomide is a fluticasone; fluticasone propionate is (for example referring to United States Patent (USP) 4; 335; 121); beclometasone; beclometasone 17-propionic ester; beclometasone 17, the 21-dipropionate; dexamethasone or its ester; Mometasone or its ester; ciclesonide; budesonide; flunisolide; or the compound (for example each claimed compound among the claim 1-22 wherein) of WO 02/12266 A1 introduction or the pharmacy acceptable salt of above any compound.When described anti-inflammatory corticosteroid is the compound of WO 02/12266 A1 introduction, preferred embodiment 1{6 α wherein, 9 α-two fluoro-, 17 α-[(2-furyl carbonyl) oxygen base]-11 beta-hydroxy-16 Alpha-Methyls-3-oxo-androstane-1,4-diene-17 β-carbothioic acid carbothiolic acid S-fluoro methyl esters) or embodiment 41{6 α, 9 alpha-difluoro-11 betas-hydroxy-16 alpha--methyl-17-alpha-[(4-methyl isophthalic acid, 3-thiazole-5-carbonyl) oxygen base]-3-oxo-androstane-1,4-diene-17 β-carbothioic acid carbothiolic acid S-fluoro methyl esters } or its pharmacy acceptable salt.Interior or the inhalation of the preferred nose of anti-inflammatory corticosteroid.Preferred fluticasone propionate, and preferred inhalation administration of human, dosage is (a) 250 micrograms, once a day, or (b) 50-250 microgram, twice of every day.
A kind of such combination medicine also is provided, and it comprises formula (I) compound or its pharmacy acceptable salt and β
2-adrenoceptor agonists and anti-inflammatory corticosteroid, for example medicine of WO03/030939 A1 introduction.Preferred this combination medicine is used for the treatment of and/or prevention of asthma, COPD or rhinallergosis.β
2-adrenoceptor agonists and/or anti-inflammatory corticosteroid can be the medicine of said medicine and/or WO 03/030939 A1 introduction.In this " three " combination medicine, β most preferably
2-adrenoceptor agonists is Salmeterol or its pharmacy acceptable salt (for example Salmeterol xinafoate), and anti-inflammatory corticosteroid is a fluticasone propionate.
Above-mentioned combination medicine can be easily used with pharmaceutical compositions, so the present invention provides a kind of pharmaceutical composition on the other hand, and described composition comprises combination medicine and one or more the pharmaceutically acceptable carrier and/or the vehicle of above definition.
Each compound in such combination medicine can sequential administration, perhaps with independent or blended pharmaceutical compositions administration simultaneously.
In one embodiment, the combination medicine of this paper definition is inhalation simultaneously, will place it in the associating suction apparatus.Another aspect of the present invention is such associating suction apparatus.Described associating suction apparatus can comprise the mixed type pharmaceutical composition (for example dry powder composite) that is used for the while inhalation, described composition comprises all compounds itself of combination medicine, the dose container that described composition is added many sealings, sealed vessel longitudinal strip or band shape are contained in the suction apparatus, and described container can be broken as required or peel off and open; For example such suction apparatus can be GB 2,242 basically, 134 A (DISKUS
TM) and/or the device above introduced.Perhaps, described combination medicine suction apparatus can be such device: each compound of combination medicine administration simultaneously, but store (the perhaps all or part of independent storage of three combination medicines) separately with for example drug alone composition forms, for example the PCT/EP03/00598 that applies for referring on January 22nd, 2003 (for example form of its claim (for example claim 1) description).
The present invention also provides a kind of method of combination medicine of this paper of preparation definition, and this method comprises:
(a) prepare independently pharmaceutical composition, be used for sequential or give each compound of combination medicine simultaneously, perhaps
(b) prepare the mixed type pharmaceutical composition, be used for giving simultaneously each compound of combination medicine,
Wherein said pharmaceutical composition comprises combination medicine and one or more pharmaceutically acceptable carrier and/or vehicle.
The combination medicine that the present invention also provides a kind of this paper for preparing by the method for this paper definition to define.
The biological test method
PDE 3, PDE 4B, PDE 4D, PDE5, PDE 6 main assay methods
Compound activity can utilize following assay method to detect.Preferred The compounds of this invention is a selectivity PDE4 inhibitor, and promptly their effects of suppressing PDE4 (for example PDE4B and/or PDE4D, preferred PDE4B) are higher and/or higher and/or than the effect height that suppresses PDE6 than the effect that suppresses PDE5 than the effect that suppresses PDE3.
PDE enzyme source and reference
The people PDE4B (especially its 2B splicing variants (HSPDE4B2B)) that recombinates is open in following document: WO 94/20079 and M.M.McLaughlin etc., " A low Km; rolipram-sensitive; cAMP-specific phosphodiesterase from human brain:cloning and expression of cDNA; biochemical characterisation ofrecombinant protein; and tissue distribution of mRNA ", J.Biol.Chem., 1993,268,6470-6476.For example, in the embodiment 1 of WO 94/20079, introduced the people PDE4B that recombinates is expressed in PDE-defective yeast bacterium yeast saccharomyces cerevisiae (Saccharomycescerevisiae) bacterial strain GL62, for example added 150 μ M CuSO
4After inducing, with 100 of yeast cell split product, the 000xg supernatant liquor partly is used to gather in the crops the PDE4B enzyme.
P.A.Baecker etc., " Isolation of a cDNA encoding a humanrolipram-sensitive cyclic AMP phoshodiesterase (PDE IV
D) ", Gene, 1994,138,253-256 discloses the people PDE4D (HSPDE4D3A) that recombinates.
K.Loughney etc., " Isolation and characterisation of cDNAs encodingPDE5A; a human cGMP-binding; cGMP-specific 3 '; 5 '-cyclic nucleotidephosphodiesterase ", Gene, 1998,216,139-147 discloses the people PDE5 that recombinates.
According to H.Coste and P.Grondin, " Characterisation of a novel potent andspecific inhibitor of type V phosphodiesterase ", Biochem.Pharmacol., 1995,50, the method that 1577-1585 introduces is from bovine aortic purifying PDE3.
The method of introducing according to following document is from bovine retina purifying PDE6:P.Catty and P.Deterre, " Activation and solubilization of the retinal cGMP-specificphosphodiesterase by limited proteolysis ", Eur.J.Biochem., 1991,199,263-269; A.Tar etc., " Purification of bovine retinal cGMPphosphodiesterase ", Methods in Enzymology, 1994,238,3-12; And/or D.Srivastava etc., " Effects of magnesium on cyclic GMP hydrolysis bythe bovine retinal rod cyclic GMP phosphodiesterase ", Biochem.J., 1995,308,653-658.
Suppress PDE 3, PDE 4B, PDE 4D, PDE 5 or PDE 6 activity: radioactivity scintillation proximity assay (SPA)
Compound suppresses the ability of PDE4B or 4D (people's recombinant chou), PDE3 (being derived from bovine aortic), PDE5 (people's recombinant chou) or PDE6 (being derived from bovine retina) catalytic activity and measures by 96 hole scintillation proximity assays (SPA).
With test compound (being DMSO solution, the DMSO solution of preferred about 2 microlitres (μ l) volume) and the 50mM Tris-HCl buffered soln (pH 7.5), the 8.3mM MgCl that contain the PDE enzyme
2, 1.7mM EGTA, 0.05% (w/v) bovine serum albumin together in Wallac Isoplates (code 1450-514) in envrionment temperature (room temperature, for example 19-23 ℃) preincubate 10-30 minute (common 30 minutes).The concentration of regulatory enzyme makes in not having the control wells of compound, is no more than 20% with the hydrolysis of undefined substrate between incubation period.Analyze for PDE3, PDE4B and PDE4D, add [5 ', 8-
3H] adenosine 3 ', 5 '-cyclic phosphoric acid (Amersham Pharmacia Biotech, code TRK.559; Or Amersham Biosciences UK Ltd, Pollards Wood, Chalfont St Giles, Buckinghamshire HP8 4SP, UK), obtain 0.05 μ Ci/ hole and~final concentration of 10nM.Analyze for PDE5 and PDE6, add [8-
3H] guanosine 3 ', 5 '-cyclic phosphoric acid (Amersham Pharmacia Biotech, code TRK.392), obtain 0.05 μ Ci/ hole and~final concentration of 36nM.The plate (preferably comprising about 100 μ l analysis of mixtures) that will comprise analysis of mixtures mixed 5 minutes on orbital shaker, at room temperature hatched 1 hour.Add phosphodiesterase SPA pearl (Amersham Pharmacia Biotech, code RPNQ 0150) (~1mg/ hole) termination test.With plate sealing, vibration, be allowed to condition at room temperature then and leave standstill 35 minutes to 1 hour (preferred 35 minutes), allow the pearl sedimentation.Use WALLAC TRILUX 1450Microbeta scintillometer to detect the bonded radioactive product.10 concentration of each compound analysis (1.5nM-30 μ M) are drawn and are suppressed curve.With ActivityBase and XLfit (IDBusiness Solutions Limited, 2 Ocean Court, Surrey Research Park, Guildford, Surrey GU2 7QB, United Kindgom) analytic curve, the result is expressed as pIC
50Value.
In a kind of alternative assay method of above-mentioned radioactivity SPA assay method, PDE4B or PDE4D restraining effect can use following fluorescence polarization (FP) assay method to measure:
Suppress PDE4B or PDE4D activity: fluorescence polarization (FP) assay method
Compound suppresses the ability of PDE4B (people's recombinant chou) or PDE4D (people's recombinant chou) catalytic activity by 384 hole IMAP fluorescence polarization (FP) assay method (IMAP Explorer test kits, Molecular Devices Corporation, Sunnydale, CA, USA; Molecular Devices code: R8062) detect.IMAP FP assay method can be measured the PDE activity with homogeneity, on-radiation analysis mode.The FP assay method is utilized the ability of immobilization trivalent metal cation (being coated on the nanoparticle (minimum pearl)) in conjunction with the F1-AMP bound phosphate groups, and described ester group is hydrolyzed to non-annularity F1-AMP form by fluorescein-labeled (F1) ring gland glycosides phosplate (F1-cAMP) and produces.Can be in conjunction with F1-cAMP.The rotation that the F1-cAMP product has slowed down bonded F1-AMP in conjunction with described pearl (with immobilization Tricationic bag quilt), the fluorescence polarization rate that causes being parallel to vertical light increases.The increase of this type of signal of PDE restraining effect minimizing/inhibition.
With test compound (a small amount of, for example about 0.5-1 μ l DMSO solution, preferred about 0.5 μ lDMSO solution) and the 10mM Tris-HCl damping fluid (pH 7.2), the 10mMMgCl that contain the PDE enzyme
2, 0.1% (w/v) bovine serum albumin and 0.05%NaN
3Together in black 384 hole microtiter plates (supplier: NUNC, code 262260) in envrionment temperature (room temperature, for example 19-23 ℃) preincubate 10-30 minute.Be determined by experiment enzyme concn, make that to hatch process reaction be linear whole.Adding fluorescein adenosine 3 ', 5 '-cyclic phosphoric acid (Molecular DevicesCorporation, Molecular Devices code: R7091) obtain the about 40nM of final concentration (the final analysis volume is about 25-40 μ l usually, preferred about 20 μ l).Each plate was mixed on orbital shaker 10 seconds, then incubated at room 40 minutes.Adding IMAP binding reagents (the same, Molecular Devices Corporation, Molecular Devices code: R7207) (60 μ l are with the test kit mother liquor of binding buffer liquid with dilution in 400: 1) termination test.Allow each plate leave standstill 1 hour in room temperature.Fluorescence polarization (FP) the rate Analyst that is parallel to vertical light
TMReading plate instrument (Molecular Devices Corporation) measures.10 concentration of each compound analysis (1.5nM-30 μ M) are drawn and are suppressed curve.With ActivityBase and XLfit (ID BusinesssSolutions Limited, 2 Ocean Court, Surrey Research Park, Guildford, Surrey GU2 7QB, United Kindgom) analytic curve.The result is expressed as pIC
50Value.
In the FP assay method, all reagent Multidrop
TM(Thermo LabsystemsOy, Ratastie 2, PO Box 100, Vantaa 01620, Finland) distributes.
For specific PDE4 inhibitor, PDE4B (or PDE4D) inhibiting value that records with SPA and FP assay method has minute differences.But in the regression analysis of 100 test compounds (not necessarily The compounds of this invention), find the pIC that records with SPA and FP assay method for PDE4B and PDE4D
50Inhibiting value is generally consistent in about 0.5log unit, and (linear regression coeffficient of PDE4B and PDE4D is respectively 0.966 and 0.971; David R.Mobbs etc., " Comparison of the IMAP Fluorescence Polarisation Assay with theScintillation Proximity Assay for Phosphodiesterase Activity " is at the 2003 Molecular Devices UK on October 2nd, 2003; Open on the Europe User Meeting, Down Hall, Harlow, Essex, United Kingdom).
Only based on each time test, generally adopt the biological data (it is active that PDE4B suppresses, the mean value an of reading or several (for example about 2-6 is individual) reading) of the part embodiment that above-mentioned SPA and/or FP assay method or its similar assay method obtain as follows.In all SPA and FP assay method, it is impossible accomplishing definitely accurately to measure, and given reading only can be accurate to pact ± 0.5 log unit, and this depends on the number of times and the mean value of reading:
The embodiment numbering | PDE4B pIC 50(± about 0.5) |
1、8、24、28、63、75 | 8.3-9.1 |
6、7、26、29、64、25 | 7.15-7.5 |
13、50 | 8.3-9.1 |
2、37、38 | 7.6-7.9 |
48、73、98、139、191、210、218、221、252、261、 282、283、304、306 | 8.7-10.0 |
Embodiment 308-314 and embodiment 368,369,379,380,382 | 8.0-9.45 |
Embodiment 316-345 | 9.0-10.1 |
Embodiment 346-355 | 8.5-9.3 |
Embodiment 356-359 | 6.8-7.4 |
Embodiment 360-367 | 7.2-9.0 |
Embodiment 370-373 | 6.9-7.9 |
Embodiment 375-378 | 7.0-8.3 |
Test the PDE4B restraining effect of nearly all embodiment, adopted above-mentioned radioactivity SPA and/or FP assay method or its similar assay method usually.The embodiment of nearly all test has pIC
50It is active that the PDE4B of=about 6 (± about 0.5) to about 10.1 (± 0.5) suppresses.When certain embodiment is that following examples are partly described, can enough effective intermediates (for example it may have a definition or enrichment or do not have benzylic carbon atoms (CR
4R
5) stereochemical structure) during reagent preparation, think that then (but not guaranteeing) its above-mentioned PDE4B suppresses pIC
50Value has the pIC of the embodiment that adopts the specified intermediate preparation of embodiment part usually
50Value.
Adopt above-mentioned or other testing method, only chosen through the embodiment of PDE4B test is optional and carried out one or more PDE3, PDE5 or the inhibiting test of PDE6.
In test PDE4B and the inhibiting embodiment of PDE5, R
3=cyclohexyl (NHR
3=formula (c)), tetrahydrochysene-2H-pyrans-4-base (NHR
3=group (h)), 4-oxo cyclohexyl (NHR
3=formula (o)), suitable-3-hydroxyl-cyclohexyl (NHR
3The formula of=cis-configuration (n)), 4-(oximido) cyclohexyl (NHR
3=formula (o2), 4-(aminocarboxyl) cyclohexyl (NHR
3=formula (p9) especially is mainly cis-isomeride or cis/trans mixture) or 1-(aminocarboxyl)-4-piperidyl (NHR
3Be formula (k2)), R
1Be ethyl, R
2For H and have preferred-NH-C (R
4) (R
5Those embodiment of)-Ar usually are better than selectivity to PDE5 to the selectivity of PDE4B, according to above EIA method and/or similarly method or other method test usually.
Vomiting:
Especially in systematicness contact back (for example oral back), some known PDE4 inhibitor can cause vomiting and/or feel sick, the degree that just causes or high or low (for example referring to Z.Huang etc., Current Opinion in Chemical Biology, 2001,5:432-438 is especially referring to 433-434 page or leaf and the reference wherein quoted).Therefore, if the emetic side effect (for example behind oral or parenteral admin) that PDE4 of the present invention inhibition compound or its salt causes is limited or manageable, these compounds or salt will be preferred (but nonessential) so.The emetic side effect of described compound or salt can cause the detection of vomitting property by for example giving potential behind the ferret; For example can detect ferret after oral or parenteral give The compounds of this invention or its salt, vomiting, duration of seizure, degree, frequency and/or the time length of retching and/or twisting.About test to a kind of optional detection method of the antiphlogistic effects of ferret, emetic side effect and therapeutic index (TI), referring to for example hereinafter in vivo test 4.Other sees for example A.Robichaud etc., " Emesis induced by inhibitors of[PDE IV] in the ferret ", Neuropharmacology, 1999,38,289-297, errata, Neuropharmacology, 2001,40,465-465.But, optional emetic side effect and the therapeutic index (TI) that can followingly measure rat easily: after giving The compounds of this invention or its salt, the different food behavior (referring to following in vivo test 2) of monitoring rat.
Other side effect:
Some known PDE4 inhibitor may cause other side effect, for example the side effect of headache and other central nervous system (CNS) mediation property; And/or stomach and intestine (GI) road obstacle.Therefore, if one or more above-mentioned side effects that PDE4 of the present invention inhibition compound or salt cause are limited or control easily that these compounds or salt will be preferred (but nonessential) so.
The in vitro tests that other is optional:
The TNF α (TNF-alpha) that produces in the inhibition people whole blood
This test is a kind of optional useful supplementary test, for example is used for the oral PDE4 inhibitor of potential.
Test compound is prepared as the DMSO mother liquor of about 10mM, directly 10mMDMSO mother liquor or rarer DMSO solution is carried out a series of dilutions with DMSO, 3 times of continuous 8 dilutions.With the artificial sampler of Biomek Fx liquid compound is joined in the assay plate.
Extract heparinization blood from the healthy volunteer, be assigned to (about 100 μ l) and contain about 0.5 or about 1.0 μ l suitably in the hole of the microtiter plate of the test compound solution of dilution.At 37 ℃, 5%CO
2Under hatch about 1 hour after, add the RPMI 1640 (containing 1%L-glutamine and 1% penicillin/streptomycin) (finally about 50ng/ml) that about 25 μ l contain LPS (lipopolysaccharides) solution (S.typhosa).With about 37 ℃ of sample, 5%CO
2Under hatched about 20 hours, add about 100 μ l physiological saline (0.138%NaCl), with about 1300g after centrifugal about 10 minutes, collect the blood plasma of dilution with Platemate or the artificial sampler of Biomek FX liquid.Determine level of tnfalpha in plasma content by the electrochemiluminescence assay method (seeing below) or the enzyme-linked immunosorbent assay (ELISA) (seeing below) that adopt the IGEN technology.
TNF α (TNF-alpha) assay method that produces among the full PBMC of inhibition people
This test is a kind of optional useful supplementary test, for example is used for the PDE4 inhibitor of potential inhalation.
Test compound is made the DMSO mother liquor of about 10mM, directly 10mM DMSO mother liquor or rarer DMSO solution are carried out a series of dilutions with DMSO, 3 times of continuous 8 dilutions.With the artificial sampler of Biomek Fx liquid compound is joined in the assay plate.
With healthy volunteer's heparinization human blood histopaque centrifugal about 30 minutes with about 1000g, thereby preparation PBMC cell (monocyte).From the interface collecting cell, centrifuge washing (about 1300g, about 10 minutes) is with 1 * 10
6Cell/ml is suspended in again and measures damping fluid (RPMI1640 that contains 10% foetal calf serum, 1%L-glutamine and 1% penicillin/streptomycin).About 50 μ l cells are joined the microtiter well of the compound solution that contains about 0.5 μ l or the suitable dilution of about 1.0 μ l.Add about 75 μ l LPS (finally about 1ng/ml), with about 37 ℃ of sample, 5%CO
2Under hatched 20 hours.Take out supernatant liquor, measure TNF concentration by electrochemiluminescence assay method or the ELISA (seeing below) that adopts the IGEN technology.
TNF α IGEN assay method
About 50 μ l supernatant liquors of whole blood or PBMC assay plate are transferred to 96 hole polypropylene boards.Each plate also comprise TNF α typical curve (about 0-30000pg/ml:R+D Systems, 210-TA).In each hole, add about 50 μ l streptavidins/biotinylation anti-TNF alpha antibodies mixture, the anti-TNF alpha monoclonal antibody of about 25 μ l ruthenium spikes and the PBS that about 100 μ l contain 0.1% bovine serum albumin, seal each plate, vibrated about 2 hours, and used IGEN instrument reading then.
TNF α ELISA assay method
(AMS Bioteclmology 211-90-164-40), according to the directions for use of manufacturers, but the TNF α working curve that adopts Pharmingen TNF α (catalog number 555212) to make, can measure people's TNF α with the commercial reagent box.
Biological assay in the body
Above-mentioned external enzymatic PDE4B suppresses assay method or usually similar assay method should be considered to bioactive main testing method.However, still introduce biological test in some additional bodies below, these tests be choose wantonly and be not to be essential for measuring drug effect or side effect, and also not necessarily carried out these tests.
Lung's neutrophilia that in vivo test 1. rat LPS bring out: the effect of orally give PDE4 inhibitor
Confirmed that it is the key character of tuberculosis such as chronic obstructive pulmonary disease (COPD) that lung's neutrophilic leukocyte flows into, COPD can comprise chronic bronchitis and/or pulmonary emphysema (G.F.Filley, Chest.2000; 117 (5); 251s-260s).The purpose of this neutrophilia model is a research orally give PDE4 inhibitor to the antiphlogistic effects in vivo of diving of the neutrophilia (the neutrophilic leukocyte inflammatory feature of simulation COPD) that sucks atomizing lipopolysaccharides (LPS) and bring out.Document part referring to following relevant technologies background.
Lewis male rat (Charles River with heavily about 300-400g, Raleigh, NC, USA) with following reagent pre-treatment: (a) test compound for example is suspended in about 0.5% methylcellulose gum (Sigma-Aldrich, St Louis, MO, USA) aqueous solution, or (b) have only solvent gives with the oral dose of 10ml/kg.For example, draw dose response curve: 2.0mg/kg, 0.4mg/kg, 0.08mg/kg, 0.016mg/kg and 0.0032mg/kg with the PDE4 inhibitor that is about following dosage usually.After the pre-treatment about 30 minutes, make rat contact with atomizing LPS that (serotype intestinal bacteria (E.coli) 026:B6 prepares by the trichoroacetic acid(TCA) extraction, can be from Sigma-Aldrich, St Louis, MO, USA obtains), atomizing LPS produces with the atomizer that contains 100 μ g/ml LPS solution.Speed with about 4L/min makes about 20 minutes of rat contact LPS aerosol.LPS contact is carried out in enclosed chamber, its interior dimensions probably for 45cm length * 24cm wide * the 20cm height.Atomizer and exposure chamber are contained in the qualified stink cupboard.After LPS contacts about 4 hours, give Sodital with the intraperitoneal of about 90mg/kg dosage and make rat euthanasia.Insert the tracheae that contacts LPS with No. 14 blunt pins and carry out bronchoalveolar lavage (BAL).Collect 25ml BAL liquid altogether after washing 5 times (each 5ml).BAL liquid is carried out total cell counting and white corpuscle differentiate the neutrophilic leukocyte influx that enters lung with calculating.Calculate each dosage neutrophilic leukocyte and suppress percentage ratio (comparing), draw the S shape dose response curve of slope variation usually with Prism Graph-Pad with solvent.This dose response curve is used to calculate the ED50 value (mg/kg body weight) that the PDE4 inhibitor suppresses the neutrophilia that LPS brings out.
Alternative method: in one of described method easier alternate embodiment, give single oral dosage 10mg/kg of rat or 1.0mg/kg more commonly used or the PDE4 inhibitor (or solvent) of 0.3mg/kg, calculate and report that the neutrophilic leukocyte of this concrete dosage suppresses percentage ratio.
Reference:
Filley G.F.Comparison of the structural and inflammatory featuresof COPD and asthma.Chest.2000;117(5)251s-260s。
Howell RE, Jenkins LP, Fielding LE and Grimes D.Inhibition ofantigen-induced pulmonary eosinophilia and neutrophilia by selectiveinhibitors of phosphodiesterase types 3 and 4 in brown Norway rats.Pulmonary Pharmacology.1995; 8:83-89.
Spond J,Chapman R,Fine J,Jones H,Kreutner W,Kung TT,Minnicozzi M.Comparison of PDE4 inhibitors,Rolipram and SB 207499(Ariflo
TM),in a rat model of pulmonary neutrophilia.PulmonaryPharmacology and Therapeutics.2001;14:157-164。
Underwood DC, Osborn RR, Bochnowicz S, Webb EF, RiemanDJ, Lee JC, Romanic AM, Adams JL, Hay DWP and Griswold DE.SB239063, a p38 MAPK inhibitor, reduces neutrophilia, inflammatorycytokines, MMP-9, and fibrosis in lung.Am J Physiol Lung Cell MolPhysiol.2000; 279:L895-L902.
The different food model of rat of in vivo test 2. vomitings
Technical background: confirmed selectivity PDE4 inhibitor multiple external and body inner model by the born of the same parents that improve many immunocytes (for example lymphocyte, monocyte) in cAMP concentration and inflammation-inhibiting.But some PDE4 inhibitor is vomitings in the side effect of a lot of species.Because many rat inflammation models are fully described, they use (referring to for example above in vivo test 1) in the method for the useful antiphlogistic effects that is used for confirming the PDE4 inhibitor.But rat does not have emetic reaction (they do not have vomiting reflex), so the relation between the useful antiphlogistic effects of PDE4 inhibitor and vomiting is difficult to directly pass through rat studies.
Yet in 1991, Takeda etc. (referring to following document part) proved that the different food response class of rat is similar to vomiting.The feed of different feeding habits is the reaction of rat illness behavior, and rat eats non-nutritive substance, for example earth or especially clay (for example kaolin), and these materials may help to absorb poison.Different feeding habits feed can be brought out by motion and chemical (chemical that especially people is had emetic action), and the medicine of the enough inhibition of energy people vomiting suppresses.Test in vivo in 2, the different food model of rat can be measured rat to the inhibiting different food reaction level of the PDE4 of pharmacology relevant dose, and it is parallel to the interior anti-inflammatory analysis (for example above in vivo test 1) of body of (independent one group) rat.
Being combined in the anti-inflammatory analysis of same species and different totality analyses and can provide The compounds of this invention/salt in rat " therapeutic index " (TI) data.Rat TI for example may be calculated the different food reaction ED50 dosage of potential emetic property and the b of a) test 2) ratio of rat anti-inflammatory action ED50 dosage (measuring) by the rat neutrophilia restraining effect in the in vivo test 1 for example, TI ratio is big more may to show that vomiting reaction is more little under many anti-inflammatory dosage.That so just can select The compounds of this invention or its salt has antiphlogistic effects and does not have emetic action or the drug dose of the low emetic action of generation.But PDE4 suppresses compound and realizes that low emetic action is not essential to the invention.
Method: experiment first day, rat is closed raising separately in cage respectively, do not have straw mattress or " nutrient fortified food ".Make rat break away from the floor of cage with wire netting.The feed cup that solid type food ball of standard rat and clay ball are housed is weighed in advance, be placed in the cage.The clay ball is from Languna Clay Co, City of Industry, and CA, USA obtains, and its size is identical with the food ball with shape.Allow rat adapt to clay 72 hours, every day is with the feed cup in the cage and food and the clay chip scales/electronic balance weighing that can be accurate to 0.1g during this period.Usually when 72 hour adaptive phase finished, rat can be not interested in the clay ball.
When finishing in 72 hours, rat is placed in the clean cage weighing feed cup.Still the rat of regular edible clay is not used in research.Before dark cycle (rat be in active state and should be on the feed), rat is divided into several treatment group, The compounds of this invention/the salt of a certain dosage of orally give (different dosage is used for different treatment group) or only give solvent, the about 2ml/kg of dose volume.In this oral administration, compound/salt can be for for example being suspended in about 0.5% methylcellulose gum (Sigma-Aldrich, St.Louis, MO, USA) form of the aqueous solution.Second day, chip in the cup of dress food and clay and the cage is weighed, calculate clay and food total amount that each rat consumed in preceding a whole night.
Following calculating dose response: at first data reduction is become quantal response, promptly the different food reaction of rat is positive or negative.If the clay that consumes surpasses control group mean value 0.3g or more than the 0.3g, rat is " the different food positive ".Usually carry out logarithm regression Calculation ED50 value with Statistica software statistics bag.Can calculate different food reaction ED50 value then, unit is the mg/kg body weight.
Different food reaction ED50 value and the inhibiting ED50 value of neutrophilia (by above in vivo test 1 measurement) of the rat of the same compound of orally give can be compared, can calculate rat therapeutic index (TI) like this:
Generally speaking, the therapeutic index that so calculates (TI) is usually significantly different with the TI (D20/D50) of for example ferret, for example usually apparently higher than the TI (D20/D50) (referring to following in vivo test 4) of ferret.
Perhaps, for example for short form test, the test compound (for example oral 10mg/kg) of single oral dosage can be only used in vivo test 2 (different food).
Reference:
Beavo JA,Contini,M.,Heaslip,R.J.Multiple cyclic nucleotidephosphodiesterases.Mol Pharmacol.1994;46:399-405。
Spond J,Chapman R,Fine J,Jones H,Kreutner W,Kung TT,Minnicozzi M.Comparison of PDE 4 inhibitors,Rolipram and SB 207499(Ariflo
TM),in a rat model of pulmonary neutrophilia.PulmonaryPharmacology and Therapeudtics.2001;14:157-164。
Takeda N, Hasegawa S, Morita M and Matsunaga T.Pica in rats isanalogous to emesis:an animal model in emesis research.Pharmacology, Biochemistry and Behavior.1991; 45:817-821.
Takeda N,Hasegawa S,Morita M,Horii A,Uno A,YamatodaniA and Matsunaga T.Neuropharmacological mechanisms of emesis.I.Effects of antiemetic drugs on motion-and apomorphine-induced pica inrats.Meth Find Exp Clin Pharmacol.1995;17(9)589-596。
Takeda N,Hasegawa S,Morita M,Horii A,Uno A,YamatodaniA and Matsunaga T.Neuropharmacological mechanisms of emesis.II.Effects of antiemetic drugs on cisplatin-induced pica in rats.Meth FindExp Clim Pharmacol.1995;17(9)647-652。
Lung's neutrophilia that the LPS of in vivo test 3. rats brings out: the effect that gives the PDE4 inhibitor in the tracheae
Pneumonia (being the neutrophilia that lipopolysaccharides (LPS) brings out specifically) animal model is adopted in this test, and (i.t.) gives the restraining effect of PDE4 inhibitor to this type of neutrophilia (antiphlogistic effects) in the tracheae can be used for studying generally acknowledged passing through.The PDE4 inhibitor is preferably dry powder or wetting aerosol form.I.t. administration is a kind of mode of inhalation, and it can topical administration lung.
Laboratory animal: with male CD (Sprague Dawley deutero-) rat (CharlesRiver, Raleigh, NC, USA or Charles River, United Kingdom) the grouping raising, 5 in every cage, pay the back and adapt at least 5 days, periodic replacement straw mattress/nest material, ad libitum access is made the SDS recipe R1 of ball shape, changes the animal level tap water with pasteurization every day.
Dry powder doser: property 3 pass joints once between administration syringe needle and syringe.(the 3 logical aseptic joint Vycon 876.00 of doser in the weighing tracheae; Or Penn Century dry powder insufflator DP-4), then a medicinal mixture or a suction level lactose (solvent contrast) are joined in the joint, closed joint prevents drug loss, and the weighing joint is determined the drug weight in the joint again.After the administration, the weighing joint is determined remaining drug weight in the joint once more.With syringe needle (No. 19 Sigma Z21934-7 syringe needles, long 152mm (6 inches), band luer needle stand) cut mechanically is to about 132mm (5.2 inches), make terminal rust to prevent their injury rats tracheaes, weighing syringe needle before administration and afterwards is to confirm not having drug residue in the syringe needle after the administration.
Wetting suspended substance doser: this device is with top similar, but is to use front end and needle shaft to the blunt administration syringe needle that is very little angle, in the softish plastics portex intubate insertion pin.
Medicine and material: (serotype: 0127:B8) (for example L3129 Lot61K4075) is dissolved in phosphate buffered saline(PBS) (PBS) with lipopolysaccharides (LPS).Preferred particulate (for example micronization) form of using the PDE4 inhibitor, for example form for preparing according to above micronization embodiment.
Dry powder for medicine gives mode, can choose the dry powder formulations embodiment that comprises medicine and suction level lactose that provides more than the use wantonly.Operable a kind of suitable suction level lactose (for example Lot E98L4675 Batch 845120) contains 10% fines (the Malvern granularity Detection has the granularity of 10% raw material less than 15 μ m).
The wetting suspended substance (water-based) of medicine can be prepared as follows: volume required solvent is added in the medicine; The solvent that uses can be for example salt solution or salt solution/tween (for example 0.2% tween 80) mixture.Wetting suspended substance about 10 minutes before use usually with ultrasonication.
Experiment is prepared and is given PDE4 inhibitor: in the following manner with rat anesthesia: place it in the synthetic glass chamber of sealing, allow their contact the mixed gas of isoflurane (4.5%), nitrous oxide (3L/min) and oxygen (1L/min).After finishing anesthesia, rat is placed on the stainless steel i.t. administration brace table.Make their back be about 35 ° of angles placement.Light with respect to throat outside at an angle with the illumination tracheae.Mouth is opened, visible top air pipe passway.The wetting suspended substance and the dry powder administration of PDE4 inhibitor are carried out according to following different operating:
Give wetting suspended substance: the portex intubate is inserted via blunt metal administration syringe needle, and described metal administration syringe needle carefully inserts in the rat tracheae in advance.By giving rat solvent or PDE4 inhibitor in the administration syringe needle tracheae, each different medicine group is used new internal prongs.Slowly give (about 10 seconds) described preparation with the syringe that connects the administration syringe needle.
Give dry powder: with (the aseptic piecing devices Vycon 876.00 of threeway of doser in the tracheae; Or Penn Century dry powder insufflator DP-4) and syringe needle insert the rat tracheae up to predetermined point, this point is at first about 1cm place more than branch point.Another operator allows syringe needle remain on specified location, pushes away syringe (preferably consistent with the aspiratory action of rat) simultaneously by Y-junction input 2 * 4ml air, and purpose is that whole medicines are discharged from joint.(perhaps, with Penn Century dry powder insufflator device input 2 * 3ml air).After administration, syringe needle and joint or device are taken out from air flue, close joint and flow out from joint to prevent any residual drug.
After giving wetting suspended substance or dry powder, rat is taken down from brace table, observe continuously and from narcosis, recover up to them.Rat is put back to rearging cage, ad libitum access and drinking-water; Whether observe has any uncommon behavior variation and record.
Contact LPS:i.t. gives solvent contrast or PDE4 inhibitor after about 2 hours, rat is placed in the synthetic glass container of sealing, is exposed to about 15 minutes of LPS aerosol (the about 150 μ g/ml of aerosol concentration).(DeVilbiss USA) produces the LPS aerosol, and it is directly stretched into the synthetic glass exposure chamber with atomizer.After contact LPS 15 minutes, rat is put back to rearging cage, ad libitum access and drinking-water.
[in an alternate embodiment, rat can contact LPS and is less than 2 hours (for example about 30 minutes) after the i.t. administration.In another alternate embodiment, rat can contact LPS more than 2 hours (for example about 4 hours to about 24 hours) after i.t. gives solvent or PDE4 inhibitor, whether has long-acting (but it is optional) with test PDE4 inhibitor]
Bronchoalveolar lavage: after 4 hours, give (i.p.) excessive vetanarcol and put to death rat in the LPS contact.In tracheae, insert polypropylene tube, with 3 * 5ml heparinization (phosphate buffered saline(PBS) (PBS) lavation lung (cleaning) of 25 units/ml).
Neutrophil count: with bronchoalveolar lavage (BAL) sample centrifugal about 7 minutes with about 1300rpm.Take out supernatant liquor, the gained cell precipitation is suspended in about 1ml PBS again.Be prepared as follows the Cell sheet glass of suspension: the BAL liquid that about 100 μ l are suspended again joins the cell centrifugation container, with about 5000rpm centrifugal about 5 minutes then.Air-dry slide glass is used Li Shiman (Leishmans) staining agent dyeing (about 20 minutes) to make then and can be carried out the cell divide counting.Also the total cell of suspension is counted.According to above twice counting, determine neutrophilic leukocyte sum among the BAL.In order to measure the restraining effect of PDE4 inhibitor inductive, the contrast neutrophil count of rat with the rat of handling of vehicle treated with the PDE4 inhibitor to neutrophilia.
By changing PDE4 inhibitor dosage (for example 0.2mg or 0.1mgPDE4 inhibitor/kg body weight is reduced to for example 0.01mg/kg), can draw dose response curve in dosing step.
The therapeutic index of clear-headed ferret orally give PDE4 inhibitor is estimated in vivo test 4.
1.1 material
Use following material to study:
Be prepared as follows the PDE4 inhibitor that is used for oral (p.o.) administration: the PDE4 inhibitor is dissolved in the acetone of fixed volume (about 1ml), adds cremophor then to about 20% of final volume.By on solution, directly introducing nitrogen gas stream evaporation acetone.In case remove acetone, supply solution to final volume with distilled water.LPS is dissolved in phosphate buffered saline(PBS).
1.2 animal
Transport male ferret (Mustela Pulorius Furo, heavy 1-2kg), allow it adapt at least 7 days.Food comprises arbitrarily edible SDS recipe C ball shape food, gives Whiskers weekly 3 times
TMCat grain.Provide the animal level tap water and the every day of pasteurization to change.
1.3 experimental program
1.3.1 give PDE4 inhibitor
Oral dose (p.o.) with 1ml/kg gives PDE4 inhibitor.Allow ferret in the fasting at night, but can freely drink water.With about 15cm administration syringe needle orally give ferret solvent or PDE4 inhibitor, promptly be given in the oesophagus along the throat back side.After the administration, ferret is put back to rearging cage, rearging cage is furnished with organic glass door so that observe, and can arbitrarily drink water.Observe ferret continuously, write down any vomiting outbreak (retching and vomiting) or behavior and change.After the about 60-90 of p.o. administration minute, allow the ferret feed.
1.3.2 contact LPS
After orally give compound or solvent contrast about 30 minutes, ferret is put into the synthetic glass container of sealing, allow it contact about 10 minutes of LPS aerosol (about 30 μ g/ml).(DeVilbiss USA) produces the LPS aerosol, and it is directly stretched into the synthetic glass exposure chamber with atomizer.After contact 10 minutes, ferret is put back to rearging cage, arbitrarily drink water, but in the later stage ad libitum access.Behind oral administration, at least 2.5 hours, observe ferret continuously comprehensively.Writing down all vomiting outbreaks and behavior changes.
1.3.3 bronchoalveolar lavage and cell counting
Contact about 6 hours of back at LPS, intraperitoneal gives excessive vetanarcol and puts to death ferret.In tracheae, insert polypropylene tube, with about 20ml heparinization (twice lavation lung of phosphate buffered saline(PBS) (PBS) of 10 units/ml).With bronchoalveolar lavage (BAL) sample centrifugal about 7 minutes with about 1300rpm.Take out supernatant liquor, the gained cell precipitation is suspended in about 1ml PBS again.The cell smear of preparation suspension with the dyeing of Li Shiman (Leishmans) staining agent, makes and can carry out the cell divide counting.Carry out total cell count with remaining resuspension sample.Determine neutrophilic leukocyte sum in the BAL sample thus.
1.3.4 pharmacokinetics reading
Write down following parameter:
A) the inhibition percentage ratio of lung's neutrophilia of bringing out of LPS determines to produce 50% inhibiting PDE4 inhibitor dosage (D50).
B) vomiting of vomiting outbreak-statistics and retch number of times, definite PDE4 inhibitor dosage (D20) that produces 20% incidence of vomiting.
C) use this assay method then, use following equation to calculate the therapeutic index (TI) of each PDE4 inhibitor:
It should be noted that: (D20/D50) significantly different with the rat TI (50/50) that calculates with oral inflammation of rat and different feeding habits feed test 1+2 usually with the experiment 4 ferret therapeutic indexs (TI) that calculate in this body, for example usually be starkly lower than rat TI (50/50).
In this test 4, use the TI calculation result of known PDE4 inhibitor roflumilast to be about:
The about 0.46mg/kg p.o. of D20=of vomiting,
The about 0.42mg/kg p.o. of the D50=of ferret neutrophilia,
Ferret TI=about 1.1.
All publications of being quoted in this specification sheets (including but not limited to patent and patent application) all are attached to this paper by reference, just as each publication is attached to this paper with its full content separately by reference.
Embodiment
All respects of the present invention are with reference to following examples introduction.These embodiment only are exemplary illustrations, shall not be construed as limitation of the scope of the invention.
In this part, " intermediate " expression is used to synthesize the synthetic method of the midbody compound of " embodiment ", and perhaps " intermediate " expression can be used for the synthetic method of the midbody compound of synthesis type (I) compound or its salt.The The compounds of this invention that " embodiment " is normally exemplary or its salt, for example formula (I) or compound or its salt (IB).
Use following abbreviation:
AcOH acetate
Ac
2The O diacetyl oxide
BEMP 2-tertbutylimido-2-diethylin-1,3-dimethyl-1,3-diaza-2-
Phospha cyclohexane
BOC
2O dimethyl dicarbonate butyl ester
The DMSO methyl-sulphoxide
The DCM methylene dichloride
The DMF dimethyl formamide
DIPEA diisopropylethylamine (' Pr
2NEt)
EDC 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride
The EtOAc ethyl acetate
Et
2The O ether
Et
3The N triethylamine
EtOH ethanol
HATU phosphofluoric acid O-(7-azepine benzo triazol-1-yl)-N, N, N ', N '-tetramethyl-urea
HBTU phosphofluoric acid O-(benzotriazole-1-yl)-N, N, N ', N '-tetramethyl-urea
HOBT hydroxybenzotriazole=I-hydroxybenzotriazole
Lawesson reagent 2, two (the 4-p-methoxy-phenyls)-1 of 4-, 3-dithia-2,4-two phosphorus heterocycle butane-
2,4-disulphide
The MeCN acetonitrile
MeOH methyl alcohol
The THF tetrahydrofuran (THF)
The HPLC high pressure liquid chromatography
The SPE Solid-Phase Extraction
(wherein: s=is unimodal, and d=is bimodal, t=triplet, q=for the NMR nucleus magnetic resonance
Quartet, bimodal bimodal of dd=, m=multiplet, H=proton number)
The LCMS liquid chromatography/mass spectrometry
The TLC thin-layer chromatography
H hour
T
RETRetention time (LCMS)
Room temperature usually about 20 ℃ to about 25 ℃ scope
General experimental detail
Machine Method used herein:
LCMS (liquid chromatography/mass spectrometry)
Waters ZQ mass spectrograph is operated mass range 100-1000amu under the positive ion electrospray spray pattern.
UV wavelength: 215-330nM
Chromatographic column: 3.3cm * 4.6mm ID, 3 μ m ABZ+PLUS
Flow velocity: 3ml/min
Volume injected: 5 μ l
Solvent orange 2 A: 95% acetonitrile+0.05% formic acid
Solvent B:0.1% formic acid+10mM ammonium acetate
Gradient: 0%A/0.7min, 0-100%A/3.5min, 100%A/1.1min, 100-0%A/0.2min
Should be noted in the discussion above that when sample detects on different Waters machines, even the chromatographic column of same type, identical flow velocity, volume injected, solvent and gradient, the retention time (T that provides here are provided
RET) (+/-0.1 minute) also may slightly change.
The mass spectrum monitoring type prepares HPLC automatically
The preparative column that uses is Supelcosil ABZplus (10cm * 2.12cm) (10cm * 2.12cm * 5 μ m usually).
UV wavelength: 200-320nM
Flow velocity: 20ml/min
Volume injected: 1ml; Or more preferably 0.5ml
Solvent orange 2 A: 0.1% formic acid
Solvent B:95% acetonitrile+5% formic acid; Or 99.95% acetonitrile more commonly used+0.05% formic acid
Gradient: 100%A/1min, 100-80%A/9min, 80-1%A/3.5min, 1%A/1.4min, 1-100%A/0.1min
The chiral column of chromatogram purification
ChiralPak AD, ChiralCel OD and ChiralCel OJ post can be from ChiralTechnologies Europe Sarl, Illkirch, France (phone :+33 (0) 388795200; [email protected]; Www.chiral.fr) obtain.
The Whelk-01 post can be from Hichrom, and 1, The Markham Centre, StationRoad, Theale, Reading, Berks.RG7.4PE, United Kingdom (phone :+44 (0) 1189303660; [email protected]; Www.hichrom.co.uk) buy.Hichrom is manufacturers Regis Technologies Inc. (8210 Austin Avenue, MortonGrove, IL60053, USA; Phone :+1-847-967-6000; Www.registech.com) commission merchant.
Intermediate and embodiment
The reagent that does not have hereinafter to describe in detail can obtain from chemical supplier (for example supplier of Que Dinging such as Sigma-Aldrich) usually.The address of the supplier of the part material that following intermediate and embodiment or above measuring method are mentioned or general chemical supplier and/or concrete contact method are as follows:
-AB Chem,Inc.,547 Davignon,Dollard-des-Ormeaux,Quebec,H9B1Y4,Canada
-ABCR GmbH & CO.KG,P.O.Box 21 01 35,76151 Karlsruhe,Germany
-ACB Blocks Ltd;Kolokolnikov Per,9/10 Building 2,Moscow,103045,Russia
-Aceto Color Intermediates (directory name), Aceto Corporation, One HollowLane, Lake Success, NY, 11042-1215, USA
-Acros Organics,A Division of Fisher Scientific Company,500American Road,Morris Plains,NJ 07950,USA
-Apin Chemicals Ltd.,82C Milton Park,Abingdon,Oxon OX14 4RY,United Kingdom
-Apollo Scientific Ltd.,Unit 1A,Bingswood Industrial Estate,WhaleyBridge,Derbyshire SK23 7LY,United Kingdom
-Aldrich (directory name), Sigma-Aldrich Company Ltd., Dorset, UnitedKingdom, phone :+44 1,202 733114; Fax :+44 1,202 715460; [email protected]; Or
-Aldrich (directory name), Sigma-Aldrich Corp., P.O.Box 14508, St.Louis, MO 63178-9916, USA; Phone :+1-314-771-5765; Fax :+1-314-771-5757; [email protected]; Or
-Aldrich (directory name), Sigma-Aldrich Chemie GmbH, Munich, Germany; Phone :+49 89 6,513 0; Fax :+49 89 6,513 1169; [email protected].
-Alfa Aesar,A Johnson Matthey Company,30 Bond Street,Ward Hill,MA 01835-8099,USA
-Amersham Biosciences UK Ltd,Pollards Wood,Chalfont St Giles,Buckinghamshire HP8 4SP,United Kingdom
-Arch Corporation,100 Jersey Avenue,Building D,New Brunswick,NJ08901,USA
-Array Biopharma Inc.,1885 33rd Street,Boulder,CO 80301,USA
-AstaTech,Inc.,8301 Torresdale Ave.,19C,Philadelphia,PA 19136,USA
-Austin Chemical Company,Inc.,1565 Barclay Blvd.,Buffalo Grove,IL 60089,USA
-Avocado Research,Shore Road,Port of Heysham Industrial Park,Heysham,Lancashire LA3 2XY,United Kingdom
-Bayer AG,Business Group Basic and Fine Chemicals,D-51368Leverkusen,Germany
-Berk Univar plc,Berk House,P.O.Box 56,Basing View,Basingstoke,Hants RG21 2E6,United Kingdom
-Bionet Research Ltd;Highfield Industrial Estate,Camelford,CornwallPL32 9QZ UK
-Butt Park Ltd.,Braysdown Works,Peasedown St.John,Bath BA28LL,United Kingdom
-Chemical Building Blocks (directory name), Ambinter, 46 quai LouisBleriot, Paris, F-75016, France
-ChemBridge Europe,4 Clark′s Hill Rise,Hampton Wood,Evesham,Worcestershire WR11 6FW,United Kingdom
-ChemService Inc.,P.O.Box 3108,West Chester,PA 19381,USA
-CiventiChem,PO Box 12041,Research Triangle Park,NC 27709,USA
-Combi-Blocks Inc.,7949 Silverton Avenue,Suite 915,San Diego,CA 92126,USA
-Dynamit Nobel GmbH, Germany; Also can obtain: SavilleWhittle Ltd (the Britain commission merchant of Dynamit Nobel), Vickers Street, ManchesterM40 8EF, United Kingdom from following company
-E.Merck, Germany; Or E.Merck (Merck Ltd), Hunter Boulevard, Magna Park, Lutterworth, Leicestershire LE17 4XN, United Kingdom
-Esprit Chemical Company,Esprit Plaza,7680 Matoaka Road,Sarasota,FL 34243,USA
-Exploratory Library (directory name), Ambinter, 46 quai Louis Bleriot, Paris, F-75016, France
-Fluka Chemie AG,Industriestrasse 25,P.O.Box 260,CH-9471 Buchs,Switzerland
-Fluorochem Ltd.,Wesley Street,Old Glossop,Derbyshire SK13 7RY,United Kingdom
-Heterocyclic Compounds Catalog(Florida Center for HeterocyclicCompounds,University of Florida,PO Box 117200,Gainsville,FL32611-7200 USA
-ICN Biomedicals,Inc.,3300 Hyland Avenue,Costa Mesa,CA 92626,USA
-Interchim Intermediates (directory name), Interchim, 213 Avenue Kennedy, BP 1140, Montlucon, Cedex, 03103, France
-Key Organics Ltd.,3,Highfield Indusrial Estate,Camelford,CornwallPL32 9QZ,United Kingdom
-Lancaster Synthesis Ltd.,Newgate,White Lund,Morecambe,LancashireLA3 3DY,United Kingdom
-Manchester Organics Ltd.,Unit 2,Ashville Industrial Estate,SuttonWeaver,Runcorn,Cheshire WA7 3PF,United Kingdom
-Matrix Scientific,P.O.Box 25067,Columbia,SC 29224-5067,USA
-Maybridge Chemical Company Ltd.,Trevillett,Tintagel,Cornwall PL340HW,United Kingdom
-Maybridge Combichem (directory name), Maybridge Chemical CompanyLtd., Trevillett, Tintagel, Cornwall PL34 0HW, United Kingdom
-Maybridge Reactive Intermediates (directory name), Maybridge ChemicalCompany Ltd., Trevillett, Tintagel, Cornwall PL34 0HW, UnitedKingdom
-MicroChemistry Building Blocks (directory name), MicroChemistry-RadaPharma, Shosse Entusiastov 56, Moscow, 111123, Russia
-Miteni S.p.A.,Via Mecenate 90,Milano,20138,Italy
-Molecular Devices Corporation,Sunnydale,CA,USA
-N.D.Zelinsky Institute,Organic Chemistry,Leninsky prospect 47,117913 Moscow B-334,Russia
-Oakwood Products Inc.,1741,Old Dunbar Road,West Columbia,SC,29172,USA
-OmegaChem Inc.,8800,Boulevard de la Rive Sud,Levis,PQ,G6V9H1,Canada
-Optimer Building Block (directory name), Array BioPharma, 3200 WalnutStreet, Boulder, CO 80301, USA
-Peakdale Molecular Ltd.,Peakdale Science Park,Sheffield Road,Chapel-en-le-Frith,High Peak SK23 0PG,United Kingdom
-Pfaltz & Bauer,Inc.,172 East Aurora Street,Waterbury,CT 06708,USA
-Rare Chemicals (directory name), Rare Chemicals GmbH, Schulstrasse 6,24214 Gettorf, Germany
-SALOR (directory name) (Sigma Aldrich Library of Rare Chemicals), Aldrich Chemical Company Inc, 1001 West Saint Paul Avenue, Milwaukee, WI 53233, USA
-Sigma (directory name), Sigma-Aldrich Corp., P.O.Box 14508, St.Louis, MO 63178-9916, USA; Other non-U.S address and other contact data are referring to above " Aldrich "
-SIGMA-RBI,One Strathmore Road,Natick,MA 01760-1312,USA
-Synchem OHG Heinrich-Plett-Strasse 40,Kassel,D-34132,Germany
-Syngene International Pvt Ltd,Hebbagodi,Hosur Road,Bangalore,India.
-TCI America,9211 North Harborgate Street,Portland,OR 97203,USA
-TimTec Building Blocks A or B,TimTec,Inc.,P O Box 8941,Newark,DE 19714-8941,USA
-TimTec Overseas Stock,TimTec Inc.,100 Interchange Blvd.Newark,DE 19711,USA
-TimTec Stock Library,TimTec,Inc.,P O Box 8941,Newark,DE19714-8941,USA
-Trans World Chemicals,Inc.,14674 Southlawn Lane,Rockville,MD20850,USA
-Ubichem PLC,Mayflower Close,Chandlers Ford Industrial Estate,Eastleigh,Hampshire SO53 4AR,United Kingdom
-Ultrafine(UFC Ltd.),Synergy House,Guildhall Close,ManchesterScience Park,Manchester M15 6SY,United Kingdom
The intermediate table look-up
The intermediate numbering | Title |
1 | 4-chloro-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-ethyl formate |
2 | The 4-amino tetrahydro pyran |
3 | 1-ethanoyl-4-amino piperidine |
4 | 1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-first |
Acetoacetic ester | |
5 | 4-(cyclohexyl amino)-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-ethyl formate |
6 | 4-[(1-ethanoyl-4-piperidyl) amino]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-ethyl formate |
7 | 1-ethyl-4-[(4-hydroxy-cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-ethyl formate |
8 | 1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-ethyl formate |
9 | 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-ethyl formate |
10 | 4-chloro-1-ethyl-6-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-ethyl formate |
11 | 1-ethyl-6-methyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-ethyl formate |
12 | 1-ethyl-4-{[(1SR, 3RS)-the 3-hydroxy-cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-ethyl formate |
13 | 1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-formic acid |
14 | 4-(cyclohexyl amino)-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-formic acid |
15 | 4-[(1-ethanoyl-4-piperidyl) amino]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-formic acid |
16 | 1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-formic acid |
17 | 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-formic acid |
18 | 1-ethyl-6-methyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-formic acid |
19 | 1-ethyl-4-{[(1SR, 3RS)-the 3-hydroxy-cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-formic acid |
20 | N-[(1E)-(2, the 4-3,5-dimethylphenyl) methylene radical]-2-methyl-2-propane sulfinyl amine |
21 | The methylene radical of 2-methyl-N-[(1E)-(2-aminomethyl phenyl)]-2-propane sulfinyl amine |
22 | N-[(1E)-(3-hydroxy phenyl) methylene radical]-2-methyl-2-propane sulfinyl amine |
23 | 2-methyl-N-{ (1E)-[3-(methoxyl group) phenyl] methylene radical }-2-propane sulfinyl amine |
24 | 2-methyl-N-{ (1E)-[4-(methoxyl group) phenyl] methylene radical }-2-propane sulfinyl amine |
25 | N-[(1E)-(4-bromophenyl) methylene radical]-2-methyl-2-propane sulfinyl amine |
26 | The methylene radical of 2-methyl-N-[(1E)-(4-aminomethyl phenyl)]-2-propane sulfinyl amine |
27 | N-{ (1E)-[4-(oxyethyl group) phenyl] methylene radical }-2-methyl-2-propane sulfinyl amine |
28 | 2-methyl-N-{ (1E)-[4-(propoxy-) phenyl] methylene radical }-2-propane sulfinyl amine |
29 | N-((1E)-and the 4-[(difluoromethyl) the oxygen base] phenyl } methylene radical)-2-methyl-2-propane sulfinyl amine |
30 | 2-methyl-N-{ (1E)-[4-(trifluoromethyl) phenyl] methylene radical }-2-propane sulfinyl amine |
31 | 2-methyl-N-{ (1E)-[4-(1-methylethyl) phenyl] methylene radical }-2-propane sulfinyl amine |
32 | N-[(1E)-(2, the 3-3,5-dimethylphenyl) methylene radical]-2-methyl-2-propane sulfinyl amine |
33 | N-[(1E)-(4-chloro-2-fluorophenyl) methylene radical]-2-methyl-2-propane sulfinyl amine |
34 | N-[(1E)-(3, the 4-3,5-dimethylphenyl) methylene radical]-2-methyl-2-propane sulfinyl amine |
35 | N-[(1E)-(3, the 5-3,5-dimethylphenyl) methylene radical]-2-methyl-2-propane sulfinyl amine |
36 | N-[(1E)-(3-chloro-4-aminomethyl phenyl) methylene radical]-2-methyl-2-propane sulfinyl amine |
37 | N-[1-(2, the 4-3,5-dimethylphenyl) ethyl]-2-methyl-2-propane sulfinyl amine |
38 | 2-methyl-N-[1-(2-aminomethyl phenyl) ethyl]-2-propane sulfinyl amine |
39 | N-{1-[4-(oxyethyl group) phenyl] ethyl }-2-methyl-2-propane sulfinyl amine |
40 | N-(1-{4-[(difluoromethyl) oxygen base] phenyl } ethyl)-2-methyl-2-propane sulfinyl amine |
41 | 2-methyl-N-{1-[4-(trifluoromethyl) phenyl] ethyl }-2-propane sulfinyl amine |
42 | N-[1-(2, the 3-3,5-dimethylphenyl) ethyl]-2-methyl-2-propane sulfinyl amine |
43 | N-[1-(4-chloro-2-fluorophenyl) ethyl]-2-methyl-2-propane sulfinyl amine |
44 | N-[1-(3-chloro-4-aminomethyl phenyl) ethyl]-2-methyl-2-propane sulfinyl amine |
45 | 2-methyl-N-[1-(2-aminomethyl phenyl) propyl group]-2-propane sulfinyl amine |
46 | N-[1-(3-hydroxy phenyl) propyl group]-2-methyl-2-propane sulfinyl amine |
47 | 2-methyl-N-{1-[3-(methoxyl group) phenyl] propyl group }-2-propane sulfinyl amine |
48 | 2-methyl-N-{1-[4-(methoxyl group) phenyl] propyl group }-2-propane sulfinyl amine |
49 | N-[1-(4-bromophenyl) propyl group]-2-methyl-2-propane sulfinyl amine |
50 | 2-methyl-N-[1-(4-aminomethyl phenyl) propyl group]-2-propane sulfinyl amine |
50a | The 2-methyl-N-[(1S)-1-(4-aminomethyl phenyl) propyl group]-2-propane sulfinyl amine |
51 | N-{1-[4-(oxyethyl group) phenyl] propyl group }-2-methyl-2-propane sulfinyl amine |
52 | 2-methyl-N-{1-[4-(propoxy-) phenyl] propyl group }-2-propane sulfinyl amine |
53 | N-(1-{4-[(difluoromethyl) oxygen base] phenyl } propyl group)-2-methyl-2-propane sulfinyl amine |
54 | 2-methyl-N-{1-[4-(trifluoromethyl) phenyl] propyl group }-2-propane sulfinyl amine |
55 | 2-methyl-N-{1-[4-(1-methylethyl) phenyl] propyl group }-2-propane sulfinyl amine |
55a | 2-methyl-N-{ (1S)-1-[4-(1-methylethyl) phenyl] propyl group }-2-propane sulfinyl amine |
56 | N-[1-(2, the 3-3,5-dimethylphenyl) propyl group]-2-methyl-2-propane sulfinyl amine |
57 | N-[1-(2, the 4-3,5-dimethylphenyl) propyl group]-2-methyl-2-propane sulfinyl amine |
58 | N-[1-(4-chloro-2-fluorophenyl) propyl group]-2-methyl-2-propane sulfinyl amine |
58a | N-[(1S)-1-(4-chloro-2-fluorophenyl) propyl group]-2-methyl-2-propane sulfinyl amine |
59 | N-[1-(3, the 4-3,5-dimethylphenyl) propyl group]-2-methyl-2-propane sulfinyl amine |
60 | N-[1-(3, the 5-3,5-dimethylphenyl) propyl group]-2-methyl-2-propane sulfinyl amine |
61 | N-[1-(3-chloro-4-aminomethyl phenyl) propyl group]-2-methyl-2-propane sulfinyl amine |
62 | [1-(2, the 4-3,5-dimethylphenyl) ethyl] amine hydrochlorate |
63 | [1-(2-aminomethyl phenyl) ethyl] amine hydrochlorate |
64 | 1-[4-(oxyethyl group) phenyl] and ethyl } amine hydrochlorate |
65 | (1-{4-[(difluoromethyl) oxygen base] phenyl } ethyl) amine hydrochlorate |
66 | 1-[4-(trifluoromethyl) phenyl] and ethyl } amine hydrochlorate |
67 | [1-(2, the 4-3,5-dimethylphenyl) ethyl] amine trifluoroacetate |
68 | [1-(4-chloro-2-fluorophenyl) ethyl] amine hydrochlorate |
69 | [1-(3-chloro-4-aminomethyl phenyl) ethyl] amine hydrochlorate |
70 | [1-(2-aminomethyl phenyl) propyl group] amine hydrochlorate |
71 | 3-(1-aminopropyl) phenolate hydrochlorate |
72 | 1-[3-(methoxyl group) phenyl] and propyl group } amine hydrochlorate |
73 | 1-[4-(methoxyl group) phenyl] and propyl group } amine hydrochlorate |
74 | [1-(4-bromophenyl) propyl group] amine hydrochlorate |
75 | [1-(4-aminomethyl phenyl) propyl group] amine hydrochlorate |
75a | [(1R)-(4-aminomethyl phenyl) propyl group] amine hydrochlorate |
76 | 1-[4-(oxyethyl group) phenyl] and propyl group } amine hydrochlorate |
77 | 1-[4-(propoxy-) phenyl] and propyl group } amine hydrochlorate |
78 | (1-{4-[(difluoromethyl) oxygen base] phenyl } propyl group) amine hydrochlorate |
79 | 1-[4-(trifluoromethyl) phenyl] and propyl group } amine hydrochlorate |
80 | 1-[4-(1-methylethyl) phenyl] and propyl group } amine hydrochlorate |
80a | { (1R)-[4-(1-methylethyl) phenyl] propyl group } amine hydrochlorate |
81 | [1-(2, the 3-3,5-dimethylphenyl) propyl group] amine hydrochlorate |
82 | [1-(2, the 4-3,5-dimethylphenyl) propyl group] amine hydrochlorate |
83 | [1-(4-chloro-2-fluorophenyl) propyl group] amine hydrochlorate |
83a | [(1R)-(4-chloro-2-fluorophenyl) propyl group] amine hydrochlorate |
84 | [1-(3, the 4-3,5-dimethylphenyl) propyl group] amine hydrochlorate |
85 | [1-(3, the 5-3,5-dimethylphenyl) propyl group] amine hydrochlorate |
86 | [1-(3-chloro-4-aminomethyl phenyl) propyl group] amine hydrochlorate |
87 | [1-(3, the 5-3,5-dimethylphenyl) ethyl] amine hydrochlorate |
88 | 3-(1-amino-ethyl) phenolate hydrochlorate |
89 | 1-[4-(1-methylethyl) phenyl] and ethyl } amine hydrochlorate |
90 | [1-(2,3-dihydro-1H-indenes-5-yl) ethyl] amine hydrochlorate |
91 | [1-(5,6,7,8-tetrahydrochysene-2-naphthyl) ethyl] amine hydrochlorate |
92 | (2,2,2-three fluoro-1-phenylethyls) amine hydrochlorate |
93 | [1-(4-bromophenyl)-2,2,2-trifluoroethyl] amine hydrochlorate |
94 | 2,2,2-three fluoro-1-[3-(methoxyl group) phenyl] and ethyl } amine hydrochlorate |
95 | (1-phenyl hexyl) amine hydrochlorate |
96 | (1-phenylpentyl) amine hydrochlorate |
97 | [cyclopropyl (phenyl) methyl] amine hydrochlorate |
98 | (2-methyl isophthalic acid-phenyl propyl) amine hydrochlorate |
99 | (1-phenyl butyl) amine hydrochlorate |
100 | [1-(2, the 4-3,5-dimethylphenyl) ethyl] amine trifluoroacetate |
101 | [1-(2, the 4-3,5-dimethylphenyl) ethyl] amine trifluoroacetate |
102 | 4-[(1-{[(1, the 1-dimethyl ethyl) the oxygen base] carbonyl }-the 4-piperidyl) amino]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-ethyl formate |
103 | 1-ethyl-4-(4-piperidyl amino)-1H-pyrazolo [3,4-b] pyridine-5-ethyl formate hydrochloride |
104 | 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-ethyl formate |
105 | 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-formic acid |
106 | 4-chloro-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-formic acid |
107 | 4-chloro-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-carbonyl chlorine |
108 | 4-chloro-1-ethyl-N-[(1R)-1-(4-aminomethyl phenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
109 | 4-chloro-1-ethyl-N-[(1R)-the 1-phenylethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
110 | [1-(aminocarboxyl)-4-piperidyl] carboxylamine 1,1-dimethyl ethyl ester |
111 | 4-amino-1-piperidine formyl amine hydrochlorate |
112 | [4-(aminocarboxyl) cyclohexyl] carboxylamine 1,1-dimethyl ethyl ester |
113 | 4-aminocyclohexane carboxamide hydrochloride |
114 | [suitable-4-(aminocarboxyl) cyclohexyl] carboxylamine 1,1-dimethyl ethyl ester |
115 | [anti--4-(aminocarboxyl) cyclohexyl] carboxylamine 1,1-dimethyl ethyl ester |
116 | Suitable-4-aminocyclohexane carboxamide hydrochloride |
117 | Instead-4-aminocyclohexane carboxamide hydrochloride |
118 | 4-{[is suitable-4-(aminocarboxyl) cyclohexyl] and amino }-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-ethyl formate |
119 | 4-{[is anti--4-(aminocarboxyl) cyclohexyl] and amino }-1-ethyl-1H-pyrazolo [3,4-b] pyrrole |
Pyridine-5-ethyl formate | |
120 | 4-{[is suitable-4-(aminocarboxyl) cyclohexyl] and amino }-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-formic acid |
121 | 4-{[is anti--4-(aminocarboxyl) cyclohexyl] and amino }-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-formic acid |
122 | 4-chloro-N-[1-(2, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
123 | N-[(1E)-(2-ethylphenyl) methylene radical]-2-methyl-2-propane sulfinyl amine |
124 | N-[(1E)-(4-ethylphenyl) methylene radical]-2-methyl-2-propane sulfinyl amine |
125 | N-[(1E)-(2, the 5-3,5-dimethylphenyl) methylene radical]-2-methyl-2-propane sulfinyl amine |
126 | N-[(1E)-(2, the 6-3,5-dimethylphenyl) methylene radical]-2-methyl-2-propane sulfinyl amine |
127 | The methylene radical of 2-methyl-N-[(1E)-(2,4, the 6-trimethylphenyl)]-2-propane sulfinyl amine |
128 | N-[(1R)-1-(2-ethylphenyl) ethyl]-2-methyl-2-propane sulfinyl amine |
129 | N-[(1R)-1-(4-ethylphenyl) ethyl]-2-methyl-2-propane sulfinyl amine |
130 | N-[(1R)-1-(2, the 5-3,5-dimethylphenyl) ethyl]-2-methyl-2-propane sulfinyl amine |
131 | The 2-methyl-N-[(1R)-1-(2,4, the 6-trimethylphenyl) ethyl]-2-propane sulfinyl amine |
132 | N-[(1S)-1-(2-ethylphenyl) propyl group]-2-methyl-2-propane sulfinyl amine |
133 | N-[(1S)-1-(4-ethylphenyl) propyl group]-2-methyl-2-propane sulfinyl amine |
134 | N-[1-(2, the 5-3,5-dimethylphenyl) propyl group]-2-methyl-2-propane sulfinyl amine |
135 | N-[(1S)-1-(2, the 6-3,5-dimethylphenyl) propyl group]-2-methyl-2-propane sulfinyl amine |
136 | The 2-methyl-N-[(1S)-1-(2,4, the 6-trimethylphenyl) propyl group]-2-propane sulfinyl amine |
137 | [(1R)-and 1-(2-ethylphenyl) ethyl] amine hydrochlorate |
138 | [(1R)-and 1-(4-ethylphenyl) ethyl] amine hydrochlorate |
139 | [(1R)-and 1-(2, the 5-3,5-dimethylphenyl) ethyl] amine hydrochlorate |
140 | [(1R)-and 1-(2,4, the 6-trimethylphenyl) ethyl] amine hydrochlorate |
141 | [(1R)-and 1-(2-ethylphenyl) propyl group] amine hydrochlorate |
142 | [(1R)-and 1-(4-ethylphenyl) propyl group] amine hydrochlorate |
143 | [(1R)-and 1-(2, the 5-3,5-dimethylphenyl) propyl group] amine hydrochlorate |
144 | [(1R)-and 1-(2, the 6-3,5-dimethylphenyl) propyl group] amine hydrochlorate |
145 | [(1R)-and 1-(2,4, the 6-trimethylphenyl) propyl group] amine hydrochlorate |
146 | 4-[((3S)-and 1-{[(1, the 1-dimethyl ethyl) the oxygen base] carbonyl }-the 3-pyrrolidyl) amino]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-ethyl formate |
147 | 4-[((3R)-and 1-{[(1, the 1-dimethyl ethyl) the oxygen base] carbonyl }-the 3-pyrrolidyl) amino]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-ethyl formate |
148 | The 1-ethyl-4-[(3S)-3-pyrrolidyl amino]-1H-pyrazolo [3,4-b] pyridine-5-ethyl formate hydrochloride |
149 | The 1-ethyl-4-[(3R)-3-pyrrolidyl amino]-1H-pyrazolo [3,4-b] pyridine-5-ethyl formate hydrochloride |
150 | 4-{[(3S)-and 1-(aminocarboxyl)-3-pyrrolidyl] amino }-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-ethyl formate |
151 | 4-{[(3R)-and 1-(aminocarboxyl)-3-pyrrolidyl] amino }-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-ethyl formate |
152 | 4-{[(3S)-and 1-(aminocarboxyl)-3-pyrrolidyl] amino }-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-formic acid |
153 | 4-{[(3R)-and 1-(aminocarboxyl)-3-pyrrolidyl] amino }-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-formic acid |
154 | (suitable-4-{[methyl (methoxyl group) amino] carbonyl } cyclohexyl) carboxylamine 1,1-dimethyl ethyl ester |
155 | (suitable-4-ethanoyl cyclohexyl) carboxylamine 1,1-dimethyl ethyl ester |
156 | 1-(suitable-the 4-aminocyclohexyl) acetophenone hydrochloride |
157 | 4-[(4-ethanoyl cyclohexyl) amino]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-ethyl formate (mixture of cis-isomeride and trans-isomer(ide)) |
158 | 4-[(4-ethanoyl cyclohexyl) amino]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-formic acid (mixture of cis-isomeride and trans-isomer(ide)) |
159 | (RS)-[suitable-4-(1-hydroxyethyl) cyclohexyl] carboxylamine 1,1-dimethyl ethyl ester |
160 | (RS)-1-(suitable-the 4-aminocyclohexyl) ethylate hydrochlorate |
161 | 1-ethyl-4-{[(1S, 3S)-and the 3-hydroxy-cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-ethyl formate and 1-ethyl-4-{[(1R, 3R)-and the 3-hydroxy-cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-ethyl formate |
162 | 1-ethyl-4-{[(1R, 3R)-the 3-hydroxy-cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-formic acid |
163 | 4-[(1-{[(1, the 1-dimethyl ethyl) the oxygen base] carbonyl }-the 4-piperidyl) amino]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-formic acid |
164 | 4-{[1-ethyl-5-([(1R)-and 1-(4-aminomethyl phenyl) ethyl] amino } carbonyl)-1H-pyrazolo [3,4-b] pyridin-4-yl] amino }-1-piperidine carboxylic acid 1,1-dimethyl ethyl ester |
165 | 4-{[5-({ [1-(2, the 4-3,5-dimethylphenyl) propyl group] amino } carbonyl)-1-ethyl-1H-pyrazolo [3,4-b] pyridin-4-yl] amino }-1-piperidine carboxylic acid 1,1-dimethyl ethyl ester |
166 | 4-amino-4-(3-aminomethyl phenyl) butyric acid |
167 | 4-({ [(1, the 1-dimethyl ethyl) oxygen base] carbonyl } amino)-4-(3-aminomethyl phenyl) butyric acid |
168 | [4-(dimethylamino)-1-(3-aminomethyl phenyl)-4-oxo butyl] carboxylamine 1,1-dimethyl ethyl ester |
169 | 4-amino-N, N-dimethyl-4-(3-aminomethyl phenyl) butanamide hydrochloride |
Intermediate 1:4-chloro-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-ethyl formate
According to G.Yu etc., J.Med Chem., 2001,44, the method for introducing among the 1025-1027, with commercially available 5-amino-1-ethyl pyrazoles preparation:
Intermediate 1A:4-oxyethyl group-1H-pyrazolo [3,4-b] pyridine-5-ethyl formate
According to T.M.Bare etc., J.Med Chem., 1989,32,2561-2573, (further with reference to Zuleski, F.R., Kirkland, K.R., Melgar, M.D.; Malbica, J.Drug.Metab.Dispos., 1985,13,139) the middle method of introducing, by the oxicracking (SeO of 1-furyl methyl derivative
2) preparation:
Intermediate 2:4-amino tetrahydro pyran
The commercially available prod: Combi-Blocks Inc., 7949 Silverton Avenue, Suite 915, San Diego, CA 92126, USA (CAS38041-19-9)
Intermediate 2A: tetrahydrochysene-2H-pyrans-4-amine hydrochlorate=4-amino tetrahydro pyran hydrochloride
Step 1:N, N-dibenzyl tetrahydrochysene-2H-pyrans-4-amine
At 0 ℃-5 ℃, dibenzylamine (34.5g) and acetate (6.7ml) are joined the stirred solution of tetrahydrochysene-4H-pyrans-4-ketone (16.4g, can from the commercially available prod that for example Aldrich obtains) and methylene dichloride (260ml).At 0 ℃-5 ℃ after 2.5 hours, add sodium triacetoxy borohydride (38.9g) in batches, allow mixture rise to room temperature.At room temperature stir spend the night after, with reaction mixture with 2M-sodium hydroxide (200ml and 50ml), water (2 * 50ml) and salt solution (50ml) wash successively, then drying, evaporate, obtain yellow oil (45g).Oily matter was stirred 30 minutes at 4 ℃ with methyl alcohol (50ml), obtain white solid product (21.5g).LCMS shows MH
+=282; T
RET=1.98min.
Step 2: tetrahydrochysene-2H-pyrans-4-amine hydrochlorate
With N, N-dibenzyl tetrahydrochysene-2H-pyrans-4-amine (20.5g) is dissolved in ethanol (210ml), at room temperature through 10% palladium/carbon catalyst (4g) in 100psi hydrogenation 72 hours.Filter reaction mixture is adjusted to pH 1 with 2M hydrogenchloride/diethyl ether solution with filtrate.Evaporating solvent obtains solid, and it is ground with ether, obtains white solid product (9.23g).
1H NMR(400MHz in d
6-DMSO,27℃,δppm)8.24(br,s,3H),3.86(dd,12,4Hz,2H),3.31(dt,2,12Hz,2H),3.20(m,1H),1.84(m,2H),1.55(dq,4,12Hz,2H)。
Intermediate 3:1-ethanoyl-4-amino piperidine
According to Yamada etc., the method for introducing among the WO 00/42011 prepares with commercially available N1-benzyl-4-amino piperidine::
Intermediate 4:1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-ethyl formate
Intermediate 1 (0.20g) and triethylamine (0.55ml) are suspended in ethanol (8ml), and adding 4-amino tetrahydro pyran (intermediate 2,0.088g).Mixture is stirred under nitrogen atmosphere, at 80 ℃ of heating 16 hours, vacuum concentration then.Resistates distributes between DCM and water.Separate each layer, with organic layer directly be loaded into the SPE post (silica gel, 5g) on, with it with following solvent sequentially eluting: (i) DCM, (ii) DCM: Et
2O (2: 1), (iii) DCM: Et
2O (1: 1), (iv) Et
2O and (v) EtOAc.Merge the part that comprises required product, vacuum concentration obtains intermediate 4 (0.21g).LCMS shows MH
+=319; T
RET=2.93min.
Prepare following compounds similarly with intermediate 1:
Intermediate 4
Substitute synthesis method: the method shown in more than substituting, the also available following method B preparation of intermediate 4:
Intermediate 1 (2.5g) is dissolved in acetonitrile (15ml).Add 4-amino tetrahydro pyran hydrochloride (intermediate 2A) (1.1g) and N, N-diisopropylethylamine (9.4ml) stirred the mixture 16 hours under nitrogen atmosphere, 85 ℃.Therefore residue trace raw material adds part 4-amino tetrahydro pyran hydrochloride (0.11g) again, continues to stir 16 hours at 85 ℃.Then with the mixture vacuum concentration.Resistates distributes between DCM and water.Separate each layer, organic layer water (2 * 20ml) further washings, dry then (Na
2SO
4), vacuum concentration.(silica gel, 90g) chromatogram is further purified, and uses hexanaphthene: eluent ethyl acetate obtains intermediate 4 (2.45g) to resistates with Biotage.LCMS shows MH
+=319; T
REK=2.90min.
Intermediate 7:1-ethyl-4-[(4-hydroxy-cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-ethyl formate
(1.5g 5.9mmol) is dissolved in MeCN (80ml) with intermediate 1.(6.18ml 35.5mmol), stirred the mixture 16 hours at 85 ℃ to add anti--4-Trans-4-Amino Cyclohexanol (0.817g, 7.1mmol obtain or (for example as hydrochloride) from TCI-America Aldrich) and DIPEA.Vacuum concentrated mixture, resistates distribute between DCM (120ml) and water (30ml).Separate each phase, with organic phase drying (Na
2SO
4), evaporation obtains light yellow solid.Solid is dissolved in the mixture of DCM (10ml) and chloroform (3ml), with the SPE post of sample to two on the identical deal (silica gel, 20g) on, with its EtOAc: hexanaphthene (being followed successively by 1: 16,1: 8,1: 4,1: 2,1: 1 and 1: 0) sequentially eluting with gradient.Merge the part that comprises required product, vacuum-evaporation obtains intermediate 7 (1.89g, white solid).LCMS shows MH
+=333; T
REK=2.79min.
Intermediate 8:1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-ethyl formate
(1.893g 5.7mmol) is suspended in acetone (12ml), at 0 ℃, the suspension that stirs is handled with Jones reagent (1.81ml) with intermediate 7.After 30 minutes, in maintaining 0 ℃ reaction mixture, add Jones reagent (1.81ml) once more.After 2 hours, in reaction mixture, add last part Jones reagent (1.44ml), and continue to stir 1 hour at 0 ℃.Add Virahol (3.8ml), water (15ml) in the reaction mixture successively.(2 * 40ml) extract the gained mixture with EtOAc.Organic extract liquid water (8ml) washing that merges, dry (Na
2SO
4), evaporation obtains gray solid.Solid is dissolved in DCM (10ml), with the SPE post of sample to two on the identical deal (silica gel, 20g) on, with its EtOAc: hexanaphthene (being followed successively by 1: 16,1: 8,1: 4,1: 2 and 1: 1) sequentially eluting with gradient.Merge the part that comprises required product, vacuum-evaporation obtains intermediate 8 (1.893g, white solid).LCMS shows MH
+=331; T
RET=2.84min.
Intermediate 9:1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-ethyl formate
Stir the mixture of intermediate 8 (200mg), hydroxylamine hydrochloride (50mg), Anhydrous potassium carbonate (420mg) and MeCN (10ml), reflux 17 hours.Cooling solution, vacuum concentration.Resistates distributes between EtOAc and water.Isolate organic phase, through dried over sodium sulfate, vacuum concentration, obtain intermediate 9 (white powder, 203mg).LCMS shows MH
+=346; T
RET=2.84min.
Intermediate 10:4-chloro-1-ethyl-6-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-ethyl formate
With 5-amino-1-ethyl pyrazoles (1.614g, 14.5mmol) and 2-(1-oxyethyl group ethylidene) diethyl malonate (3.68g, 16.0mmol, according to P.P.T.Sah, J.Amer.Chem.Soc., 1931,
53, the method for introducing in 1836) mixture under Dean Stark condition in 150 ℃ of heating 5 hours.Phosphoryl chloride (25ml) is carefully joined in the mixture, 130 ℃, reflux under heating gained solution 18 hours.Vacuum concentrated mixture under cooling, joins remaining oily matter in the water (100ml) then carefully.(3 * 100ml) extract the organic extract liquid anhydrous Na of merging to the gained mixture with DCM
2SO
4Drying, vacuum concentration.(silica gel, 90g) purifying is with EtOAc-sherwood oil (1: 19) wash-out with the Biotage chromatogram for remaining oily matter.Merge the part that comprises required product, vacuum concentration obtains intermediate 10 (1.15g).LCMS shows MH
+=268; T
RET=3.18min.
Intermediate 11:1-ethyl-6-methyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-ethyl formate
With 4-amino tetrahydro pyran hydrochloride (intermediate 2A, 0.413g, 3.0mmol) join intermediate 10 (0.268g, 1.0mmol), (0.87ml is 5.0mmol) and in the mixture of MeCN (3ml) for DIPEA.Heated the gained mixtures 24 hours at 85 ℃.Vacuum is removed volatile matter, and resistates is dissolved in chloroform (1.5ml), last sample to the SPE post (silica gel, 5g) on.This post is used Et successively
2O, EtOAc and EtOAc-MeOH (9/1) wash-out.Merge the part that comprises required product, vacuum concentration obtains by the required product of contamination of raw material (intermediate 10).(silica gel 5g) is further purified, and with EtOAc-hexanaphthene (1: 3) wash-out, obtains intermediate 11 (0.248g) with the SPE post.LCMS shows MH
+=333; T
RET=2.75min.
Intermediate 12:1-ethyl-4-{[(1SR, 3RS)-the 3-hydroxy-cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-ethyl formate
[suitable-(3-hydroxyl hexamethylene-1-yl) amino, racemic]
With 3-Trans-4-Amino Cyclohexanol (0.677g, 5.9mmol, J.Chem.Soc. for example, PerkinTrans 1,1994,537 to have introduced 3.3: 1 of 3-Trans-4-Amino Cyclohexanol suitable: MeCN anti-preparation process of mixture) (10ml) and EtOH (1ml) at room temperature join intermediate 1 (1.24g, 4.9mmol), DIPEA (4.26ml, 24.5mmol) and the stirred solution of MeCN (25ml).Stirred the gained mixture 17 hours at 85 ℃.Vacuum concentrated mixture, resistates distribute between DCM (50ml) and water (10ml).Separate each phase, with organic phase drying (Na
2SO
4), evaporation obtains orange-brown oily matter.Oily matter with the Biotage chromatogram purification (silica gel, 100g), with 30-50%EtOAc/ hexanaphthene wash-out, obtain intermediate 12 (white foam shape thing, 0.68g).LCMS shows MH
+=333; T
RET=2.76min.
Intermediate 13:1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-formic acid
The ethanol of intermediate 4 (0.21g): water (95: 5,10ml) handled with sodium hydroxide (0.12g) by solution.50 ℃ of heated mixt 8 hours, vacuum concentration was water-soluble then, is acidified with acetic acid to pH 4.The gained white solid is shifted out in filtration, vacuum-drying, obtain intermediate 13 (pale solid, 0.156g).LCMS shows MH
+=291; T
RET=2.11min.
A kind of alternative preparation method of intermediate 13:
The ethanol of intermediate 4 (37.8g): water (4: 1,375ml) handled with sodium hydroxide (18.9g) by solution.50 ℃ of heated mixt 5 hours, vacuum concentration was water-soluble then, and (2M) is acidified to pH 2 with aqueous hydrochloric acid.The gained white solid is shifted out in filtration, vacuum-drying, obtain intermediate 13 (pale solid, 29.65g).LCMS shows MH
+=291; T
RET=2.17min.
Intermediate 14:4-(cyclohexyl amino)-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-formic acid
(5.37g, (2.72g, water 68mmol) (20ml) solution-treated stirred the gained mixture 3 hours at 50 ℃ to EtOH 17mmol) (30ml) solution to intermediate 5 with sodium hydroxide.The vacuum concentration reaction mixture, water-soluble (250ml), refrigerative solution use the 5M hcl acidifying to pH 1.Filter to collect the gained solid, vacuum-drying, obtain intermediate 14 (white solid, 4.7g).LCMS shows MH
+=289; T
RET=2.83min.
Intermediate 15:4-[(1-ethanoyl-4-piperidyl) amino]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-formic acid
(8.55ml 2M) joins in EtOH (13ml) solution of intermediate 6 (1.55g) with aqueous sodium hydroxide solution.50 ℃ of heated mixt 18 hours; neutralize with aqueous hydrochloric acid then; vacuum-evaporation; obtain 1-ethyl-4-(4-piperidyl amino)-1H-pyrazolo [3; 4-b] pyridine-5-formic acid and 4-[(1-ethanoyl-4-piperidyl) amino]-mixture of 1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-formic acid.
Acetate (0.36ml) is joined in the stirring the mixture of HATU (2.41g), DIPEA (2.21ml) and DMF (65ml).Stir after 15 minutes; mixture is joined 1-ethyl-4-(4-piperidyl amino)-1H-pyrazolo [3; 4-b] pyridine-5-formic acid and 4-[(1-ethanoyl-4-piperidyl) amino]-mixture of 1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-formic acid in, stirred reaction mixture 15 hours.The vacuum concentration reaction mixture, (silica gel, 90g) purifying are used DCM: MeOH (0%-5%MeOH) wash-out obtains intermediate 15 (1.36g, white solid) to resistates with the Biotage chromatogram.LCMS shows MH
+=334; T
RET=2.06min.
Intermediate 16:1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-formic acid
(0.053g, water 1.32nmol) (0.41ml) solution join intermediate 8, and (0.1g is in the stirred solution of ethanol 0.303mmol) (1ml), at 50 ℃ of heating gained mixtures with sodium hydroxide.After 1 hour, the refrigerative reaction mixture is adjusted to pH 3 with 2M hydrochloric acid, with EtOAc (2 * 6ml) extractions.With the organic extract liquid drying (Na that merges
2SO
4), evaporation obtains intermediate 16 (0.072g, white solid).LCMS shows MH
+=303; T
RET=2.13min.
A kind of alternative preparation method of intermediate 16:
(0.792g, water 19.8mmol) (6ml) solution join intermediate 8, and (1.487g is in the stirred solution of EtOH 4.5mmol) (15ml), at 50 ℃ of heating gained mixtures with sodium hydroxide.After 1 hour, the refrigerative reaction mixture is adjusted to pH 4 with 2M hydrochloric acid, with EtOAc (3 * 30ml) extractions.With the organic extract liquid drying (Na that merges
2SO
4), evaporation obtains intermediate 16 (1.188g, white solid).LCMS shows MH
+=303; T
RET=2.12min.
Intermediate 17:1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-formic acid
With intermediate 16 (0.58g, 1.92mmol), hydroxylamine hydrochloride (0.26g, 3.74mmol) and DIPEA (0.65g, MeCN 5.03mmol) (35ml) solution stirring, reflux 3 hours, cooling then, standing over night at room temperature.Under agitation add Glacial acetic acid (1ml).The vacuum concentration reaction mixture.Add EtOAc (10ml), stirred gained suspension 30 minutes.Go up then sample to the SPE post (silica gel, 20g) on.This post is used the mixture (250: 1) of EtOAc and Glacial acetic acid successively, and the mixture of EtOAc, MeOH and Glacial acetic acid (500: 16: 1) wash-out obtains intermediate 17 (0.327g, white solid).LCMS shows MH
+=318; T
RET=2.21min.
Intermediate 18:1-ethyl-6-methyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-formic acid
With the 2M sodium hydroxide solution (0.75ml, 1.5mmol) join intermediate 11 (0.248g, in EtOH 0.75mmol) (2ml) solution, reflux mixture 16 hours.Reaction mixture is concentrated, and water (1ml) dilution with 2M hydrochloric acid (0.75ml) acidifying, to be settled out solid, to be filtered and is collected, and obtains intermediate 18 (0.168g).LCMS shows MH
+=305; T
RET=1.86min.
Intermediate 19:1-ethyl-4-{[(1SR, 3RS)-the 3-hydroxy-cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-formic acid
(suitable-3-hydroxyl hexamethylene-1-base is amino, racemic)
With intermediate 12 (0.681g, EtOH 2.05mmol) (7ml) solution sodium hydroxide (0.362g, water 9.05mmol) (2.9ml) solution-treated.Stir the gained mixture at 50 ℃.After 3 hours, the vacuum concentration reaction mixture obtains remaining oily matter, and with its water-soluble (3ml), cooling then uses the 2M hcl acidifying to pH 3.Stirred 1 hour at 0 ℃, filter and collect the gained precipitation, with cold water (0.5ml) washing, vacuum-drying, obtain intermediate 19 (white solid, 0.491g).LCMS shows MH
+=305; T
RET=2.14min.
Intermediate 20-86
Adopt D.A.Cogan, and the method for G.Liu and J.Ellman exploitation (Tetrahedron, 1999,55,8883-8904), after improving, be used for the preparation of these intermediates.At Cogan, Liu in the paper of Ellman, uses (S)-tertiary butyl sulfinyl amine in the chemical reaction that similar and following intermediate 20-86 describes, it is said at the carbon atom place adjacent shown below, obtain the product that general stereochemical structure is the diastereomer enrichment with nitrogen-atoms:
(promptly insert the R in the paper as shown in the figure
4Group, branched chain type benzyl only are exemplary examples); This stereochemical structure (R in the paper
4) generation (promptly before any optional diastereomeric separation) in the reaction that forms carbon-carbon bond.Therefore believe, contain enantiomer/diastereomer that the substituent compound of α (intermediate 37-86) enrichment has (R) stereochemical structure (at the benzylic carbon atoms place) at the benzylic carbon atoms place.
Intermediate 20:N-[(1E)-(2, the 4-3,5-dimethylphenyl) methylene radical]-2-methyl-2-propane sulfinyl amine
With (S)-tertiary butyl sulfinyl amine (0.20g, THF 1.65mmol) (2ml) solution joins 2, (0.22g is 1.57mmol) (for example from Aldrich obtain) for the 4-dimethylbenzaldehyde.Solution is supplemented to 10ml with THF.Add titanium ethanolate (0.75g, 3.38mmol), in 75 ℃ of reacting by heating mixtures 2 hours.Reaction mixture is poured in the saturated brine under vigorous stirring.Diatomite is joined in the gained suspension, filter, wash with DCM.By hydrophobic filter plate with organic phase and aqueous phase separation.Evaporate DCM.Resistates is used mixture (4: the 1) wash-out of mixture (9: 1), hexanaphthene and the EtOAc of hexanaphthene and EtOAc successively with 50g SPE column purification.Merge the part that comprises required product, vacuum concentration obtains intermediate 20 (0.29g, white solid).LCMS shows MH
+=238; T
RET=3.43min.
According to similar method, prepare following intermediate 21-36 with (S)-tertiary butyl sulfinyl amine and suitable commercially available aldehyde (phenyl aldehyde of replacement):
Intermediate 37:N-[1-(2, the 4-3,5-dimethylphenyl) ethyl]-2-methyl-2-propane sulfinyl amine
Under agitation, with the Et of 3.0M methyl-magnesium-bromide
2O solution (2.6ml) is added drop-wise to intermediate 20, and (0.14g is 0.59mmol) and in-10 ℃ of solution of anhydrous THF (5ml).-10 ℃ of stirred reaction mixtures 3 hours, in 24 hours, progressively rise to 20 ℃ then.Reaction mixture to 0 ℃ drips saturated ammonium chloride under vigorous stirring.In case stop bubbling, add ammonium chloride (5ml) again, then add DCM (30ml).Stirred reaction mixture 30 minutes filters organic phase by hydrophobic filter plate then.Evaporation DCM, remaining intermediate 37 (0.15g, white solid) (mixture of diastereomer believes that enrichment has the diastereomer at (R) stereochemical structure (at the benzylic carbon atoms place)).LCMS shows MH
+=254; T
RET=3.13min.
According to similar method, with the diethyl ether solution (R of intermediate 20-36 and 3.0M methyl-magnesium-bromide
4=Me) or the diethyl ether solution (R of 3.0M ethylmagnesium bromide
4=Et) preparation following intermediate 38-61:
(believing that enrichment has the diastereomer at (R) stereochemical structure (at the benzylic carbon atoms place))
The diastereomer of separation of intermediates 57
The mixture of diastereomer (intermediate 57 3g) obtains following two kinds of diastereomers of intermediate 57 with silica gel short column chromatography purifying (is elutriant with 10-50% ethyl acetate/cyclohexane give):
Intermediate 57a (diastereomer 1):
Output=322mg (less important diastereomer believes to have (S) stereochemical structure at the benzylic carbon atoms place).
LCMS shows MH
+=268; T
RET=3.23min.
Intermediate 57b (diastereomer 2):
Output=1.76g (main diastereomer believes to have (R) stereochemical structure at the benzylic carbon atoms place).
LCMS shows MH
+=268; T
RET=3.23min.
The racemoid of relevant following intermediate 62 is referring to Tim Tec Building Blocks B:
Intermediate 62:1-(2, the 4-3,5-dimethylphenyl) ethyl] amine hydrochlorate
(believe it is the mixture of enantiomer, and main enantiomer having (R) stereochemical structure)
Allow intermediate 37 (151mg, 0.60mmol), the solution left standstill of 4.0M hydrogenchloride/two alkane (1ml) and MeOH (1ml) 1 hour.Evaporating solvent.Resistates is used the Et that contains several MeOH
2O grinds, and obtains solids suspension.Leach solid, drying obtains intermediate 62 (76mg, white solid).LCMS shows MH
+=150; T
RET=1.84min.
Prepare following intermediate 63-86 with intermediate 38-61 according to similar method:
(except that intermediate 82a and 82b, believe that intermediate 63-86 is the mixture of enantiomer, and main enantiomer having (R) stereochemical structure)
Intermediate 87:[1-(3, the 5-3,5-dimethylphenyl) ethyl] amine hydrochlorate (Jpn.Kokai Tokkyo KohoJP 62294669 (1987))
(racemic)
With (3, the 5-dimethyl) methyl phenyl ketone (0.95g, 7.0mmol) (for example can obtain) from LancasterSynthesis, methane amide (1.4ml, 1.58g, 35.0mmol) and formic acid (0.81ml, 0.97g, mixture 21.0mmol) 160 ℃ the heating 18 hours.Reaction mixture is distributed between EtOAc and water.Isolate organic phase, with solution of potassium carbonate and sodium chloride solution washing, through dried over sodium sulfate, vacuum concentration.Resistates is handled with 2M hydrochloric acid (10ml), with gained mixture reflux 18 hours, is cooled to room temperature, with DCM (2 * 10ml) washings.The vacuum concentration aqueous solution, remaining intermediate 87 (0.42g, white solid).LCMS shows MH
+=150; T
RET=1.88min.
According to similar method, (be compounds X-C (O)-Ar, wherein Ar is for choosing the phenyl that replaces wantonly or condensing C with suitable acetophenone derivs
5-6The phenyl of cycloalkyl, X are R
4Perhaps R
5) the following racemic intermediate 88-99 of (except as otherwise noted, otherwise be the commercially available prod) preparation:
(racemic)
Intermediate 100-101:[1-(2, the 4-3,5-dimethylphenyl) ethyl] the amine trifluoroacetate
[(R)-and (S)-enantiomer]
Intermediate 62 (0.40g) splits with preparation type chiral column chromatogram, adopts 2 inches * 20 centimetres ChiralCel OJ posts, and usefulness contains the heptane of 0.1% trifluoroacetic acid and alcoholic acid mixture (2: 98) as eluent.With the intermediate 100 (enantiomer of wash-out at first: 0.21g) with the intermediate 101 (enantiomer of wash-out secondly: 0.12g) on this post, separate.LCMS shows the MH of two kinds of enantiomers
+=150; T
RET=1.76min.
Intermediate 102:4-[(1-{[(1, the 1-dimethyl ethyl) the oxygen base] carbonyl }-the 4-piperidyl) amino]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-ethyl formate
With acetonitrile (50ml) solution of intermediate 1 (2.3g) solid 4-amino-1-piperidine carboxylic acid 1,1-dimethyl ethyl ester (2g for example can obtain from AstaTech) and DIPEA (8.6ml) handle.In 90 ℃ of reacting by heating mixtures 16 hours.Removal of solvent under reduced pressure, resistates are distributed between DCM (100ml) and water (75ml).Collect organic moiety by hydrophobic filter plate, removal of solvent under reduced pressure, obtain intermediate 102 (white solid, 3.9g).LCMS shows MH
+=418; T
RET=3.35min.
Intermediate 103:1-ethyl-4-(4-piperidyl amino)-1H-pyrazolo [3,4-b] pyridine-5-ethyl formate hydrochloride
With 4.0M hydrogenchloride/1,4-two alkane (30ml) were handled with intermediate 102 (3.9g), 22 ℃ of stirred reaction mixtures 1 hour.Remove and to desolvate, obtain intermediate 103 (white solid, 3.9g).LCMS shows MH
+=318; T
RET=2.21min.
Intermediate 104:4-{[1-(aminocarboxyl)-4-piperidyl] amino }-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-ethyl formate
Use trimethylsilyl isocyanate (1.99ml), DIPEA (2.6ml) to handle successively THF (100ml) suspension of intermediate 103 (3.9g), 22 ℃ of stirred solutions 2 hours.Volatile solvent is removed in decompression, and resistates distributes between DCM (50ml) and water (25ml).Collected organic layer.Water extracts once more with DCM (50ml).Merge organic layer, by hydrophobic filter plate and water sepn, concentrating under reduced pressure, obtain intermediate 104 (white solid, 3.9g).LCMS shows MH
+=361; T
RET=2.45min.
Intermediate 105:4-{[1-(aminocarboxyl)-4-piperidyl] amino }-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-formic acid
With ethanol (50ml) solution of intermediate 104 (3.9g) water (20ml) solution-treated, in 80 ℃ of reacting by heating mixtures 16 hours with sodium hydroxide (1.77g).LCMS shows the urea moiety generation hydrolysis of part.Remove and desolvate,, regulate pH to 3 (2M HCl), filter and collect gained white precipitate, drying resistates water-soluble (5ml).Precipitation is dissolved in ethanol.Solution is handled with trimethylsilyl isocyanate (3ml) and DIPEA (10ml), stirs 16 hours at 22 ℃ then.Remove and to desolvate,, regulate pH to 3 (2MHCl), filter and collect the gained white precipitate resistates water-soluble (5ml), drying, obtain intermediate 105 (white solid, 2.66g).LCMS shows MH
+=333; T
RET=2.00min.
Intermediate 106:4-chloro-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-formic acid
With 1 of intermediate 1 (20g), 4-two alkane (100ml) solution are with water (30ml) solution-treated of potassium hydroxide (18g), 22 ℃ of stirred reaction mixtures 24 hours.Evaporating solvent is acidified to pH 3 (2M HCl) with resistates.Filter to collect the gained white precipitate, drying, obtain intermediate 106 (white solid, 16.9g).LCMS shows MH
+=226; T
RET=2.45min.
Substitute synthesis method: water (20ml) solution-treated of two alkane (28ml) solution of intermediate 1 (3.5g) being used potassium hydroxide (6.3g).Stirred the mixture 2 hours, vacuum concentration is acidified to pH 3 with the 2M aqueous hydrochloric acid then, uses ethyl acetate extraction.Separate each layer, organic layer is through dried over sodium sulfate, vacuum concentration then, obtain intermediate 106 (white solid, 2.4g).LCMS shows MH
+=226; T
RET=2.62min.
Intermediate 107:4-chloro-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-carbonyl chlorine
With thionyl chloride (100ml) vlil of intermediate 106 (17.8g) 3.5 hours.Cooling solution is to room temperature.Vacuum is removed thionyl chloride, and any remaining thionyl chloride is by removing with toluene (30ml) component distillation, obtain intermediate 107 (the light brown solid, 16.8g).LCMS (MeOH solution) shows MH
+=240 (methyl esters); T
RET=2.88min.
Intermediate 108:4-chloro-1-ethyl-N-[(1R)-1-(4-aminomethyl phenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
THF (20ml) solution of intermediate 107 (2.0g) is handled with (R)-(+)-1-(4-aminomethyl phenyl) ethamine (1.11g) (for example can obtain from Lancaster Synthesis) and DIPEA (1.06g).22 ℃ of stirred reaction mixtures 24 hours.Evaporating solvent is dissolved in DCM (50ml) with resistates.Solution washs with 5% citric acid solution (50ml) and 0.5M sodium hydrogen carbonate solution (50ml), dry (Na
2SO
4), filter the back and concentrate, obtain intermediate 108 (white solid, 1.61g).LCMS shows MH
+=343; T
RET=3.22min.
According to similar method, be fit to the following intermediate 109 of (R)-(+)-1-phenyl-ethyl amine (for example obtaining) preparation from Aldrich:
Intermediate 109:4-chloro-1-ethyl-N-[(1R)-the 1-phenylethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
LCMS shows MH
+=329; T
RET=3.0min.
Intermediate 110:[1-(aminocarboxyl)-4-piperidyl] carboxylamine 1,1-dimethyl ethyl ester
With 4-piperidyl amino formic acid 1, DCM (10ml) solution of 1-dimethyl ethyl ester (0.35g for example can obtain from Syngene or AstaTech) is handled with trimethylsilyl isocyanate (1.1ml).22 ℃ of stirred reaction mixtures 72 hours.Mixture dilutes with saturated sodium bicarbonate solution (20ml).Collect organic phase by hydrophobic filter plate, evaporation, obtain intermediate 110 (white foam shape thing, 0.29g).
1H NMR(400MHz inCDCl
3,27℃,δppm)4.45(br,s,3H).3.90(d,2H),3.65(br,m,1H),2.9-3.0(dt,2H),1.95-2.0(br,dd,2H),1.45(s,9H),1.3-1.4(dq,2H)。
Intermediate 111:4-amino-1-piperidine formyl amine hydrochlorate
With 4.0M hydrogenchloride/1 of intermediate 110 (0.29g), 4-two alkane (5ml) solution stirred 4 hours at 22 ℃.Evaporating solvent, obtain intermediate 111 (white foam shape thing, 0.27g).
1H NMR(400MHz in d
6-DMSO,27℃,δppm)8.1(br,s,2H),3.95(d,2H),3.15(m,1H),2.7(dt,2H),1.85(dd,2H),1.35(m,2H)。
Intermediate 112:[4-(aminocarboxyl) cyclohexyl] carboxylamine 1,1-dimethyl ethyl ester
(Fluka, DMF 1g) (30ml) solution is handled with HATU (1.72g) and DIPEA (5.4ml) with 4-({ [(1, the 1-dimethyl ethyl) oxygen base] carbonyl } amino) naphthenic acid.22 ℃ of stirred reaction mixtures 10 minutes.Add 0.5M ammonia/1,4-two alkane solution (40ml) were 22 ℃ of stirred reaction mixtures 72 hours.Evaporating solvent, following purifying resistates: crude mixture is loaded on the 50g aminopropyl SPE post, uses ethyl acetate (100ml), methyl alcohol (100ml) wash-out successively.Methyl alcohol partly is evaporated to yellow oily, thereby isolates intermediate 112 (0.99g).LCMS shows MH
+=242; T
RET=2.2min.
Intermediate 113:4-aminocyclohexane carboxamide hydrochloride
With 4.0M hydrogenchloride/1,4-two alkane (14ml) joined in the intermediate 112 (0.99g), 22 ℃ of stirred reaction mixtures 30 minutes.Evaporating solvent obtains yellow gumminess intermediate 113 (1.03g).
1H NMR(400MHz in d
6-DMSO,27℃,δppm)7.9(br,S,2H),3.9(br,S,2H),3.10(m,1H),1.92(m,2H),1.68(m,4H),1.50(m,2H)。
Intermediate 114:[is suitable-4-(aminocarboxyl) cyclohexyl]-carboxylamine 1,1-dimethyl ethyl ester
With suitable-4-({ [(1, the 1-dimethyl ethyl) oxygen base] carbonyl } amino) hexanaphthene-formic acid (5.0g) (for example can obtain), EDC (5.9g) and HOBT (4.17g) solution stirring 20 minutes from Fluka.Add ammonia solution (proportion=0.88; 8ml).At room temperature stirred reaction mixture spends the night, and vacuum concentration distributes between DCM and saturated sodium bicarbonate solution.Isolate water, wash with DCM.The organism that merges is through dried over mgso, and vacuum concentration obtains intermediate 114 (4.84g, white solid).LCMS shows MH
+=243; T
RET=2.3min.
According to similar approach, prepare following intermediate 115 with anti--4-({ [(1, the 1-dimethyl ethyl) oxygen base] carbonyl } amino) naphthenic acid (for example can obtain) from Fluka:
Intermediate 115:[is anti--4-(aminocarboxyl) cyclohexyl]-carboxylamine 1,1-dimethyl ethyl ester
LCMS shows MNH
4 +=260; T
RET=2.24min.
Intermediate 116: suitable-4-aminocyclohexane carboxamide hydrochloride
4.0M HCl/ two alkane (50ml) are joined in the stirred solution of intermediate 114 (4.84g) and two alkane (100ml).At room temperature stirred reaction mixture is 1 hour, leaves standstill 3 days at 0 ℃ then.The vacuum concentration reaction mixture obtains intermediate 116 (4.1g, white solid).LCMS shows MH
+=143; T
RET=0.31min.
According to similar approach, prepare following intermediate 117 with intermediate 115:
Intermediate 117: anti--4-aminocyclohexane carboxamide hydrochloride
LCMS shows MH
+=143; T
RET=0.30min.
Intermediate 118:4-{[is suitable-4-(aminocarboxyl) cyclohexyl] and amino }-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-ethyl formate
With ethanol (140ml) solution stirring of intermediate 1 (2.0g), intermediate 116 (1.55g) and DIPEA (6.9ml), reflux spends the night.Add intermediate 116 (420mg) and DIPEA (3.5ml) once more.Stirred reaction mixture, reflux spends the night, cooling, vacuum concentration.Resistates distributes between DCM and saturated sodium bicarbonate solution.The vacuum concentration organic phase.The mixture of resistates with DCM and hexanaphthene ground, obtain solid.Leach solid, drying obtains intermediate 118 (2.16g, yellow solid).LCMS shows MH
+=360; T
RET=2.56min.
According to similar approach, prepare following intermediate 119 with intermediate 1 and intermediate 117:
Intermediate 119:4-{[is anti--4-(aminocarboxyl) cyclohexyl] and amino }-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-ethyl formate
LCMS shows MH
+=360; T
RET=2.84min.
Intermediate 120:4-{[is suitable-4-(aminocarboxyl) cyclohexyl] and amino }-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-formic acid
Intermediate 118 (1.54g), sodium hydroxide (0.68g) and 95% aqueous ethanolic solution (EtOH that contains 5% water) mixture (60ml) is stirred, 50 ℃ of heated overnight.Solvent removed in vacuo.Resistates is water-soluble.Under agitation cooling solution is to 0-5 ℃, with 2M HCl acidifying.With gained suspension refrigeration 3 days, suction filtration then.Dried residue in vacuum drying oven obtains intermediate 120 (1.58g, yellow solid).LCMS shows MH
+=332; T
RET=2.06min.
According to similar method, prepare following intermediate 121 with intermediate 1 and intermediate 119:
Intermediate 121:4-{[is anti--4-(aminocarboxyl) cyclohexyl] and amino }-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-formic acid
LCMS shows MH
+=332; T
RET=2.06min.
Intermediate 122:4-chloro-N-[1-(2, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(believe it is the mixture of enantiomer, and main enantiomer having (R) stereochemical structure)
Prepare according to being similar to the method for preparing intermediate 108 with intermediate 82 and 107.LCMS shows MH
+=371; T
RET=3.32min.
Intermediate 123-145,50a, 55a, 58a, 75a, 80a and 83a
20-86 is the same with intermediate, adopts D.A.Cogan, and the method for G.Liu and J.Ellman exploitation (Tetrahedron, 1999,55,8883-8904), after improving, be used for the preparation of these intermediates.At Cogan, Liu, in the paper of Ellman, in the chemical reaction of similar and following intermediate 123-127 and 128-136 description, use (S)-tertiary butyl sulfinyl amine, it is said at the carbon atom place adjacent shown below, obtain the product that general stereochemical structure is the diastereomer enrichment with nitrogen-atoms:
(promptly insert the R in the paper as shown in the figure
4Group, branched chain type benzyl only are exemplary examples); This stereochemical structure (R in the paper
4) generation (promptly before any optional diastereomeric separation) in the reaction that forms carbon-carbon bond.Because intermediate 128-136,50a, 55a and 58a method comprise the additional step that separates diastereomer, so believe that containing the substituent compound of α (intermediate 128-136,50a, 55a and 58a and intermediate 137-145,75a, 80a and 83a) at the benzylic carbon atoms place is made up of the enantiomer/diastereomer with (R) stereochemical structure (at the benzylic carbon atoms place) basically herein.
Intermediate 123-127
According to the similar approach that is used to prepare intermediate 20, prepare following intermediate 123-127 with (S)-tertiary butyl sulfinyl amine and suitable commercially available aldehyde (phenyl aldehyde of replacement):
Intermediate 128-136,50a, 55a and 58a
Intermediate 128 synthesis methods
At-78 ℃, the diethyl ether solution (3.8ml) of 3.0M methyl-magnesium-bromide is joined in the stirred solution of intermediate 123 (0.91g) and anhydrous DCM (20ml).-78 ℃ of stirred reaction mixtures 1 hour, rise to room temperature, at room temperature stirred 24 hours.Reaction mixture is to-78 ℃.Ether (1.9ml) solution that adds 3.0M methyl-magnesium-bromide solution again.-78 ℃ of stirred reaction mixtures 1 hour, rise to room temperature, at room temperature stirred 2 hours, be cooled to 0 ℃ then, under agitation drip saturated ammonium chloride solution (10ml), drip DCM (20ml) again.Filter organic phase by hydrophobic filter plate.Evaporate DCM.Resistates SPE post (50g, silica gel, 0%-100% ethyl acetate/hexanaphthene gradient) purifying.Merge the part (for example can be the part with 100% eluent ethyl acetate) that contains main diastereomer, evaporation obtains solid intermediate 128.LCMS shows MH
+=254, T
RET=3.07 or 3.12.
According to the above-mentioned identical or similar approach that is used for intermediate 128, with intermediate 124-127,26,31 or 33 and diethyl ether solution (the R of 3.0M methyl-magnesium-bromide
4=Me) or the diethyl ether solution (R of 3.0M ethylmagnesium bromide
4=Et) preparation following intermediate 129-136,50a, 55a and 58a:
(believing that intermediate 128-136,50a, 55a and 58a are made up of the isomer with (R) stereochemical structure (at the benzylic carbon atoms place) basically)
Intermediate 137-145,75a, 80a and 83a
According to the similar approach that is used for synthetic intermediate 62, prepare following intermediate 137-145,75a, 80a and 83a with intermediate 128-136,50a, 55a or 58a:
(believing that intermediate 137-145,75a, 80a and 83a are made up of the enantiomer with (R) stereochemical structure (at the benzylic carbon atoms place) basically)
Intermediate 146:4-[((3S)-and 1-{[(1, the 1-dimethyl ethyl) the oxygen base] carbonyl }-the 3-pyrrolidyl) amino]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-ethyl formate
Intermediate 1 (680mg), DIPEA (2.3ml) and (3S)-3-amino-1-pyrrolidinecarboxylic acid 1, MeCN (15ml) solution stirring of 1-dimethyl ethyl ester (500mg) (for example obtaining), reflux 16 hours from Aldrich.Evaporating solvent, resistates distributes between DCM and water.Separate organic phase by hydrophobic filter plate.Evaporating solvent, resistates 100g " flashmaster " column purification (for example can be, United Kingdom obtains) from Jones Chromatography Ltd., the mixture that uses EtOAc and hexanaphthene is as eluent, obtain intermediate 146 (720mg, solid).LCMS shows MH
+=404; T
RET=3.20min.
According to similar approach, with intermediate 1 and (3R)-3-amino-1-pyrrolidinecarboxylic acid 1, the following intermediate 147 of 1-dimethyl ethyl ester (for example obtaining) preparation from Aldrich:
Intermediate 147:4-[((3R)-and 1-{[(1, the 1-dimethyl ethyl) the oxygen base] carbonyl }-the 3-pyrrolidyl) amino]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-ethyl formate
LCMS shows MH
+=404; T
RET=3.20min.
Intermediate 148:1-ethyl-4-[(3S)-3-pyrrolidyl amino]-1H-pyrazolo [3,4-b] pyridine-5-ethyl formate hydrochloride
4.0M hydrogenchloride/two alkane (30ml) solution of intermediate 146 (720mg) were stirred 3 hours at 22 ℃.Evaporating solvent obtains intermediate 148 (606mg, white solid).LCMS shows MH
+=304; T
RET=2.00min.
According to similar approach, prepare following intermediate 149 with intermediate 147:
Intermediate 149:1-ethyl-4-[(3R)-3-pyrrolidyl amino]-1H-pyrazolo [3,4-b] pyridine-5-ethyl formate hydrochloride
LCMS shows MH
+=304; T
RET=2.00min.
Intermediate 150:4-{[(3S)-and 1-(aminocarboxyl)-3-pyrrolidyl] amino }-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-ethyl formate
With DCM (30ml) solution stirring of intermediate 148 (606mg), use DIPEA (1.15ml), trimethylsilyl isocyanate (1.03ml) to handle successively.22 ℃ of stirred reaction mixtures 2 hours.Solution with water is washed.The water dichloromethane extraction.The organism that makes merging concentrates then by hydrophobic filter plate, obtains intermediate 150 (660mg, solid).LCMS shows MH
+=347; T
RET=2.40min.
According to similar approach, prepare following intermediate 151 with intermediate 149:
Intermediate 151:
4-{[(3R)-and 1-(aminocarboxyl)-3-pyrrolidyl] amino }-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-ethyl formate
LCMS shows MH
+=347; T
RET=2.40min.
Intermediate 152:4-{[(3S)-and 1-(aminocarboxyl)-3-pyrrolidyl] amino }-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-formic acid
The ethanol (15ml) of intermediate 150 (660mg) and sodium hydroxide (300mg) and the mixture of water (8ml) are stirred, 60 ℃ of heating 2 hours.Solvent removed in vacuo.(8ml) joins in the resistates with water, with 2M hcl acidifying gained solution.Suction filtration gained suspension.The vacuum-drying resistates obtains intermediate 152 (270mg, solid).LCMS shows MH
+=319; T
RET=1.90min.
According to similar approach, prepare following intermediate 153 with intermediate 151:
Intermediate 153:4-{[(3R)-and 1-(aminocarboxyl)-3-pyrrolidyl] amino }-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-formic acid
LCMS shows MH
+=319; T
RET=1.90min.
Intermediate 154:(is suitable-4-{[methyl (methoxyl group) amino] and carbonyl } cyclohexyl) carboxylamine 1,1-dimethyl ethyl ester
With suitable-4-({ [(1, the 1-dimethyl ethyl) oxygen base] carbonyl } amino) THF (60ml) solution of naphthenic acid (1.0g) (for example can obtain from Fluka), EDC (0.95g), HOBT (0.61g) and DIPEA (2.1ml) stirred 30 minutes at 22 ℃, add N then, O-dimethyl hydroxylamine hydrochloride (0.5g).Stirred reaction mixture 7 hours.Remove and desolvate, resistates distributes between DCM and saturated sodium bicarbonate solution.Isolate organic phase, evaporating solvent.With sample on the resistates to 20g SPE post.This post obtains intermediate 154 (768mg) with 10-50%EtOAc/ hexanaphthene wash-out.
Intermediate 155:(is suitable-4-ethanoyl cyclohexyl) and carboxylamine 1,1-dimethyl ethyl ester
THF (25ml) solution of intermediate 154 (768mg) is cooled to 0 ℃.In 5 minutes, drip the diethyl ether solution (2.2ml) of 3.0M methyl-magnesium-bromide fast.0-5 ℃ of stirred reaction mixture 3 hours.The diethyl ether solution (0.9ml) that adds the 3.0M methyl-magnesium-bromide once more.Spend the night at 0-5 ℃ of stirred reaction mixture.Drip 1M hydrochloric acid (20ml).Reaction mixture extracts with EtOAc.Organic extract liquid is through Na
2SO
4Drying, vacuum concentration.With sample on the resistates to 10g SPE post.This post obtains intermediate 155 (340mg) with mixture (1: the 1) wash-out of hexanaphthene and EtOAc.
Intermediate 156:1-(suitable-the 4-aminocyclohexyl) acetophenone hydrochloride
The stirred solution of intermediate 155 (115mg) and two alkane (1ml) is handled with 4M hydrogenchloride/two alkane solution (240 μ l).At room temperature stirred reaction mixture is 4 hours, and refrigeration is spent the night then.The vacuum concentration reaction mixture obtains intermediate 156 (72mg, solid).
Intermediate 157:4-[(4-ethanoyl cyclohexyl) amino]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-ethyl formate (mixture of cis and trans-isomer(ide))
With EtOH (10ml) solution stirring of intermediate 1 (93mg), intermediate 156 (72mg) and DIPEA (0.32ml), reflux spends the night.Evaporating solvent, resistates distributes between DCM and saturated sodium bicarbonate solution.Isolate organic phase, concentrate.Resistates prepares the HPLC purifying automatically with the mass spectrum monitoring type, obtains intermediate 157 (102mg), is the mixture of cis-isomeride and trans-isomer(ide).LCMS shows MH
+=359; T
RET=3.05min.
Intermediate 158:4-[(4-ethanoyl cyclohexyl) amino]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-formic acid (mixture of cis-isomeride and trans-isomer(ide))
The 95%EtOH aqueous solution of intermediate 157 (102mg) and sodium hydroxide (45mg) is stirred, 50 ℃ of heated overnight.Solvent removed in vacuo.Water is joined in the resistates gained solution 2M hcl acidifying.Filter gained suspension.The vacuum-drying resistates obtains intermediate 158.Aqueous filtrate extracts with EtOAc and DCM.Organic extract liquid is merged, concentrate, obtain more intermediates 158.The ultimate production of intermediate 158 is 70mg.LCMS shows MH
+=331; T
RET=2.46min.
Intermediate 159:(RS)-[suitable-4-(1-hydroxyethyl) cyclohexyl] carboxylamine 1,1-dimethyl ethyl ester
At 0-5 ℃, the toluene solution (0.77ml) of 1.5M diisobutyl aluminium hydride is added drop-wise to the stirred solution of intermediate 155 (112mg) and THF (5ml).Reaction mixture is stirred, rise to ambient temperature overnight.The toluene solution (0.31ml) that adds diisobutyl aluminium hydride once more.Reaction mixture was left standstill weekend at 22 ℃, use saturated potassium sodium tartrate solution (15ml) to handle then.Stirred the mixture 0.75 hour, and extracted with EtOAc.The extraction liquid that merges washs with saturated nacl aqueous solution, through dried over mgso, concentrates.With sample on the resistates to 2g SPE post.This post obtains intermediate 159 (10mg) with 0-20%EtOAc/ hexanaphthene wash-out.
Intermediate 160:(RS)-1-(suitable-the 4-aminocyclohexyl) ethylate hydrochlorate
Two alkane (0.5ml) of intermediate 159 (10mg) are handled with 4M hydrogenchloride/two alkane solution (240 μ l).At room temperature stirred reaction mixture is 5 hours, then standing over night.Remove and to desolvate, obtain intermediate 160 (solid, 7mg).
Intermediate 161:1-ethyl-4-{[(1SR, 3SR)-the 3-hydroxy-cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-ethyl formate
[anti--(3-hydroxyl hexamethylene-1-yl) amino, racemic]
With the 3-Trans-4-Amino Cyclohexanol (mixture of cis-isomeride and trans-isomer(ide), 4.25g) (for example from AB Chem, the mixture that Inc., Canada obtain; Or referring to for example J.Chem.Soc., Perkin Trans 1,1994,537, obtain the suitable of 3-Trans-4-Amino Cyclohexanol: back mixing compound (3.3: 1)), the solution stirring of intermediate 1 (7.8g), DIPEA (25ml), MeCN (50ml) and EtOH (5ml), reflux 16 hours.Removal of solvent under reduced pressure, resistates distributes between DCM and water.Concentrate organic phase, with sample on the resistates to 100g SPE post.This post obtains intermediate 161 (trans-isomer(ide)s: 326mg) with mixture (1: the 2) wash-out of EtOAc and hexanaphthene.LCMS shows MH
+=333; T
RET=2.90min.
Intermediate 162:1-ethyl-4-{[(1SR, 3SR)-the 3-hydroxy-cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-formic acid
[anti--(3-hydroxyl hexamethylene-1-yl) amino, racemic]
The mixture of intermediate 161 (326mg), sodium hydroxide (156mg), water (2ml) and EtOH (4.6ml) is stirred, 60 ℃ of heating 5 hours, cooling then, concentrating under reduced pressure.Resistates is water-soluble.Solution 2M hcl acidifying.Filter gained suspension.The vacuum-drying resistates obtains intermediate 162 (270mg, white solid).LCMS shows MH
+=305; T
RET=2.21min.
Intermediate 163:4-[(1-{[(1, the 1-dimethyl ethyl) the oxygen base] carbonyl }-the 4-piperidyl) amino]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-formic acid
The mixture of intermediate 102 (750mg), sodium hydroxide (290mg), EtOH (20ml) and water (5ml) is stirred, 50 ℃ of heating 2.5 hours, cooling then, concentrating under reduced pressure.Under agitation, water (20ml) solution of resistates is cooled to 0-5 ℃, with the 2M hcl acidifying to pH=5.Filter the gained solids suspension.Solid residue washes with water, and drying obtains intermediate 163 (575mg, white solid).LCMS shows MH
+=390; T
RET=2.86min.
Intermediate 164:4-{[1-ethyl-5-([(1R)-and 1-(4 aminomethyl phenyl) ethyl] amino } carbonyl)-1H-pyrazolo [3,4-b] pyridin-4-yl] amino }-1-piperidine carboxylic acid 1,1-dimethyl ethyl ester
DMF (5ml) solution of intermediate 163 (100mg), EDC (54mg), HOBT (38mg) and DIPEA (0.11ml) is joined [(1R)-1-(4-aminomethyl phenyl) ethyl] amine (38mg) (for example can obtain) from Lancaster.Allow solution left standstill spend the night.Evaporating solvent.Resistates distributes between DCM and saturated sodium bicarbonate solution.Isolate organic phase, evaporation.Resistates is by 10g SPE column purification, and the ethyl acetate of usefulness gradient and hexanaphthene (0-100%EtOAc) obtain intermediate 164 (125mg) as eluent.LCMS shows MH
+=507; T
RET=3.85min.
According to similar approach, prepare following intermediate 165 with intermediate 163 and intermediate 82:
Intermediate 165:4-{[5-({ [1-(2, the 4-3,5-dimethylphenyl) propyl group] amino } carbonyl)-1-ethyl-1H-pyrazolo [3,4-b] pyridin-4-yl] amino }-1-piperidine carboxylic acid 1,1-dimethyl ethyl ester
(believe it is mixture of isomers, and main isomer having (R) stereochemical structure at the benzylic carbon atoms place).LCMS shows MH
+=535; T
RET=3.min.
Intermediate 166:4-amino-4-(3-aminomethyl phenyl) butyric acid
Triethylamine (6.3g) is joined 4-(3-aminomethyl phenyl)-4-ketobutyric acid (for example can be obtained from Oakwood Products Inc., 8g) and in cold (0-5 ℃) solution of DCM (100ml).In 15 minutes, slowly add hydroxylamine hydrochloride (3.47g).At room temperature stirred reaction mixture spends the night.(2 * 75ml) extract reaction mixture with the 10%w/v sodium hydrogen carbonate solution.Merge aqueous extraction liquid,, be acidified to pH=2, with ethyl acetate (3 * 100ml) extractions with concentrated hydrochloric acid with the ether washing.The acetic acid ethyl acetate extract water and the salt water washing that merge, through dried over sodium sulfate, vacuum concentration obtains intermediate oxime (8g).Methyl alcohol (50ml) solution hydrogenation under room temperature, 4Kg hydrogen pressure of oxime (4g) is spent the night, use 10% palladium/carbon as catalyzer.By the diatomite filtration reaction mixture.With the diatomite methanol wash, concentrate the filtrate and the washings that merge.Resistates is made soup compound in ethyl acetate.Filter gained suspension.Dried residue, obtain intermediate 166 (white solid, 3.5g).
Intermediate 167:
4-({ [(1, the 1-dimethyl ethyl) oxygen base] carbonyl } amino)-4-(3 aminomethyl phenyl) butyric acid
Under 0-5 ℃, (the dimethyl dicarbonate butyl ester 4g) joins in methyl alcohol (50ml) solution of intermediate 166 (3.3g) and triethylamine (2.6g) with " BOC acid anhydride ".At room temperature stirred reaction mixture is 2 hours.Add 10%w/v sodium hydrogen carbonate solution (100ml).Reaction mixture washs with ether, is acidified to pH=3 with the 20%w/v citric acid solution, with ethyl acetate (3 * 50ml) extractions.The organism water and the salt water washing that merge, through dried over sodium sulfate, vacuum concentration obtains intermediate 167 (5.6g, white solid).
Intermediate 168:[4-(dimethylamino)-1-(3-aminomethyl phenyl)-4-oxo butyl] carboxylamine 1,1-dimethyl ethyl ester
The EtOH solution (0.46ml) of 30%w/v dimethylamine is joined in the stirred solution of intermediate 167 (250mg), HOBT (126mg), EDC (180mg), DIPEA (0.37ml) and MeCN.Stirred reaction mixture 24 hours.Solvent removed in vacuo, resistates distributes between EtOAc and 0.5M sodium hydrogen carbonate solution.Organic phase is washed with saturated brine, passes through 10g sal epsom post drying under suction.Vacuum concentrated solution.Resistates is by 10g SPE column purification, and the mixture (1: 1) of using hexanaphthene and EtOAc obtains intermediate 168 (109mg, white solid) as eluent.LCMS shows MH
+=321; T
RET=2.88min.
Intermediate 169:4-amino-N, N-dimethyl-4-(3-aminomethyl phenyl) butanamide hydrochloride
Intermediate 168 (108mg) is handled with 4M hydrogenchloride/two alkane solution (2ml).Stirred reaction mixture 6.5 hours, vacuum concentration then.Resistates is ground with ether.Decant goes out ether.Resistates is by 5g SPE silicagel column purifying, and the 10-50% methanol/ethyl acetate of using gradient obtains intermediate 169 (56mg, white solid) as eluent.LCMS shows MH
+=221; T
RET=1.74min.
Intermediate 170:
Intermediate 170 can be synthetic according to following reaction process:
The final step of above intermediate 170 reaction process can be chosen following carrying out wantonly:
Intermediate 170:1-n-propyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-formic acid
Optional synthesis method: with 2M sodium hydroxide solution (0.7ml) join corresponding ethyl ester (intermediate 171) (0.23g), in the stirred suspension of ethanol (5ml) and water (1.5ml).After at room temperature stirring is spent the night, add 2M-sodium hydroxide solution (0.7ml) once more, reaction mixture was heated 2.5 hours at 43 ℃.Concentrated reaction solution, the 2M-hcl acidifying is used in water (5ml) dilution.Filter to collect the gained precipitation, wash with water, drying, obtain intermediate 170 (white solid, 0.14g).LCMS shows MH
+=305; T
RET=2.42min.
The penult step of above intermediate 170 reaction process (preparation intermediate 171) can be chosen following carrying out wantonly:
Intermediate 171:1-n-propyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-ethyl formate
Optional synthesis method: (0.067g, 60% is scattered in the oil) joins in the stirred solution of intermediate 172 (0.47g) and DMF (19ml) with sodium hydride, adds n-propyl iodide (0.17ml) then.Stirred the mixture 16 hours at 23 ℃, concentrate then, with chloroform (30ml) dilution, with 1: 1 water: salt brine solution (30ml) washing, separate the concentrated organic layer in back.(silica gel, 10g) purifying are used 10ml methylene dichloride, ether: hexanaphthene (1: 1) and ether wash-out to resistates with the SPE post.Concentrate the ether that merges: hexanaphthene (1: 1) part and ether part obtain copal gum shape intermediate 171 (0.23g).LCMS shows MH
+=333; T
RET=3.14min.
Third from the bottom step (preparation intermediate 172) can be chosen following carrying out wantonly in above intermediate 170 reaction process:
Intermediate 172:4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-ethyl formate
Optional synthesis method 1:
Intermediate 1A (0.035g) is added Reactivial
TM, handle with 4-amino tetrahydro pyran (0.05ml).90 ℃ of heated mixt 1.5 hours, allow it be cooled to room temperature, between chloroform (2ml) and water (1ml), distribute.Separate each layer, concentrate organic phase.Crude product prepares the HPLC purifying automatically with the mass spectrum monitoring type, obtain intermediate 172 (pale solid, 0.011g).LCMS shows MH
+=291; T
RET=2.08min.
Another kind of optional synthesis method 2:
Intermediate 1A (2g) is suspended in 4-amino tetrahydro pyran (2g), 90 ℃ of heated mixt 6 hours.Allow residual mixture be cooled to room temperature, between chloroform (50ml) and water (50ml), distribute.Separate each phase, organic phase is evaporated to dried.With resistates Et
2O (30ml) grinds, and collects insoluble solids, drying, obtain intermediate 172 (emulsifiable paste shape solid, 2.24g).LCMS shows MH
+=291, T
RET=2.19min.
Intermediate 173:1-(2-hydroxyethyl)-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-ethyl formate
Ethylene bromohyrin (0.008ml) is joined in dry DMF (1.5ml) solution of intermediate 172 (0.03g), contain 2-tertbutylimido-2-diethylin-1 in the solution, 3-dimethyl-1,3-diaza-2-phospha cyclohexane be (conjugated polymer, loading capacity 2.3mmol/g, 0.045g).Mixture 23 ℃ of vibrations 16 hours, is discharged solution then from resin, resin washs with DMF.Concentrate the organism that merges, (silica gel, 1g) purifying is with 70-100% ethyl acetate/hexanaphthene wash-out with the SPE post for resistates.The part that concentrate to merge, obtain intermediate 173 (white solid, 0.011g).LCMS shows MH
+=335, T
RET=2.47min.
Intermediate 175:(R)-(+)-3-amido tetrahydrofuran 4-tosylate
Can be from Fluka Chemie AG, Germany obtains (CAS 111769-27-8)
Intermediate 176:(S)-(-)-3-amido tetrahydrofuran 4-tosylate
Can be from E.Merck, Germany obtains; Or from E.Merck (Merck Ltd), HunterBoulevard, Magna Park, Lutterworth, Leicestershire LE17 4XN, UnitedKingdom obtains (CAS 104530-80-5)
Intermediate 177: tetrahydrochysene-2H-thiapyran-4-amine
According to Subramanian etc., J.Org.Chem., 1981,46, the method for introducing among the 4376-4383 is with commercially available tetrahydric thiapyran-4-ketone preparation.Can prepare its hydrochloride by ordinary method subsequently.
Intermediate 178: tetrahydrochysene-3-thiophenine
According to the similar approach of intermediate 177, with commercially available tetramethylene sulfide-4-ketone preparation.The preparation of oxime is referring to Grigg etc., Tetrahedron, and 1991,47,4477-4494, the oxime reduction reaction is referring to Unterhalt etc., Arch.Pharm., 1990,317-318.
Intermediate 179: tetrahydrochysene-3-thiophenine 1,1-dioxide hydrochloride
Can obtain (CAS-6338-70-1) from Sigma Aldrich Library of Rare Chemicals (SALOR).The hydrochloride for preparing this amine according to ordinary method.
Intermediate 180: tetrahydrochysene-2H-thiapyran-4-amine-1,1-dioxide hydrochloride
According to the similar approach of intermediate 177, with commercially available tetrahydric thiapyran-4-ketone preparation.Be oxidized to 1,1-dioxo-tetrahydrochysene-1 λ
6The reaction of-thiapyran-4-ketone is referring to Rule etc., J.Org.Chem., 1995,60,1665-1673.The preparation of oxime is referring to Truce etc., J.Org.Chem., and 1957,617,620, the oxime reduction reaction is referring to Barkenbus etc., J.Am.Chem.Soc., 1955,77,3866.The hydrochloride for preparing this amine subsequently according to ordinary method.
Intermediate 181:1-methyl-4-oxyethyl group-1H-pyrazolo [3,4-b] pyridine-5-ethyl formate
Anhydrous dimethyl formamide (DMF) mixture (4ml) of intermediate 1A (0.47g) and Anhydrous potassium carbonate (0.83g) (in advance at 100 ℃ of heat dryings) is handled vigorous stirring 3 hours with methyl iodide (0.26ml).Filtering mixt then, vacuum concentrated filtrate obtains remaining oily matter, and it (25ml) and between water (25ml) is distributed at methylene dichloride (DCM).Separate each layer, (2 * 25ml) further extract water with DCM.The organic extract liquid anhydrous sodium sulfate drying that merges is evaporated to orange solids, with sample on it to the SPE post (silica gel, 20g) on.Pillar is used following elutriant wash-out: EtOAc successively: gasoline (1: 4,1: 2 and 1: 1), chloroform: methyl alcohol (49: 1,19: 1 and 9: 1).Merge the part that comprises required product, vacuum concentration obtains intermediate 181 (0.165g).LCMS shows MH
+=250; T
RET=2.59min.
Intermediate 182:4-chloro-1-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-ethyl formate
The mixture of 5-amino-1-methylpyrazole (4.0g) and ethoxy methylene diethyl malonate (9.16ml) was heated 5 hours in 150 ℃ under Dean Stark condition.Phosphoryl chloride (55ml) is joined in the mixture carefully, 130 ℃ of reflux gained solution 18 hours.Vacuum concentrated mixture cools off remaining oily matter then in ice bath, water (100ml) is handled (attention heat release) carefully.(3 * 100ml) extract the organic extract liquid anhydrous sodium sulfate drying of merging, vacuum concentration to the gained mixture with DCM.(silica gel 90g), is used Et to residual solid with the Biotage chromatogram purification
2O: gasoline (1: 3) wash-out.Merge the part that comprises required product, vacuum concentration obtains intermediate 182 (4.82g).LCMS shows MH
+=240; T
RET=2.98min.
Intermediate 183:4-chloro-1-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-formic acid
Two alkane (30ml) solution of intermediate 182 (4.0g) are used water (20ml) solution-treated of potassium hydroxide (7.54g).Stirred the mixture 16 hours, water (150ml) dilution then is acidified to pH 3 with the 5M aqueous hydrochloric acid.Mixture stirred in ice bath 15 minutes, filter to collect then, with the icy water washing, through Vanadium Pentoxide in FLAKES vacuum-drying, obtain intermediate 183 (white solid, 2.83g).LCMS shows MH
+=212; T
RET=2.26min.
Intermediate 184:1-ethyl-4-[(3S)-tetrahydrofuran (THF)-3-base is amino]-1H-pyrazolo [3,4-b] pyridine-5-ethyl formate
Intermediate 184
With intermediate 1 (0.05g) and (S)-(-)-3-amido tetrahydrofuran 4-tosylate (intermediate 176) (0.052g) is suspended in ethanol (1ml), adds triethylamine (0.14ml).Mixture in nitrogen atmosphere, 80 ℃ of stirrings down, was heated 24 hours.After being cooled to room temperature, ethanol is removed in evaporation under nitrogen gas stream, and resistates distributes between DCM (2ml) and water (1.5ml).Separate each layer, organic layer is concentrated into dried.With SPE post (silica gel, 5g) purifying, pillar EtOAc: hexanaphthene (1: 16,1: 8,1: 4,1: 2,1: 1 and 1: 0) gradient elution.Merge the part that comprises required product, vacuum concentration obtains intermediate 184 (0.052g).LCMS shows MH
+=305; T
RET=2.70min.
Prepare following compounds similarly:
Intermediate 189:4-[(1,1-titanium dioxide tetramethylene sulfide-3-yl) amino]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-ethyl formate
Intermediate 1 (0.05g) and intermediate 179 (0.027g) are suspended in ethanol (1ml), add triethylamine (0.14ml).Mixture is stirred under 80 ℃, nitrogen atmosphere, heated 24 hours.After being cooled to room temperature, ethanol is removed in evaporation under nitrogen gas stream, and resistates distributes between DCM (2ml) and water (1.5ml).Separate each layer, organic layer is concentrated into dried.(silica gel, 5g) purifying are used EtOAc: hexanaphthene (1: 8,1: 4,1: 2,1: 1 and 1: 0) gradient elution with the SPE post.Merge the part that comprises required product, vacuum concentration obtains intermediate 189 (0.045g), is the mixture of enantiomer.LCMS shows MH
+=353; T
RET=2.60min.
Prepare following compounds similarly:
Intermediate 191:1-ethyl-4-[(3S)-tetrahydrofuran (THF)-3-base is amino]-1H-pyrazolo [3,4-b] pyridine-5-formic acid
Ethanol with intermediate 184 (0.037g): water (95: 5,3ml) handled with sodium hydroxide (0.019g) by solution.50 ℃ of heated mixt 16 hours, vacuum concentration then.With resistates water-soluble (1.5ml), be acidified with acetic acid to pH 4.Gained white solid precipitation, vacuum-drying are shifted out in filtration.Filtrate is used ethyl acetate extraction, collected organic layer, and vacuum concentration obtains the part white solid again.Merge two parts of solids, obtain intermediate 191 (0.033g).LCMS shows MH
+=277; T
RET=2.05min.
Prepare following compounds similarly:
Intermediate 198:4-(cyclohexyl amino)-1H-pyrazolo [3,4-b] pyridine-5 ethyl formate
Intermediate 1A (0.69g) is suspended in hexahydroaniline (1.01ml), 90 ℃ of heated mixt 3 hours.Allow residual mixture be cooled to room temperature, between chloroform (25ml) and water (25ml), distribute.Separate each phase, organic phase is evaporated to dried.With resistates Et
2O (25ml) grinds, and collects insoluble solids, drying, obtain intermediate 198 (the light brown solid, 0.58g).LCMS shows MH
+=289; T
RET=2.91min.
Intermediate 199:4-(cyclohexyl amino)-1H-pyrazolo [3,4-b] pyridine-5-formic acid
2M sodium hydroxide solution (0.5ml) is joined in the stirred suspension of intermediate 198 (0.2g), two alkane (4ml) and water (0.5ml).At room temperature stir spend the night after, in 40 ℃ of reacting by heating mixtures 8 hours.Add 2M-sodium hydroxide solution (1.5ml) once more, reaction mixture was heated 48 hours at 40 ℃.Concentrated reaction solution, the Glacial acetic acid acidifying is used in water (10ml) dilution.Filter and collect the gained precipitation, wash with water, drying obtains intermediate 199 (0.18g).LCMS shows MH
+=261; T
RET=2.09min.
Intermediate 200:4-(cyclohexyl amino)-1-ethyl-6-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-ethyl formate
(0.149g, (0.201g, 0.75mmol), N, (0.65ml is 3.73mmol) and in the mixture of acetonitrile (3ml) for the N-diisopropylethylamine 1.5mmol) to join intermediate 10 with hexahydroaniline.Heated the gained mixtures 40 hours at 85 ℃.Vacuum is removed volatile matter, and resistates is dissolved in chloroform (1.5ml), last sample to the SPE post (silica gel, 5g) on.The SPE post is used Et successively
2O, EtOAc and MeOH wash-out.Merge the part that comprises required product, vacuum concentration obtains intermediate 200 (0.128g).LCMS shows MH
+=331; T
RET=3.64min.
Intermediate 201:4-(cyclohexyl amino)-1-ethyl-6-methyl isophthalic acid H-pyrazolo [3,4-b] pyridine-5-formic acid
(0.39ml, (0.128g is in ethanol 0.39mmol) (1.5ml) solution, 50 ℃ of heated mixt 16 hours 0.78mmol) to join corresponding ethyl ester (intermediate 200) with the 2M sodium hydroxide solution.Concentrated reaction mixture, obtained aqueous solution, filters and collects to be settled out solid with the neutralization of 2M hydrochloric acid.Filtrate is gone up sample to OASIS
Hydrophilic-lipophilic balance (HLB) column extractor
*(1g), with column extractor water successively, methanol-eluted fractions.Evaporation methyl alcohol part obtains solid, and itself and initial precipitated solid are merged, and obtains intermediate 201 (0.083g, white solid), is speculated as carboxylic acid.
*OASIS
The HLB column extractor can be from Waters Corporation, 34 Maple Street, and Milord, MA 01757, and USA obtains.Column extractor comprises the pillar that contains the multipolymer sorbent material, the HLB that sorbent material has should make, the aqueous solution is by this pillar wash-out the time, solute is absorbed or is adsorbed on the inside or the surface of sorbent material, and when with organic solvent (for example methyl alcohol) wash-out, solute is released to organic (for example methyl alcohol) solution.This is a kind of solute and isolating method of aqueous solvent of making.
Intermediate 202:1-ethyl-6-methyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-formic acid
With the 2M sodium hydroxide solution (0.75ml, 1.5mmol) join intermediate 11 (0.248g, in ethanol 0.75mmol) (2ml) solution, reflux mixture 16 hours.Reaction mixture is concentrated, and water (1ml) dilution with 2M hydrochloric acid (0.75ml) acidifying, to be settled out solid, to be filtered and is collected, and obtains intermediate 202 (0.168g).LCMS shows MH
+=305; T
RET=1.86min.
The amino pimelinketone hydrochloride of intermediate 203:4-
(0.5ml, 2.0mmol 4M) join 4-oxo cyclohexyl t-butyl carbamate (0.043g with hydrogenchloride/two alkane solution, 0.20mmol, can be from AstaTech Inc., Philadelphia, USA obtains) and the stirred solution of two alkane (0.5ml) in, at room temperature stir the mixture.After 1 hour, evaporation reaction mixture, obtain intermediate 203 (emulsifiable paste shape solid, 34mg).
1H NMR (400MHz in d
6-DMSO, 27 ℃, δ ppm) 8.09 (br, s, 3H), 3.51 (tt, 11,3.5Hz, 1H), 2.45 (part is smudgy for m, 2H), 2.29 (m, 2H), 2.16 (m, 2H), 1.76 (m, 2H).
Intermediate 204:1-ethyl-4-(tetrahydrochysene-2H-pyrans-3-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-ethyl formate
(0.76g 3.0mmol) is dissolved in acetonitrile (10ml) with intermediate 1.Add tetrahydrochysene-2H-pyrans-3-amine hydrochlorate (0.5g, 3.6mmol, Anales De Quimica, 1988,84,148) and N, (3.14ml's N-diisopropylethylamine 18.0mmol), stirred the mixture 24 hours at 85 ℃.After 24 hours, (0.14g 1.02mmol), continues to stir at 85 ℃ to add part tetrahydrochysene-2H-pyrans-3-amine hydrochlorate again.After 8 hours, vacuum concentrated mixture.Resistates distributes between DCM (20ml) and water (12ml).Separate each layer, water layer further extracts with DCM (12ml).Dry (Na
2SO
4) organic extract liquid that merges, vacuum concentration obtains brown solid, with SPE post (silica gel, 20g) purifying, pillar ethyl acetate: hexanaphthene (1: 16,1: 8,1: 4,1: 2,1: 1,1: 0) gradient elution.Merge the part that comprises required product, evaporation obtains intermediate 204 (0.89g).LCMS shows MH
+=319; T
RET=2.92min.
Intermediate 205:1-ethyl-4-(tetrahydrochysene-2H-pyrans-3-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-formic acid
With intermediate 204 (0.89g, ethanol 2.79mmol) (16.7ml) solution sodium hydroxide (0.47g, water 11.7mmol) (3.1ml) solution-treated.Stir the mixture at 50 ℃.After 12 hours, the vacuum concentration reaction mixture obtains remaining oily matter, and with its water-soluble (16ml), cooling then uses the 2M hcl acidifying to pH 3.0 ℃ stir 30 minutes after, filter and collect the gained precipitation, with cold water (2ml) washing, vacuum-drying, obtain intermediate 205 (white solid, 0.73g).LCMS shows MH
+=291; T
RET=2.19min.
Intermediate 206:(4,4-difluoro cyclohexyl) carboxylamine 1,1-dimethyl ethyl ester
With diethylaminosulfur trifluoride (DAST) (0.06ml, 0.47mmol) join (4-oxo cyclohexyl) carboxylamine 1,1-dimethyl ethyl ester (250mg, 1.17mmol, can be from AstaTechInc., Philadelphia, USA obtains) and the stirred solution of anhydrous methylene chloride (5ml), under nitrogen atmosphere, 20 ℃, stir the mixture.After 22 hours, reaction mixture to 0 ℃ is handled with saturated sodium bicarbonate solution (4ml), allows it rise to room temperature then.Separate each phase by hydrophobic filter plate, water is further used DCM (5ml) extraction.The organic phase that vacuum concentration merges obtains orange solids (369mg), with SPE column chromatography (silica gel, 10g) be further purified, pillar DCM wash-out obtains containing 20% (4-fluoro-3-tetrahydrobenzene-1-yl) carboxylamine 1, the intermediate 206 (140mg) of 1-dimethyl ethyl ester.
1H NMR(400MHz,CDCl
3,27℃,δppm)。Submember: δ 5.11 (dm, 16Hz, 1H), 4.56 (br, 1H), 3.80 (br, 1H), 2.45-1.45 (m ' s, 6H is excessive), 1.43 (s, 9H), main component: δ 4.43 (br, 1H), 3.58 (br, 1H), 2.45-1.45 (m ' s, 8H is excessive), 1.45 (s, 9H).
Intermediate 207:(4,4-difluoro cyclohexyl) amine hydrochlorate
With hydrogenchloride/two alkane solution (4M, 1.6ml) under 20 ℃, join intermediate 206 (140mg, 0.6mmol) and the stirred solution of two alkane (1.6ml).After 3 hours, the vacuum concentration reaction mixture obtains containing the intermediate 207 (96.5mg) of 4-fluoro-3-tetrahydrobenzene-1-amine.
1HNMR (400MHz, d
6-DMSO, 27 ℃, δ ppm) submember: δ 8.22 (br, 3H is excessive), 5.18 (dm, 16Hz, 1H), 3.28-3.13 (m, 1H is excessive), 2.41-1.53 (m ' s, 6H is excessive).Main component: δ 8.22 (br, 3H is excessive), 3.28-3.13 (m, 1H is excessive), 2.41-1.53 (m ' s, 8H is excessive).Also there is impurity.
Intermediate 208-229: dissimilar R
3NH
2
*R for intermediate 219-223
3NH
2, R
3NH
2Be cis or trans-isomer(ide) (if having shown configuration): for intermediate 221-223, R
3NH
2Be generally the 3-amino-hexamethylene-1-base amine or the 2-amino-hexamethylene-1-base amine of racemic form.
Most of intermediate 208-229 itself or after deprotection, protection and/or functional group change mutually can choose wantonly in the preparation of formula (I) compound or its precursor and be used as R
3NH
2Amine is for example in aforesaid method A or B and/or method D; Optional subsequently at the 4-of for example prepared Pyrazolopyridine compound (R
3NH) group deprotection, protection and/or functional group change mutually.
The embodiment table look-up
The embodiment numbering | Title |
1 | The 1-ethyl-N-[(1R)-the 1-phenyl propyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
2 | 1-ethyl-N-(1-methyl isophthalic acid-phenylethyl)-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
3 | 1-ethyl-N-{1-[4-(methyl sulphonyl) phenyl] ethyl }-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
4 | N-(diphenyl methyl)-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
5 | 1-ethyl-N-[1-(3-pyridyl) ethyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
6 | The 1-ethyl-N-[(1S)-the 1-phenyl propyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
7 | The 1-ethyl-N-[(1S)-the 1-phenylethyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
8 | The 1-ethyl-N-[(1R)-the 1-phenylethyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
9 | 1-ethyl-N-[1-methyl isophthalic acid-(4-pyridyl) ethyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
10 | The 1-ethyl-N-[(1R)-the 1-phenylethyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
11 | N-[1-(4-chloro-phenyl-) propyl group]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
12 | 1-ethyl-N-{1-[4-(oxyethyl group) phenyl] ethyl }-4-(tetrahydrochysene-2H-pyrans-4-base ammonia |
Base)-1H-pyrazolo [3,4-b] pyridine-5-methane amide | |
13 | 1-ethyl-N-(3-hydroxyl-1-phenyl propyl)-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
14 | 1-ethyl-N-[1-(3-hydroxy phenyl) ethyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
15 | N-[2-(dimethylamino)-1-phenylethyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
16 | 1-ethyl-N-[1-phenyl-2-(1-pyrrolidyl) ethyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
17 | 1-ethyl-N-[1-(hydroxymethyl)-1-phenyl propyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
18 | 1-ethyl-N-{1-[4-(propoxy-) phenyl] ethyl }-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
19 | 3-({ [1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-yl] carbonyl } amino)-3-phenylpropionic acid methyl esters |
20 | 1-ethyl-N-[1-(4-fluorophenyl) ethyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
21 | N-[1-(4-chloro-phenyl-) ethyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
22 | ({ [1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-yl] carbonyl } amino) (phenyl) ethyl acetate |
23 | 1-ethyl-N-{ (1R)-1-[3-(methoxyl group) phenyl] ethyl }-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
24 | The 1-ethyl-N-[(1S)-2-(methoxyl group)-1-phenylethyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
25 | N-[(1R)-2-amino-2-oxo-1-phenylethyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
26 | The 1-ethyl-N-[(1R)-2-hydroxyl-1-phenylethyl]-4-(tetrahydrochysene-2H-pyrans-4-base ammonia |
Base)-1H-pyrazolo [3,4-b] pyridine-5-methane amide | |
27 | The 1-ethyl-N-[(1R)-1-(4-nitrophenyl) ethyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
28 | The 1-ethyl-N-[(1S)-2-hydroxyl-1-phenylethyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
29 | The 1-ethyl-N-[(1R)-2-(methoxyl group)-1-phenylethyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
30 | 1-ethyl-N-(2-hydroxyl-1,1-diphenyl-ethyl)-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
31 | N-[1-(3-cyano-phenyl) ethyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
32 | N-[cyano group (phenyl) methyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
33 | N-{ cyclopropyl [4-(methoxyl group) phenyl] methyl }-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
34 | 1-ethyl-N-[1-(1-naphthyl) ethyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
35 | N-(1, the 2-diphenyl-ethyl)-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
36 | 1-ethyl-N-{1-[4-(methoxyl group) phenyl] butyl }-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
37 | The 1-ethyl-N-[(1R)-1-(1-naphthyl) ethyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
38 | The 1-ethyl-N-[(1S)-1-(1-naphthyl) ethyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
39 | N-[1-(aminocarboxyl)-1-phenyl propyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
40 | 1-ethyl-N-(1-benzyl ring amyl group)-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazoles |
And [3,4-b] pyridine-5-methane amide | |
41 | 1-ethyl-N-(4-phenyl tetrahydrochysene-2H-pyrans-4-yl)-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
42 | 1-ethyl-N-(1-phenycyclopropyl)-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
43 | N-{1-[4-(cyclohexyloxy)-3-aminomethyl phenyl] ethyl }-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
44 | N-{1-[3-(cyclohexyloxy)-4-(methoxyl group) phenyl] ethyl }-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
45 | N-[1-(2, the 3-dichlorophenyl) ethyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
46 | N-{1-[4-(cyclohexyloxy)-3-hydroxy phenyl] ethyl }-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
47 | N-{1-[4-(cyclopentyloxy) phenyl] ethyl }-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
48 | 1-ethyl-N-[1-(4-aminomethyl phenyl) ethyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
49 | N-{1-[4-(1, the 1-dimethyl ethyl) phenyl] suberyl }-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
50 | N-[1-(4-bromophenyl) ethyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
51 | The 1-ethyl-N-[(1S)-1-(4-iodophenyl) ethyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
52 | N-{1-[4-(amino-sulfonyl) phenyl] ethyl }-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
53 | 1-ethyl-N-(1-methyl isophthalic acid-phenyl propyl)-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
54 | N-[1-(1,3-benzodioxole-5-yl) cyclohexyl]-1-ethyl-4-(tetrahydrochysene-2H- |
Pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide | |
55 | 1-ethyl-N-{1-[4-(methoxyl group) phenyl] cyclohexyl }-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
56 | 1-ethyl-N-[1-(4-fluorophenyl) cyclohexyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
57 | N-[1-(3-chloro-phenyl-) cyclopentyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
58 | N-[1-(2-chloro-phenyl-) cyclopentyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
59 | N-{1-[4-(1, the 1-dimethyl ethyl) phenyl] cyclohexyl }-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
60 | 1-ethyl-N-{1-[4-(1-methylethyl) phenyl] ethyl }-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
61 | N-[1-(3, the 5-3,5-dimethylphenyl) ethyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
62 | 1-ethyl-N-[(1S, 2R)-2-hydroxyl-1-phenyl propyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
63 | 1-ethyl-N-{ (1R)-1-[4-(methoxyl group) phenyl] ethyl }-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
64 | 1-ethyl-N-{ (1S)-1-[4-(methoxyl group) phenyl] ethyl }-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
65 | 1-ethyl-N-(1-phenyl hexyl)-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
66 | 1-ethyl-N-(1-phenylpentyl)-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
67 | 1-ethyl-N-(2-methyl isophthalic acid-phenyl propyl)-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
68 | 1-ethyl-N-(1-phenyl butyl)-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo |
[3,4-b] pyridine-5-methane amide | |
69 | 1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-N-(2,2,2-three fluoro-1-phenylethyls)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
70 | N-[cyclopropyl (phenyl) methyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
71 | 1-ethyl-N-[1-(4-fluorophenyl) propyl group]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
72 | N-[1-(2, the 3-dichlorophenyl) propyl group]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
73 | The 1-ethyl-N-[(1R)-1-(4-aminomethyl phenyl) ethyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
74 | 1-ethyl-N-(1-phenylethyl)-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
75 | N-[(1R)-1-(4-bromophenyl) ethyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
76 | N-[1-(4-chloro-phenyl-)-2-hydroxyethyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
77 | N-[1-(3, the 4-dichlorophenyl)-2-hydroxyethyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
78 | 1-ethyl-N-{1-[3-(methoxyl group) phenyl] propyl group }-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
79 | 1-ethyl-N-{1-[4-(methoxyl group) phenyl] propyl group }-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
80 | N-[1-(4-bromophenyl) propyl group]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
81 | 1-ethyl-N-{1-[4-(propoxy-) phenyl] propyl group }-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
82 | N-[1-(3, the 5-3,5-dimethylphenyl) propyl group]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base ammonia |
Base)-1H-pyrazolo [3,4-b] pyridine-5-methane amide | |
83 | 1-ethyl-N-[1-(4-aminomethyl phenyl) propyl group]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
84 | 1-ethyl-N-{1-[4-(1-methylethyl) phenyl] propyl group }-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
85 | 1-ethyl-N-[1-(2-aminomethyl phenyl) ethyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
86 | N-(1-{4-[(difluoromethyl) oxygen base] phenyl } ethyl)-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
87 | 1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-N-{1-[4-(trifluoromethyl) phenyl] ethyl }-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
88 | 1-ethyl-N-[1-(2-aminomethyl phenyl) propyl group]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
89 | 1-ethyl-N-{1-[4-(oxyethyl group) phenyl] propyl group }-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
90 | N-(1-{4-[(difluoromethyl) oxygen base] phenyl } propyl group)-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
91 | 1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-N-{1-[4-(trifluoromethyl) phenyl] propyl group }-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
92 | N-[1-(3, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
93 | N-[1-(2, the 3-3,5-dimethylphenyl) ethyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
94 | N-[1-(2, the 4-3,5-dimethylphenyl) ethyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
95 | N-[1-(4-chloro-2-fluorophenyl) ethyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
96 | N-[1-(3-chloro-4-aminomethyl phenyl) ethyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base ammonia |
Base)-1H-pyrazolo [3,4-b] pyridine-5-methane amide | |
97 | N-[1-(2, the 3-3,5-dimethylphenyl) propyl group]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
98 | N-[1-(2, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
99 | N-[1-(4-chloro-2-fluorophenyl) propyl group]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
100 | N-[1-(3-chloro-4-aminomethyl phenyl) propyl group]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
101 | 1-ethyl-N-[1-(3-hydroxy phenyl) propyl group]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
102 | N-[1-(2,3-dihydro-1H-indenes-5-yl) ethyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
103 | 1-ethyl-N-[1-(5,6,7,8-tetrahydrochysene-2-naphthyl) ethyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
104 | N-[1-(4-bromophenyl)-2,2, the 2-trifluoroethyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
105 | 1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-N-{2,2,2-three fluoro-1-[3-(methoxyl group) phenyl] ethyl }-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
106 | 4-(cyclohexyl amino)-1-ethyl-N-{1-[4-(methyl sulphonyl) phenyl] ethyl }-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
107 | 4-(cyclohexyl amino)-1-ethyl-N-[(1R)-the 1-phenyl propyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
108 | 4-(cyclohexyl amino)-N-(diphenyl methyl)-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
109 | 4-(cyclohexyl amino)-1-ethyl-N-[(1R)-the 1-phenylethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
110 | ({ [4-(cyclohexyl amino)-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-yl] carbonyl } ammonia |
Base) (phenyl) ethyl acetate | |
111 | N-[1-(4-chloro-phenyl-) ethyl]-4-(cyclohexyl amino)-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
112 | 4-(cyclohexyl amino)-1-ethyl-N-(1-methyl isophthalic acid-phenylethyl)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
113 | 4-(cyclohexyl amino)-1-ethyl-N-[1-(4-fluorophenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
114 | N-[1-(4-chloro-phenyl-) propyl group]-4-(cyclohexyl amino)-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
115 | 4-(cyclohexyl amino)-N-(1, the 2-diphenyl-ethyl)-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
116 | 4-(cyclohexyl amino)-1-ethyl-N-{1-[4-(propoxy-) phenyl] ethyl }-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
117 | 3-({ [4-(cyclohexyl amino)-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-yl] carbonyl } amino)-3-phenylpropionic acid methyl esters |
118 | 4-(cyclohexyl amino)-1-ethyl-N-[1-(hydroxymethyl)-1-phenyl propyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
119 | 4-(cyclohexyl amino)-1-ethyl-N-(3-hydroxyl-1-phenyl propyl)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
120 | 4-(cyclohexyl amino)-1-ethyl-N-{1-[4-(oxyethyl group) phenyl] ethyl }-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
121 | 4-(cyclohexyl amino)-1-ethyl-N-[1-(3-hydroxy phenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
122 | 4-(cyclohexyl amino)-1-ethyl-N-[1-phenyl-2-(1-pyrrolidyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
123 | 4-(cyclohexyl amino)-N-[2-(dimethylamino)-1-phenylethyl]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
124 | 4-(cyclohexyl amino)-1-ethyl-N-[(1R)-2-(methoxyl group)-1-phenylethyl]-the 1H-pyrrole |
Azoles is [3,4-b] pyridine-5-methane amide also | |
125 | N-[(1R)-2-amino-2-oxo-1-phenylethyl]-4-(cyclohexyl amino)-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
126 | 4-(cyclohexyl amino)-1-ethyl-N-[(1R)-2-hydroxyl-1-phenylethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
127 | 4-(cyclohexyl amino)-1-ethyl-N-[(1S)-2-hydroxyl-1-phenylethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
128 | 4-(cyclohexyl amino)-1-ethyl-N-{ (1R)-1-[3-(methoxyl group) phenyl] ethyl }-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
129 | 4-(cyclohexyl amino)-1-ethyl-N-[(1S)-2-(methoxyl group)-1-phenylethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
130 | 4-(cyclohexyl amino)-1-ethyl-N-[(1R)-1-(4-nitrophenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
131 | 4-(cyclohexyl amino)-1-ethyl-N-[(1S)-1-(1-naphthyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
132 | 4-(cyclohexyl amino)-1-ethyl-N-[phenyl (4-phenyl-1,3-thiazoles-2-yl) methyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
133 | N-[cyano group (phenyl) methyl]-4-(cyclohexyl amino)-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
134 | 4-(cyclohexyl amino)-1-ethyl-N-[1-(1-naphthyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
135 | 4-(cyclohexyl amino)-1-ethyl-N-(2-hydroxyl-1,1-diphenyl-ethyl)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
136 | 4-(cyclohexyl amino)-1-ethyl-N-{ (1R)-1-[4-(methoxyl group) phenyl] ethyl }-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
137 | 4-(cyclohexyl amino)-1-ethyl-N-[1-(4-fluorophenyl) propyl group]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
138 | 4-(cyclohexyl amino)-N-[1-(2, the 3-dichlorophenyl) propyl group]-1-ethyl-1H-pyrazolo |
[3,4-b] pyridine-5-methane amide | |
139 | 4-(cyclohexyl amino)-1-ethyl-N-[(1R)-1-(4-aminomethyl phenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
140 | 4-(cyclohexyl amino)-1-ethyl-N-(1-phenylethyl)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
141 | N-[(1R)-1-(4-bromophenyl) ethyl]-4-(cyclohexyl amino)-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
142 | 4-(cyclohexyl amino)-N-[1-(2, the 3-dichlorophenyl) ethyl]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
143 | 4-(cyclohexyl amino)-1-ethyl-N-{1-[3-(methoxyl group) phenyl] propyl group }-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
144 | 4-(cyclohexyl amino)-1-ethyl-N-{1-[4-(methoxyl group) phenyl] propyl group }-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
145 | N-[1-(4-bromophenyl) propyl group]-4-(cyclohexyl amino)-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
146 | 4-(cyclohexyl amino)-1-ethyl-N-{1-[4-(propoxy-) phenyl] propyl group }-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
147 | 4-(cyclohexyl amino)-N-[1-(3, the 5-3,5-dimethylphenyl) propyl group]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
148 | 4-(cyclohexyl amino)-1-ethyl-N-[1-(4-aminomethyl phenyl) propyl group]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
149 | 4-(cyclohexyl amino)-1-ethyl-N-{1-[4-(1-methylethyl) phenyl] propyl group }-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
150 | 4-(cyclohexyl amino)-1-ethyl-N-[1-(2-aminomethyl phenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
151 | 4-(cyclohexyl amino)-N-(1-{4-[(difluoromethyl) oxygen base] phenyl } ethyl)-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
152 | 4-(cyclohexyl amino)-1-ethyl-N-{1-[4-(trifluoromethyl) phenyl] ethyl }-the 1H-pyrazoles |
And [3,4-b] pyridine-5-methane amide | |
153 | 4-(cyclohexyl amino)-1-ethyl-N-[1-(2-aminomethyl phenyl) propyl group]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
154 | 4-(cyclohexyl amino)-1-ethyl-N-{1-[4-(oxyethyl group) phenyl] propyl group }-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
155 | 4-(cyclohexyl amino)-N-(1-{4-[(difluoromethyl) oxygen base] phenyl } propyl group)-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
156 | 4-(cyclohexyl amino)-1-ethyl-N-{1-[4-(trifluoromethyl) phenyl] propyl group }-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
157 | 4-(cyclohexyl amino)-N-[1-(3, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
158 | 4-(cyclohexyl amino)-N-[1-(2, the 3-3,5-dimethylphenyl) ethyl]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
159 | 4-(cyclohexyl amino)-N-[1-(2, the 4-3,5-dimethylphenyl) ethyl]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
160 | N-[1-(4-chloro-2-fluorophenyl) ethyl]-4-(cyclohexyl amino)-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
161 | N-[1-(3-chloro-4-aminomethyl phenyl) ethyl]-4-(cyclohexyl amino)-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
162 | 4-(cyclohexyl amino)-N-[1-(2, the 3-3,5-dimethylphenyl) propyl group]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
163 | 4-(cyclohexyl amino)-N-[1-(2, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
164 | N-[1-(4-chloro-2-fluorophenyl) propyl group]-4-(cyclohexyl amino)-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
165 | N-[1-(3-chloro-4-aminomethyl phenyl) propyl group]-4-(cyclohexyl amino)-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
166 | 4-(cyclohexyl amino)-1-ethyl-N-[1-(3-hydroxy phenyl) propyl group]-the 1H-pyrazolo [3,4- |
B] pyridine-5-methane amide | |
167 | N-[1-(4-chloro-phenyl-)-2-hydroxyethyl]-4-(cyclohexyl amino)-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
168 | 4-(cyclohexyl amino)-N-[1-(2,3-dihydro-1H-indenes-5-yl) ethyl]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
169 | 4-(cyclohexyl amino)-1-ethyl-N-[1-(5,6,7,8-tetrahydrochysene-2-naphthyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
170 | 4-[(1-ethanoyl-4-piperidyl) amino]-the 1-ethyl-N-[(1S)-the 1-phenyl propyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
171 | 4-[(1-ethanoyl-4-piperidyl) amino]-the 1-ethyl-N-[(1R)-the 1-phenylethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
172 | 4-[(1-ethanoyl-4-piperidyl) amino]-N-(diphenyl methyl)-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
173 | 4-[(1-ethanoyl-4-piperidyl) amino]-1-ethyl-N-{1-[4-(methyl sulphonyl) phenyl] ethyl }-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
174 | 4-[(1-ethanoyl-4-piperidyl) amino]-the 1-ethyl-N-[(1R)-the 1-phenyl propyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
175 | N-[1-(4-chloro-phenyl-) ethyl]-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
176 | N-[1-(4-chloro-phenyl-) propyl group]-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
177 | The 1-ethyl-N-[(1S)-1-(4-nitrophenyl) ethyl]-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
178 | The 1-ethyl-N-[(1R)-1-(4-nitrophenyl) ethyl]-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
179 | 1-ethyl-N-{1-[4-(oxyethyl group) phenyl] ethyl }-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
180 | 1-ethyl-4-[(4-oxo cyclohexyl) amino]-N-{1-[4-(propoxy-) phenyl] ethyl }- |
1H-pyrazolo [3,4-b] pyridine-5-methane amide | |
181 | 1-ethyl-N-[1-(4-fluorophenyl) ethyl]-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
182 | The 1-ethyl-N-[(1R)-2-hydroxyl-1-phenylethyl]-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
183 | 1-ethyl-4-[(4-oxo cyclohexyl) amino]-N-(1-phenyl propyl)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
184 | (2R)-[(1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-yl } carbonyl) amino] [3-(methoxyl group) phenyl] acetate |
185 | 1-ethyl-N-{1-[4-(1-methylethyl) phenyl] ethyl }-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
186 | 1-ethyl-N-[1-(2-aminomethyl phenyl) ethyl]-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
187 | N-[1-(3, the 5-3,5-dimethylphenyl) ethyl]-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
188 | 1-ethyl-N-{ (1R)-1-[4-(methoxyl group) phenyl] ethyl }-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
189 | 1-ethyl-N-[1-(4-fluorophenyl) propyl group]-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
190 | N-[1-(2, the 3-dichlorophenyl) propyl group]-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
191 | The 1-ethyl-N-[(1R)-1-(4-aminomethyl phenyl) ethyl]-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
192 | 1-ethyl-4-[(4-oxo cyclohexyl) amino]-N-(1-phenylethyl)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
193 | N-[(1R)-1-(4-bromophenyl) ethyl]-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
194 | The 1-ethyl-N-[(1S)-2-hydroxyl-1-phenylethyl]-4-[(4-oxo cyclohexyl) amino]- |
1H-pyrazolo [3,4-b] pyridine-5-methane amide | |
195 | N-[1-(4-chloro-phenyl-)-2-hydroxyethyl]-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
196 | N-(1-{4-[(difluoromethyl) oxygen base] phenyl } ethyl)-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
197 | 1-ethyl-4-[(4-oxo cyclohexyl) amino]-N-{1-[4-(trifluoromethyl) phenyl] ethyl }-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
198 | 1-ethyl-N-[1-(2-aminomethyl phenyl) propyl group]-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
199 | 1-ethyl-N-{1-[4-(oxyethyl group) phenyl] propyl group }-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
200 | N-(1-{4-[(difluoromethyl) oxygen base] phenyl } propyl group)-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
201 | 1-ethyl-4-[(4-oxo cyclohexyl) amino]-N-{1-[4-(trifluoromethyl) phenyl] propyl group }-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
202 | N-[1-(3, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
203 | 1-ethyl-4-[(4-oxo cyclohexyl) amino]-N-[(1R)-the 1-phenyl propyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
204 | 1-ethyl-N-{ (1R)-1-[3-(methoxyl group) phenyl] ethyl }-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
205 | N-[1-(2, the 3-3,5-dimethylphenyl) ethyl]-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
206 | N-[1-(2, the 4-3,5-dimethylphenyl) ethyl]-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
207 | N-[1-(4-chloro-2-fluorophenyl) ethyl]-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
208 | N-[1-(3-chloro-4-aminomethyl phenyl) ethyl]-1-ethyl-4-[(4-oxo cyclohexyl) amino]- |
1H-pyrazolo [3,4-b] pyridine-5-methane amide | |
209 | N-[1-(2, the 3-3,5-dimethylphenyl) propyl group]-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
210 | N-[1-(2, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
211 | N-[1-(4-chloro-2-fluorophenyl) propyl group]-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
212 | N-[1-(3-chloro-4-aminomethyl phenyl) propyl group]-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
213 | 1-ethyl-N-[1-(3-hydroxy phenyl) ethyl]-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
214 | 1-ethyl-N-[1-(3-hydroxy phenyl) propyl group]-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
215 | N-[1-(2, the 3-dichlorophenyl) ethyl]-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
216 | 1-ethyl-N-{1-[3-(methoxyl group) phenyl] propyl group }-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
217 | 1-ethyl-N-{1-[4-(methoxyl group) phenyl] propyl group }-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
218 | N-[1-(4-bromophenyl) propyl group]-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
219 | 1-ethyl-4-[(4-oxo cyclohexyl) amino]-N-{1-[4-(propoxy-) phenyl] propyl group }-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
220 | N-[1-(3, the 5-3,5-dimethylphenyl) propyl group]-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
221 | 1-ethyl-N-[1-(4-aminomethyl phenyl) propyl group]-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
222 | 1-ethyl-N-{1-[4-(1-methylethyl) phenyl] propyl group }-4-[(4-oxo cyclohexyl) ammonia |
Base]-1H-pyrazolo [3,4-b] pyridine-5-methane amide | |
223 | 1-ethyl-N-(1-{4-[(1-methylethyl) oxygen base] phenyl } ethyl)-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
224 | 1-ethyl-4-[(4-oxo cyclohexyl) amino]-N-[1-(5,6,7,8-tetrahydrochysene-2-naphthyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
225 | N-[1-(4-bromophenyl)-2,2, the 2-trifluoroethyl]-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
226 | 1-ethyl-4-[(4-oxo cyclohexyl) amino]-N-{2,2,2-three fluoro-1-[3-(methoxyl group) phenyl] ethyl }-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
227 | 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-[1-(5,6,7,8-tetrahydrochysene-2-naphthyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
228 | 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-[(1S)-2-hydroxyl-1-phenylethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
229 | N-[1-(2,3-dihydro-1H-indenes-5-yl) ethyl]-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
230 | N-[1-(4-chloro-phenyl-)-2-hydroxyethyl]-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
231 | 1-ethyl-N-{1-[4-(oxyethyl group) phenyl] ethyl }-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
232 | 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-{1-[4-(propoxy-) phenyl] ethyl }-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
233 | 1-ethyl-N-[1-(4-fluorophenyl) ethyl]-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
234 | 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-[(1R)-2-hydroxyl-1-phenylethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
235 | 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-(1-phenyl propyl)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
236 | 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-{1-[4-(1-methylethyl) phenyl] second |
Base }-1H-pyrazolo [3,4-b] pyridine-5-methane amide | |
237 | N-[1-(3, the 5-3,5-dimethylphenyl) ethyl]-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
238 | 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-{ (1R)-1-[4-(methoxyl group) phenyl] ethyl }-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
239 | 1-ethyl-N-[1-(4-fluorophenyl) propyl group]-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
240 | N-[1-(2, the 3-dichlorophenyl) propyl group]-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
241 | 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-[(1R)-1-(4-aminomethyl phenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
242 | 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-(1-phenylethyl)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
243 | N-[(1R)-1-(4-bromophenyl) ethyl]-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
244 | N-[1-(2, the 3-dichlorophenyl) ethyl]-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
245 | N-[1-(4-chloro-phenyl-) propyl group]-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
246 | N-[1-(4-chloro-phenyl-) ethyl]-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
247 | 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-{1-[3-(methoxyl group) phenyl] propyl group }-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
248 | 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-{1-[4-(methoxyl group) phenyl] propyl group }-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
249 | N-[1-(4-bromophenyl) propyl group]-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
250 | 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-{1-[4-(propoxy-) phenyl] propyl group }- |
1H-pyrazolo [3,4-b] pyridine-5-methane amide | |
251 | N-[1-(3, the 5-3,5-dimethylphenyl) propyl group]-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
252 | 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-[1-(4-aminomethyl phenyl) propyl group]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
253 | 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-{1-[4-(1-methylethyl) phenyl] propyl group }-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
254 | 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-[1-(2-aminomethyl phenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
255 | N-(1-{4-[(difluoromethyl) oxygen base] phenyl } ethyl)-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
256 | 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-{1-[4-(trifluoromethyl) phenyl] ethyl }-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
257 | 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-[1-(2-aminomethyl phenyl) propyl group]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
258 | 1-ethyl-N-{1-[4-(oxyethyl group) phenyl] propyl group }-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
259 | N-(1-{4-[(difluoromethyl) oxygen base] phenyl } propyl group)-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
260 | 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-{1-[4-(trifluoromethyl) phenyl] propyl group }-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
261 | N-[1-(3, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
262 | 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-[(1R)-the 1-phenyl propyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
263 | 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-{ (1R)-1-[3-(methoxyl group) phenyl] ethyl }-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
264 | N-[1-(2, the 3-3,5-dimethylphenyl) ethyl]-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }- |
1H-pyrazolo [3,4-b] pyridine-5-methane amide | |
265 | N-[1-(2, the 4-3,5-dimethylphenyl) ethyl]-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
266 | N-[1-(4-chloro-2-fluorophenyl) ethyl]-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
267 | N-[1-(3-chloro-4-aminomethyl phenyl) ethyl]-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
268 | N-[1-(2, the 3-3,5-dimethylphenyl) propyl group]-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
269 | N-[1-(2, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
270 | N-[1-(4-chloro-2-fluorophenyl) propyl group]-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
271 | N-[1-(3-chloro-4-aminomethyl phenyl) propyl group]-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
272 | 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-[1-(3-hydroxy phenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
273 | 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-[1-(3-hydroxy phenyl) propyl group]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
274 | N-[1-(2, the 4-3,5-dimethylphenyl) ethyl]-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
275 | N-[1-(2, the 4-3,5-dimethylphenyl) ethyl]-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
276 | N-[1-(3, the 5-3,5-dimethylphenyl) ethyl]-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
277 | N-[1-(3, the 5-3,5-dimethylphenyl) ethyl]-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
278 | 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-(1-{4-[(1-methylethyl) oxygen base] |
Phenyl } ethyl)-1H-pyrazolo [3,4-b] pyridine-5-methane amide | |
279 | 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-(1-{4-[(1-methylethyl) oxygen base] phenyl } ethyl)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
280 | 1-ethyl-N-[1-(4-fluorophenyl) ethyl]-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
281 | 1-ethyl-N-[1-(4-fluorophenyl) ethyl]-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
282 | N-[1-(4-chloro-phenyl-) propyl group]-1-ethyl-4-{[(1S, 3R)-and/or (1R, 3S)-the 3-hydroxy-cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
283 | 1-ethyl-4-{[(1S, 3R)-and/or (1R, 3S)-the 3-hydroxy-cyclohexyl] amino }-N-[(1R)-1-(4-aminomethyl phenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
284 | N-[1-(2, the 4-3,5-dimethylphenyl) ethyl]-1-ethyl-4-{[(1S, 3R)-and/or (1R, 3S)-the 3-hydroxy-cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide (isomer 1) |
285 | N-[1-(2, the 4-3,5-dimethylphenyl) ethyl]-1-ethyl-4-{[(1S, 3R)-and/or (1R, 3S)-the 3-hydroxy-cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide (isomer 2) |
286 | N-[1-(3, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-4-{[(1S, 3R)-and/or (1R, 3S)-the 3-hydroxy-cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
287 | N-[1-(4-chloro-phenyl-) propyl group]-1-ethyl-6-methyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
288 | N-[1-(4-chloro-phenyl-) ethyl]-1-ethyl-6-methyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
289 | N-[1-(4-chloro-phenyl-) ethyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide (enantiomer 1) |
290 | N-[1-(4-chloro-phenyl-) ethyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide (enantiomer 2) |
291 | N-[1-(4-chloro-phenyl-) propyl group]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide (enantiomer 1) |
292 | N-[1-(4-chloro-phenyl-) propyl group]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H- |
Pyrazolo [3,4-b] pyridine-5-methane amide (enantiomer 2) | |
293 | 1-ethyl-N-{1-[4-(oxyethyl group) phenyl] ethyl }-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide (enantiomer 1) |
294 | 1-ethyl-N-{1-[4-(oxyethyl group) phenyl] ethyl }-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide (enantiomer 2) |
295 | N-[1-(2, the 4-3,5-dimethylphenyl) ethyl]-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide (enantiomer 1) |
296 | N-[1-(2, the 4-3,5-dimethylphenyl) ethyl]-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide (enantiomer 2) |
297 | N-[1-(3, the 5-3,5-dimethylphenyl) ethyl]-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide (enantiomer 1) |
298 | N-[1-(3, the 5-3,5-dimethylphenyl) ethyl]-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide (enantiomer 2) |
299 | 1-ethyl-N-(1-{4-[(1-methylethyl) oxygen base] phenyl } ethyl)-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide (enantiomer 1) |
300 | 1-ethyl-N-(1-{4-[(1-methylethyl) oxygen base] phenyl } ethyl)-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide (enantiomer 2) |
301 | 1-ethyl-N-[1-(4-fluorophenyl) ethyl]-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide (enantiomer 1) |
302 | 1-ethyl-N-[1-(4-fluorophenyl) ethyl]-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide (enantiomer 2) |
303 | N-[1-(2, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide (enantiomer 1) |
304 | N-[1-(2, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide (enantiomer 2) |
305 | 1-ethyl-4-{[(1S, 3R)-and/or (1R, 3S)-and the 3-hydroxy-cyclohexyl] amino }-N-[(1R)-1-(4-aminomethyl phenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide (diastereomer 1) |
306 | 1-ethyl-4-{[(1S, 3R)-and/or (1R, 3S)-and the 3-hydroxy-cyclohexyl] amino }-N-[(1R)-1-(4-aminomethyl phenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide (diastereomer 2) |
307 | N-[1-(2, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide (enantiomer 2) hydrochloride |
308 | 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-the 1-ethyl-N-[(1R)-1-(4-aminomethyl phenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
309 | 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-the 1-ethyl-N-[(1R)-the 1-phenylethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
310 | 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-N-[(1R)-1-(4-bromophenyl) ethyl]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
311 | 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-N-[1-(2, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
312 | 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-N-[1-(3-chloro-4-aminomethyl phenyl) propyl group]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
313 | 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-N-[1-(4-chloro-2-fluorophenyl) propyl group]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
314 | 4-{[4-(aminocarboxyl) cyclohexyl] amino }-the 1-ethyl-N-[(1R)-the 1-phenylethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
314A | 4-{ is suitable-[4-(aminocarboxyl) cyclohexyl] amino }-the 1-ethyl-N-[(1R)-the 1-phenylethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
315 | N-[(1S)-1-(2, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
316 | N-[(1R)-1-(2, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
317 | N-[(1R)-1-(2, the 5-3,5-dimethylphenyl) ethyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
318 | 1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-N-[(1R)-1-(2,4, the 6-Three methyl Benzene |
Base) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide | |
319 | The 1-ethyl-N-[(1R)-1-(2-ethylphenyl) ethyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
320 | The 1-ethyl-N-[(1R)-1-(4-ethylphenyl) ethyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
321 | The 1-ethyl-N-[(1R)-1-(4-aminomethyl phenyl) propyl group]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
322 | The 1-ethyl-N-[(1R)-1-(4-ethylphenyl) propyl group]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
323 | 1-ethyl-N-{ (1R)-1-[4-(1-methylethyl) phenyl] propyl group }-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
324 | N-[(1R)-1-(4-chloro-2-fluorophenyl) propyl group]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
325 | N-[(1R)-1-(2, the 6-3,5-dimethylphenyl) propyl group]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
326 | N-[(1R)-1-(2, the 5-3,5-dimethylphenyl) propyl group]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
327 | The 1-ethyl-N-[(1R)-1-(2-ethylphenyl) propyl group]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
328 | 1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-N-[(1R)-1-(2,4, the 6-trimethylphenyl) propyl group]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
329 | 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-N-[(1R)-1-(2, the 5-3,5-dimethylphenyl) ethyl]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
330 | 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-the 1-ethyl-N-[(1R)-1-(4-ethylphenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
331 | 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-the 1-ethyl-N-[(1R)-1-(2-ethylphenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
332 | 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-the 1-ethyl-N-[(1R)-1-(2,4, the 6-front three |
The base phenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide | |
333 | 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-N-[(1R)-1-(2, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
334 | 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-N-[1-(4-chloro-phenyl-) ethyl]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
335 | 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-the 1-ethyl-N-[(1R)-the 1-phenyl propyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
336 | 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-N-[1-(4-chloro-phenyl-) propyl group]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
337 | 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-1-ethyl-N-[1-(4-fluorophenyl) propyl group]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
338 | 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-the 1-ethyl-N-[(1R)-1-(4-aminomethyl phenyl) propyl group]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
339 | 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-the 1-ethyl-N-[(1R)-1-(4-ethylphenyl) propyl group]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
340 | 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-1-ethyl-N-{ (1R)-1-[4-(1-methylethyl) phenyl] propyl group }-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
341 | 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-N-[(1R)-1-(4-chloro-2-fluorophenyl) propyl group]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
342 | 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-N-[(1R)-1-(2, the 6-3,5-dimethylphenyl) propyl group]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
343 | 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-N-[(1R)-1-(2, the 5-3,5-dimethylphenyl) propyl group]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
344 | 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-the 1-ethyl-N-[(1R)-1-(2-ethylphenyl) propyl group]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
345 | 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-the 1-ethyl-N-[(1R)-1-(2,4, the 6-trimethylphenyl) propyl group]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
346 | 4-{[4-(aminocarboxyl) cyclohexyl] amino }-N-[1-(4-chloro-phenyl-) propyl group]-the 1-ethyl- |
1H-pyrazolo [3,4-b] pyridine-5-methane amide | |
347 | 4-{[4-(aminocarboxyl) cyclohexyl] amino }-the 1-ethyl-N-[(1R)-the 1-phenyl propyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
348 | 4-{[4-(aminocarboxyl) cyclohexyl] amino }-N-(1-{4-[(difluoromethyl) oxygen base] phenyl } ethyl)-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
349 | 4-{[4-(aminocarboxyl) cyclohexyl] amino }-N-[1-(4-chloro-phenyl-) ethyl]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
350 | 4-{[4-(aminocarboxyl) cyclohexyl] amino }-1-ethyl-N-[1-(4-fluorophenyl) propyl group]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
351 | 4-{[4-(aminocarboxyl) cyclohexyl] amino }-N-[(1R)-1-(4-bromophenyl) ethyl]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
352 | 4-{[is suitable-4-(aminocarboxyl) cyclohexyl] and amino }-N-[(1R)-1-(2, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
353 | 4-{[is suitable-4-(aminocarboxyl) cyclohexyl] and amino }-the 1-ethyl-N-[(1R)-1-(4-aminomethyl phenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
354 | 4-{[is suitable-4-(aminocarboxyl) cyclohexyl] and amino }-the 1-ethyl-N-[(1R)-the 1-phenylethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
355 | 4-{[is suitable-4-(aminocarboxyl) cyclohexyl] and amino }-N-[(1R)-1-(4-bromophenyl) ethyl]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
356 | 4-{[is anti--4-(aminocarboxyl) cyclohexyl] and amino }-N-[(1R)-1-(2, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
357 | 4-{[is anti--4-(aminocarboxyl) cyclohexyl] and amino }-the 1-ethyl-N-[(1R)-1-(4-aminomethyl phenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
358 | 4-{[is anti--4-(aminocarboxyl) cyclohexyl] and amino }-the 1-ethyl-N-[(1R)-the 1-phenylethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
359 | 4-{[is anti--4-(aminocarboxyl) cyclohexyl] and amino }-N-[(1R)-1-(4-bromophenyl) ethyl]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
360 | 4-{[(3S)-and 1-(aminocarboxyl) tetramethyleneimine-3-yl] amino }-N-[1-(2, the 4-dimethyl benzene |
Base) propyl group]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide | |
361 | 4-{[(3S)-and 1-(aminocarboxyl) tetramethyleneimine-3-yl] amino }-the 1-ethyl-N-[(1R)-1-(4-aminomethyl phenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
362 | 4-{[(3S)-and 1-(aminocarboxyl) tetramethyleneimine-3-yl] amino }-N-[1-(3, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
363 | 4-{[(3S)-and 1-(aminocarboxyl) tetramethyleneimine-3-yl] amino }-N-[(1R)-1-(4-bromophenyl) ethyl]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
364 | 4-{[(3R)-and 1-(aminocarboxyl) tetramethyleneimine-3-yl] amino }-N-[1-(2, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
365 | 4-{[(3R)-and 1-(aminocarboxyl) tetramethyleneimine-3-yl] amino }-the 1-ethyl-N-[(1R)-1-(4-aminomethyl phenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
366 | 4-{[(3R)-and 1-(aminocarboxyl) tetramethyleneimine-3-yl] amino }-N-[1-(3, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
367 | 4-{[(3R)-and 1-(aminocarboxyl) tetramethyleneimine-3-yl] amino }-N-[(1R)-1-(4-bromophenyl) ethyl]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
368 | 4-{[is suitable-3-(aminocarboxyl) cyclobutyl] and amino }-the 1-ethyl-N-[(1R)-1-(4-aminomethyl phenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
369 | 4-{[is suitable-3-(aminocarboxyl) cyclobutyl] and amino }-N-[1-(2, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
370 | 4-[(is anti--4-ethanoyl cyclohexyl) and amino]-the 1-ethyl-N-[(1R)-1-(4-aminomethyl phenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
371 | 4-[(4-ethanoyl cyclohexyl) amino]-N-[(1R)-1-(2, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
372 | 4-[(is suitable-4-ethanoyl cyclohexyl) and amino]-the 1-ethyl-N-[(1R)-1-(4-aminomethyl phenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
373 | 4-{[is suitable-4-(1-hydroxyethyl) cyclohexyl] and amino }-N-[1-(2, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
374 | 1-ethyl-4-{[is anti--the 3-hydroxy-cyclohexyl] and amino }-N-[(1R)-1-(4-aminomethyl phenyl) second |
Base]-1H-pyrazolo [3,4-b] pyridine-5-methane amide | |
375 | N-[(1S)-1-(2, the 4-3,5-dimethylphenyl) ethyl]-1-ethyl-4-{[is anti--the 3-hydroxy-cyclohexyl] and amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
376 | N-[(1R)-1-(2, the 4-3,5-dimethylphenyl) ethyl]-1-ethyl-4-{[is anti--the 3-hydroxy-cyclohexyl] and amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
377 | N-[(1R)-1-(4-bromophenyl) ethyl]-1-ethyl-4-{[is anti--the 3-hydroxy-cyclohexyl] and amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
378 | N-[1-(3, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-4-{[is anti--the 3-hydroxy-cyclohexyl] and amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
379 | N-[4-(dimethylamino)-1-(3-aminomethyl phenyl)-4-oxo butyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
380 | 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-N-[4-(dimethylamino)-1-(3-aminomethyl phenyl)-4-oxo butyl]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide |
381 | The 1-ethyl-N-[(1R)-1-(4-aminomethyl phenyl) ethyl]-4-(4-piperidyl amino)-1H-pyrazolo [3,4-b] pyridine-5-carboxamide hydrochloride |
382 | N-[1-(2, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-4-(4-piperidyl amino)-1H-pyrazolo [3,4-b] pyridine-5-carboxamide hydrochloride |
Embodiment 1-105
Universal method:
The mixture of the DMF (0.4ml) of intermediate 13 (0.1mmol), HATU (0.1mmol) and DIPEA (0.4mmol) was at room temperature vibrated 10 minutes.Add amine reagent A r-C (R then
4) (R
5)-NH
2DMF (0.1mmol) (0.2ml) solution stirs several minutes with mixture, obtains solution.Solution was at room temperature stored 16 hours, then vacuum concentration.Resistates is dissolved in chloroform (0.5ml), last sample to the SPE post (aminopropyl, 0.5g) on.This post use successively chloroform (1.5ml), EtOAc (1.5ml) and EtOAc: MeOH (9: 1,1.5ml) wash-out.Vacuum concentration comprises the part of required product, and resistates prepares the HPLC purifying automatically with the mass spectrum monitoring type.
According to the method described above or its similar approach, with intermediate 13 and suitable amine reagent A r-C (R
4) (R
5)-NH
2Preparation following examples 1-105:
As embodiment 78-101 amine reagent A r-C (R
4) (R
5)-NH
2During preparation, described amine reagent is suitable a kind of among the intermediate 62-82 (not comprising intermediate 75a, 80a, 82a, 82b and 83a), shown in above embodiment 1-105 form, believe that embodiment 78-101 is the mixture of enantiomer, and main enantiomer has (R) stereochemical structure (promptly at the benzylic carbon atoms place).
The alternative preparation method of embodiment 73
With thionyl chloride (20ml) solution stirring of intermediate 13 (2.0g), reflux 2.5 hours.Cooling solution, vacuum is removed thionyl chloride, remaining intermediate acyl chlorides (2.1g).With THF (100ml) solution stirring of acyl chlorides (2.1g), (R)-1-(4-aminomethyl phenyl) ethamine (1.0g) and DIPEA (1.4g) 18 hours.The vacuum concentration reaction mixture.Resistates distributes between 0.5M sodium bicarbonate (250ml) and ethyl acetate (250ml).Isolate organic phase, water (250ml) washing, through dried over sodium sulfate, vacuum concentration obtains foam.With foam hexanaphthene and Et
2The mixture of O (5: 1) crystallization.With hexanaphthene and Et
2The mixture of O (5: 1) recrystallization once obtains embodiment 73 (0.96g, white needles thing).LC-MS shows MH
+=408; T
RET=3.05min.
Embodiment 106-169
Universal method:
The mixture of intermediate 14 (0.1mmol), HATU (0.1mmol), DIPEA (0.4mmol) and DMF (0.4ml) was at room temperature vibrated 10 minutes.Add amine Ar-C (R then
4) (R
5)-NH
2DMF (0.1mmol) (0.2ml) solution stirs several minutes with mixture, obtains solution.Solution was at room temperature stored 16 hours, then vacuum concentration.Resistates is dissolved in chloroform (0.5ml), last sample to the SPE post (aminopropyl, 0.5g) on.This post use successively chloroform (1.5ml), EtOAc (1.5ml) and EtOAc: MeOH (9: 1,1.5ml) wash-out.Vacuum concentration comprises the part of required product, and resistates prepares the HPLC purifying automatically with the mass spectrum monitoring type.
According to the method described above or its similar approach, with intermediate 14 and suitable amine Ar-C (R
4) (R
5)-NH
2Preparation following examples 106-169:
As embodiment 143-166 amine reagent A r-C (R
4) (R
5)-NH
2During preparation, described amine reagent is suitable a kind of among the intermediate 62-82 (not comprising intermediate 75a, 80a, 82a, 82b and 83a), shown in above embodiment 106-169 form, believe that embodiment 143-166 is the mixture of enantiomer, and main enantiomer has (R) stereochemical structure (promptly at the benzylic carbon atoms place).
Embodiment 170-174
Universal method:
The mixture of intermediate 15 (0.1mmol), HATU (0.1mmol), DIPEA (0.4mmol) and DMF (0.4ml) was at room temperature vibrated 10 minutes.Add amine Ar-C (R then
4) (R
5)-NH
2DMF (0.1mmol) (0.2ml) solution stirs several minutes with mixture, obtains solution.Solution was at room temperature stored 16 hours, then vacuum concentration.Resistates is dissolved in chloroform (0.5ml), last sample to the SPE post (aminopropyl, 0.5g) on.This post use successively chloroform (1.5ml), EtOAc (1.5ml) and EtOAc: MeOH (9: 1,1.5ml) wash-out.Vacuum concentration comprises the part of required product, and resistates prepares the HPLC purifying automatically with the mass spectrum monitoring type.
According to the method described above or its similar approach, with intermediate 15 and suitable amine Ar-C (R
4) (R
5)-NH
2Preparation following examples 170-174:
Embodiment 175-226
Universal method:
The mixture of intermediate 16 (0.1mmol), HATU (0.1mmol), DIPEA (0.4mmol) and DMF (0.4ml) was at room temperature vibrated 10 minutes.Add amine Ar-C (R then
4) (R
5)-NH
2DMF (0.1mmol) (0.2ml) solution stirs several minutes with mixture, obtains solution.Solution was at room temperature stored 16 hours, then vacuum concentration.Resistates is dissolved in chloroform (0.5ml), last sample to the SPE post (aminopropyl, 0.5g) on.This post use successively chloroform (1.5ml), EtOAc (1.5ml) and EtOAc: MeOH (9: 1,1.5ml) wash-out.Vacuum concentration comprises the part of required product, and resistates prepares the HPLC purifying automatically with the mass spectrum monitoring type.
According to the method described above or its similar approach, with intermediate 16 and suitable amine Ar-C (R
4) (R
5)-NH
2Preparation following examples 175-226:
When embodiment 196-202,205-212,214 and 216-222 with amine reagent A r-C (R
4) (R
5)-NH
2During preparation, described amine reagent is suitable a kind of among the intermediate 62-82 (not comprising intermediate 75a, 80a, 82a, 82b and 83a), shown in above embodiment 175-226 form, believe embodiment 196-202,205-212,214 and 216-222 be the mixture of enantiomer, and main enantiomer has (R) stereochemical structure (promptly at the benzylic carbon atoms place).
Embodiment 227
With intermediate 17 (25mg, 0.079mmol), HATU (35mg, 0.092mmol) and DIPEA (50mg, the mixture of MeCN 0.387mmol) (2.0ml) at room temperature stirred 10 minutes.(30mg 0.142mmol), stirred the mixture 2.5 hours, then standing over night to add intermediate 91 then.Vacuum concentrated solution.Resistates is dissolved in EtOAc, last sample to the SPE post (silica gel, 5g) on.This post EtOAc wash-out.Vacuum concentration comprises the part of required product, obtains embodiment 227 white solids.LCMS shows MH
+=475; T
RET=3.32min.
Embodiment 228-230
According to being similar to the method for preparing embodiment 227, with intermediate 17 and suitable amine Ar-C (R
4) (R
5)-NH
2Preparation following examples 228-230:
Embodiment 231-281
Universal method:
With the mixture reflux of suitable ketone (0.05mmol), hydroxylamine hydrochloride (0.07mmol), DIPEA (0.05ml) and MeCN (1.0ml) 5 hours.Remove and desolvate.Resistates is dissolved in chloroform, last sample to the SPE post (silica gel, 0.5g) on.This post EtOAc wash-out.Vacuum concentration comprises the part of required product, obtains suitable oxime.
According to the method described above or its similar approach prepare following examples 231-281:
When embodiment 196-202,205-212,214 and 216-222 with amine reagent A r-C (R
4) (R
5)-NH
2During preparation, described amine reagent is suitable a kind of among the intermediate 62-82 (not comprising intermediate 75a, 80a, 82a, 82b and 83a), shown in above embodiment 175-226 form, believe that disclosed embodiment 247-253,255-261,264-271 and 273 generally are mixture of isomers in the above embodiment 231-281 form, and main isomer has (R) stereochemical structure (promptly at the benzylic carbon atoms place).
Embodiment 282-286
[suitable-(3-hydroxyl hexamethylene-1-yl) amino; The mixture of cis-stereoisomer (1: 1)]
Universal method:
The mixture of intermediate 19 (0.075mmol), HATU (0.09mmol), DIPEA (0.19mmol) and MeCN (2.0ml) was at room temperature stirred 10 minutes, join amine reagent A r-C (R then
4) (R
5)-NH
2(0.075mmol).At room temperature stirred reaction mixture is 7 hours.Remove and desolvate by on reaction mixture, being blown into nitrogen.Resistates distributes between EtOAc (5ml) and 0.5M sodium bicarbonate (5ml).Isolate organic phase, water (5ml) washing is through dried over mgso.Blow out solvent, with resistates vacuum-drying, remaining required product.
According to the method or its similar approach, with intermediate 19 and suitable amine Ar-C (R
4) (R
5)-NH
2Preparation following examples 282-286:
As embodiment 286 usefulness amine reagent A r-C (R
4) (R
5)-NH
2During preparation, described amine reagent is to go up the intermediate 84 shown in the table, believes that embodiment 286 is mixture of isomers, and main isomer has (R) stereochemical structure (promptly at the benzylic carbon atoms place).
Embodiment 287-288
Universal method:
The mixture of the DMF (0.4ml) of intermediate 18 (0.1mmol), HATU (0.1mmol) and DIPEA (0.4mmol) was at room temperature vibrated 10 minutes.Add amine reagent A r-C (R then
4) (R
5)-NH
2DMF (0.1mmol) (0.2ml) solution stirs several minutes with mixture, obtains solution.Solution was at room temperature stored 16 hours, then vacuum concentration.Resistates is dissolved in chloroform (0.5ml), last sample to the SPE post (aminopropyl, 0.5g) on.This post use successively chloroform (1.5ml), EtOAc (1.5ml) and EtOAc: MeOH (9: 1,1.5ml) wash-out.Vacuum concentration comprises the part of required product, and resistates prepares the HPLC purifying automatically with the mass spectrum monitoring type.
According to the method or its similar approach, with intermediate 18 and suitable amine Ar-C (R
4) (R
5)-NH
2Preparation following examples 287-288:
Embodiment 289-306
The isomer that separates embodiment with chiral column
Universal method:
Usually, following embodiment or be racemic, it is the isomer mixture of the main isomer of common enrichment, and described main isomer has (R) stereochemical structure (promptly at the benzylic carbon atoms place), split by preparation type chiral column chromatogram, with 2 inches * 20 centimetres Whelk 0-1 chiral columns, the mixture of 100%EtOH or EtOH and normal heptane is as eluent, perhaps 2 inches ChiralPak AD chiral column, 100% ethanol is as eluent.In form, " isomer 1 " is corresponding to first kind of enantiomer from the chiral column wash-out, and " isomer 2 " is corresponding to second kind of enantiomer.
Embodiment 283 (mixture of diastereomer) is its component isomer by preparation type chiral column chromatographic separation also, adopts 2 inches ChiralCel OD chiral columns, and heptane and alcoholic acid mixture (95: 5) are as eluent.In form, " isomer 1 " is corresponding to first kind of enantiomer from the chiral column wash-out, and " isomer 2 " is corresponding to second kind of enantiomer.
The preparation method of the hydrochloride of embodiment 307 embodiment 304
N-[1-(2, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide (enantiomer 2) hydrochloride
Under agitation, to the Et of embodiment 304 (1.3g)
2O (30ml) solution drips molar excess (with respect to embodiment 304, promptly surpassing the embodiment 304 of 1 molar equivalent) 1.0M hydrogenchloride/Et fast
2O.Allow gained suspension leave standstill 2 hours.Solvent removed in vacuo.The residual solid ethyl alcohol recrystallization obtains hydrochloride (0.64g, white needles thing).LC-MS shows MH
+=436; T
RET=3.35min.
Embodiment 308:4-{[1-(aminocarboxyl)-4-piperidyl] amino }-the 1-ethyl-N-[(1R)-1-(4-aminomethyl phenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
Under room temperature for example, DMF (1ml) solution of intermediate 105 (0.066mmol) is handled with EDC (0.066mmol), HOBT (0.066mmol) and DIPEA (0.151mmol), then usefulness
(0.066mmol) (for example can obtain) to handle from Lancaster Synthesis.Reaction mixture was left standstill 16 hours at 22 ℃.Evaporation DMF, resistates distributes between DCM (5ml) and saturated sodium bicarbonate aqueous solution (2ml).By hydrophobic filter plate collected organic layer, evaporation.Resistates prepares the HPLC purifying automatically with the mass spectrum monitoring type, obtains gumminess title compound (8.9mg).LCMS shows MH
+=450; T
RET=2.76min.
Substantially according to the method described above, with intermediate 105 and suitable amine Ar-C (R
4) (R
5)-NH
2Preparation following examples 309-313:
When embodiment 311,312 and 313 uses intermediate 82,86 and 83 (as implied above) preparation respectively, believe that embodiment 311,312 and 313 is mixtures of enantiomer, and main enantiomer has (R) stereochemical structure (promptly at the benzylic carbon atoms place).
The another kind of preparation method of embodiment 309: 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-the 1-ethyl-N-[(1R)-the 1-phenylethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
The mixture of intermediate 109 (27mg), intermediate 111 (16mg) and MeCN (2ml) is handled with DIPEA (35 μ l).With reaction mixture reflux 72 hours.Evaporating solvent, resistates distribute between DCM (5ml) and saturated sodium bicarbonate aqueous solution (2ml).By hydrophobic filter plate collected organic layer, evaporation.Resistates prepares the HPLC purifying automatically with the mass spectrum monitoring type, obtain embodiment 309 (white solid, 5.0mg).LCMS shows MH
+=436; T
RET=2.62min.
Embodiment 314:4-{[4-(aminocarboxyl) cyclohexyl] amino }-the 1-ethyl-N-[(1R)-the 1-phenylethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
MeCN (1ml) solution of intermediate 109 (0.08mmol) is handled with intermediate 113 (0.088mmol) and DIPEA (0.2mmol).Reflux reaction mixture 20 hours.Evaporating solvent, resistates distribute between DCM (5ml) and water (2ml).Collect organic phase by hydrophobic filter plate, evaporation.Resistates prepares the HPLC purifying automatically with the mass spectrum monitoring type, obtain embodiment 314 (white solid, 12.2mg).LCMS shows MH
+=435; T
RET=2.7min.
In embodiment 314, R
3NH group (i.e. [4-(aminocarboxyl) cyclohexyl] amino) is preferably cis-configuration.In the case, (embodiment 314A), this compound are 4-{ suitable-[4-(aminocarboxyl) cyclohexyl] amino }-the 1-ethyl-N-[(1R)-the 1-phenylethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide.
Embodiment 315-328
Universal method:
The mixture of intermediate 13 (0.1mmol), HATU (0.1mmol), DIPEA (0.4mmol) and DMF (0.4ml) was at room temperature vibrated 10 minutes.Add amine reagent A r-C (R then
4) (R
5)-NH
2DMF (0.1mmol) (0.2ml) solution stirs several minutes with mixture, obtains solution.Solution was at room temperature stored 16 hours, then vacuum concentration.Resistates is dissolved in chloroform (0.5ml), last sample to the SPE post (aminopropyl, 0.5g) on.This post use successively chloroform (1.5ml), EtOAc (1.5ml) and EtOAc: MeOH (9: 1,1.5ml) wash-out.Vacuum concentration comprises the part of required product, and resistates prepares the HPLC purifying automatically with the mass spectrum monitoring type.
According to the method or its similar approach, with intermediate 13 and suitable amine reagent A r-C (R
4) (R
5)-NH
2Preparation following examples 315-328:
(in these embodiments, believing that embodiment 316-328 is made up of the enantiomer that has (R) stereochemical structure at the benzylic carbon atoms place basically, as follows)
Embodiment 329:4-{[1-(aminocarboxyl)-4-piperidyl] amino }-N-[(1R)-1-(2, the 5-3,5-dimethylphenyl) ethyl]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(believe basically and form, be as implied above) by the enantiomer that has (R) stereochemical structure at the benzylic carbon atoms place
Acetonitrile (5ml) solution of intermediate 105 (29mg), HATU (36mg) and DIPEA (0.037ml) was at room temperature stirred 10 minutes.Add intermediate 139 (18mg).Reaction mixture was left standstill 16 hours at 22 ℃.Evaporating solvent.Resistates is dissolved in chloroform, last sample to the SPE post (aminopropyl, 2g) on.The SPE post is at first used the chloroform wash-out, uses 20% methanol/ethyl acetate wash-out then, obtains embodiment 329 (23mg, amorphous solid).LCMS shows MH
+=464; T
RET=2.87min.
Embodiment 330-345
According to the identical or similar method (for example using the reagent of identical or similar mole number) that is used for embodiment 329, with intermediate 105 and suitable amine Ar-C (R
4) (R
5)-NH
2Preparation following examples 330-345:
(in these embodiments, believing that embodiment 330-333, embodiment 335 and embodiment 338-345 are made up of the enantiomer that has (R) stereochemical structure at the benzylic carbon atoms place basically, as follows)
Embodiment 346-351
(in these embodiments, believe that embodiment 348 is isomer mixtures of the main isomer of enrichment, and described main isomer having (R) stereochemical structure at the benzylic carbon atoms place)
Universal method:
The mixture of intermediate 120 (0.1mmol), HATU (0.1mmol), DIPEA (0.4mmol) and DMF (0.4ml) was at room temperature vibrated 10 minutes.Add amine reagent A r-C (R then
4) (R
5)-NH
2DMF (0.1mmol) (0.2ml) solution stirs several minutes with mixture, obtains solution.Solution was at room temperature stored 16-64 hour, then vacuum concentration.Resistates is dissolved in chloroform (0.5ml), last sample to the SPE post (aminopropyl, 0.5g) on.This post use successively chloroform (1.5ml), EtOAc (1.5ml) and EtOAc: MeOH (9: 1,1.5ml) wash-out.Vacuum concentration comprises the part of required product, and resistates prepares the HPLC purifying automatically with the mass spectrum monitoring type.
According to the method or its similar approach, with intermediate 120 and suitable amine reagent A r-C (R
4) (R
5)-NH
2Preparation following examples 346-351.Each embodiment is separated into the mixture (at cyclohexane ring) of cis-isomeride and trans-isomer(ide), and cis-isomeride is a main component.
Embodiment 352-355
(in these embodiments, believing that embodiment 352 is made up of the isomer that has (R) stereochemical structure at the benzylic carbon atoms place basically at least, as follows)
Universal method:
The mixture of intermediate 120 (0.09mmol), EDC (0.1mmol), HOBT (0.1mmol) and DMF (1ml) was at room temperature stirred 30 minutes.Add DIPEA (0.23mmol), solution is joined amine reagent A r-C (R
4) (R
5)-NH
2In the DMF solution (0.12mmol).Stirred the mixture 30 minutes, at room temperature left standstill then 16 hours.Evaporating solvent.Resistates distributes between DCM and saturated sodium bicarbonate solution.Isolate organic phase, evaporation.Resistates prepares the HPLC purifying automatically with the mass spectrum monitoring type, obtains required product.
According to the method or its similar approach, with intermediate 120 and suitable amine reagent A r-C (R
4) (R
5)-NH
2Preparation following examples 352-355:
Embodiment 356-359
(in these embodiments, believing that embodiment 356 is made up of the isomer that has (R) stereochemical structure at the benzylic carbon atoms place basically at least, as follows)
Universal method:
The mixture of the DMF (1ml) of intermediate 121 (0.09mmol), EDC (0.1mmol) and HOBT (0.1mmol) was at room temperature stirred 30 minutes.Add DIPEA (0.23mmol), solution is joined amine reagent A r-C (R
4) (R
5)-NH
2In the DMF solution (0.12mmol).Stirred the mixture 30 minutes.At room temperature left standstill then 16 hours.Evaporating solvent.Resistates distributes between DCM and saturated sodium bicarbonate solution.Isolate organic phase, evaporation.Resistates prepares the HPLC purifying automatically with the mass spectrum monitoring type, obtains required product.
According to the method or its similar approach, with intermediate 121 and suitable amine reagent A r-C (R
4) (R
5)-NH
2Preparation following examples 356-359:
Embodiment 360-363
(in these embodiments, believe that embodiment 360 is non-enantiomer mixtures of the main diastereomer of enrichment, embodiment 362 may also be so, and described main diastereomer has (R) stereochemical structure at the benzylic carbon atoms place)
Universal method:
The mixture of the acetonitrile (2ml) of intermediate 152 (30mg), HATU (120mg) and DIPEA (0.09ml) is joined amine reagent A r-C (R
4) (R
5)-NH
2(0.09mmol).Mixture was at room temperature left standstill 16 hours.Evaporating solvent.Resistates distributes between DCM and saturated sodium bicarbonate solution.Isolate organic phase, evaporation.Resistates prepares the HPLC purifying automatically with the mass spectrum monitoring type, obtains required product.
According to the method or its similar approach, with intermediate 152 and suitable amine reagent A r-C (R
4) (R
5)-NH
2Preparation following examples 360-363:
Embodiment 364-367
(in these embodiments, believe that embodiment 364 is non-enantiomer mixtures of the main diastereomer of enrichment, embodiment 366 may also be so, and described main diastereomer has (R) stereochemical structure at the benzylic carbon atoms place)
Universal method:
The mixture of intermediate 153 (30mg), HATU (120mg), DIPEA (0.09ml) and acetonitrile (2ml) is joined amine reagent A r-C (R
4) (R
5)-NH
2(0.09mmol).Mixture was at room temperature left standstill 16 hours.Evaporating solvent.Resistates distributes between DCM and saturated sodium bicarbonate solution.Isolate organic phase, evaporation.Resistates prepares the HPLC purifying automatically with the mass spectrum monitoring type, obtains required product.
According to the method or its similar approach, with intermediate 153 and suitable amine reagent A r-C (R
4) (R
5)-NH
2Preparation following examples 364-367:
Embodiment 368-369
Embodiment 368
With intermediate 108 (25mg), the amino tetramethylene methane amide of suitable-3-(Chemical AbstractsService, CAS 84182-57-0) (10mg), the mixture reflux of DIPEA (23mg) and acetonitrile (4ml) 24 hours.Reaction mixture, evaporating solvent.Resistates prepares the HPLC purifying automatically with the mass spectrum monitoring type, obtains embodiment 368 (19mg, white solid).
Embodiment 369
According to the similar approach of preparation embodiment 368, embodiment 369 usefulness are suitable-and the amino tetramethylene methane amide of 3-and intermediate 122 prepare.Believe that embodiment 369 is isomer mixtures of the main isomer of enrichment, and described main isomer has (R) stereochemical structure at the benzylic carbon atoms place.
Embodiment 370-372
Embodiment 370: at cyclohexane ring is trans embodiment 371
Embodiment 372: at cyclohexane ring is cis
(in these embodiments, embodiment 371 is isomer mixtures of the main isomer of enrichment, and believes that described main isomer has (R) stereochemical structure at the benzylic carbon atoms place)
The mixture of intermediate 158 (23mg), EDC (15mg), HOBT (10.5mg), DIPEA (27 μ l) and DMF (1ml) was at room temperature stirred 30 minutes, join then [(1R)-and 1-(4-aminomethyl phenyl) ethyl] amine (10.5mg) (for example can obtain) from Lancaster.Stirred the mixture 3 hours.At room temperature left standstill then 16 hours.Add EDC (7.5mg) and HOBT (5.3mg) once more, allow mixture leave standstill 3 hours.Add [(1R)-1-(4-aminomethyl phenyl) ethyl] amine (5.3mg) once more, allow the mixture standing over night.Evaporating solvent.Resistates distributes between DCM and saturated sodium bicarbonate.Isolate organic phase, evaporation.Resistates prepares the HPLC purifying automatically with the mass spectrum monitoring type, obtains embodiment 370 (10.1mg; Main component comprises 4-(anti--4-ethanoyl cyclohexyl) amino).
According to the purification process of embodiment 370, isolate isomeric ketone embodiment 372, be submember (3.7mg comprises 4-(suitable-4-ethanoyl cyclohexyl) amino).
According to the method described above or its similar approach, prepare following examples 371 (at the cyclohexane ring place is the mixture of cis-isomeride and trans-isomer(ide), believes basically and is made up of the isomer that has (R) stereochemical structure at the benzylic carbon atoms place) with intermediate 158 and suitable amine reagent (preferred intermediate 82b):
Embodiment 373:4-{[is suitable-4-(1-hydroxyethyl) cyclohexyl] and amino }-N-[1-(2, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(believe it is the isomer mixture of the main isomer of enrichment, and described main isomer having (R) stereochemical structure at the benzylic carbon atoms place)
The mixture of intermediate 122 (13mg), intermediate 160 (7mg), DIPEA (0.3ml) and ethanol (1ml) is stirred, and reflux spends the night.With mixture cooling, evaporating solvent.Resistates distributes between DCM and sodium hydrogen carbonate solution.Concentrate organic phase.Make resistates pass through silicagel column, the mixture of hexanaphthene and EtOAc obtains embodiment 373 (3mg) as eluent.LCMS shows MH
+=478; T
RET=3.35min.
Embodiment 374-378
At the relative stereochemical structure in cyclohexane ring place as shown in the figure, racemic; Being that racemic instead-(3-hydroxyl hexamethylene-1-yl) amino=racemic (anti--the 3-hydroxy-cyclohexyl) is amino (believe that embodiment 378 is isomer mixtures of the main isomer of enrichment, and described main isomer has (R) stereochemical structure at the benzylic carbon atoms place; Believe that embodiment 375 and 376 is made up of the isomer that has stereochemical structure as follows at the benzylic carbon atoms place basically)
Universal method:
The mixture of intermediate 162 (25mg), HATU (32mg), DIPEA (68 μ l) and acetonitrile (2ml) is joined amine reagent A r-C (R
4) (R
5)-NH
2(0.08mmol).Mixture was at room temperature left standstill 72 hours.Evaporating solvent.Resistates prepares the HPLC purifying automatically with the mass spectrum monitoring type, obtains required product.
According to the method or its similar approach, with intermediate 162 and suitable amine reagent A r-C (R
4) (R
5)-NH
2Preparation following examples 374-378:
Embodiment 379:N-[4-(dimethylamino)-1-(3-aminomethyl phenyl)-4-oxo butyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
The mixture of intermediate 13 (19mg), HOBT (10mg), EDC (14mg), DIPEA (26mg) and acetonitrile (2.5ml) was stirred 10 minutes, join then in the intermediate 169 (20mg).With solution stirring 3 hours, standing over night at room temperature then.Add DIPEA (53mg) once more.Stirred reaction mixture 6 hours at room temperature left standstill 3 days then.Solvent removed in vacuo.Resistates distributes between DCM and 1M sodium hydrogen carbonate solution.Isolate organic phase, wash with water, vacuum concentration.Resistates is by 1g SPE column purification, and pillar as eluent, obtains embodiment 379 (18mg, colourless gum) with the 50-0% cyclohexane/ethyl acetate.LCMS shows MH
+=493; T
RET=2.83min.
Embodiment 380:4-{[1-(aminocarboxyl)-4-piperidyl] amino }-N-[4-(dimethylamino)-1-(3-aminomethyl phenyl)-4-oxo butyl]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
According to the similar approach of preparation embodiment 379, with intermediate 105 and intermediate 169 preparation embodiment 380.LCMS shows MH
+=535; T
RET=2.61min.
Embodiment 381-382
Universal method:
With suitable intermediate carbamate (intermediate 164 or 165; 0.2-0.25mmol) 4M hydrogenchloride/two alkane (5ml) solution at room temperature stirred 1 hour.Vacuum concentrated solution, remaining solid product.
The following example 381 and 382 prepares according to similar method:
Believe that embodiment 382 is the isomer mixtures that contain main isomer, and described main isomer has (R) stereochemical structure at the benzylic carbon atoms place.
Claims (71)
1. a following formula (I) compound or its salt:
Wherein:
Ar has with following formula (x) or (z) structure:
R
1Be C
1-3Alkyl, C
1-3Fluoro-alkyl or-CH
2CH
2OH;
R
2Be hydrogen atom (H), methyl or C
1Fluoro-alkyl;
R
3Be the optional C that replaces
3-8Cycloalkyl or the optional monounsaturated C that replaces
5-7Cycloalkenyl group or optional following formula (aa), (bb) or the heterocyclic radical (cc) that replaces;
N wherein
1And n
2Be 1 or 2 independently; Y is O, S, SO
2Or NR
10R wherein
10Be hydrogen atom (H), C
1-2Alkyl, C
1-2Fluoro-alkyl, C (O) NH
2, C (O)-C
1-2Alkyl, C (O)-C
1Fluoro-alkyl or-C (O)-CH
2O-C
1Alkyl;
R wherein
3C
3-8Cycloalkyl or formula (aa), (bb) or heterocyclic radical (cc) are chosen wantonly on ring carbon atom and are replaced for following substituting group independently by 1-2: oxo (=O); OH; C
1-2Alkoxyl group; C
1-2Fluoroalkyl; NHR
21, R wherein
21Be hydrogen atom (H) or C
1-4Straight chained alkyl; C
1-2Alkyl; C
1-2Fluoro-alkyl;-CH
2OH;-CH
2CH
2OH;-CH
2NHR
22, R wherein
22Be H or C
1Alkyl;-C (O) OR
23, R wherein
23Be H;-C (O) NHR
24, R wherein
24Be H or C
1Alkyl;-C (O) R
25, R wherein
25Be C
1-2Alkyl; Fluorine; Oximido (=N-OH); Or (C
1-4Alkoxyl group) imino-(=N-OR
26, R wherein
26Be C
1-4Alkyl); Wherein any OH, alkoxyl group, fluoroalkyl or NHR
21Substituting group not with formula (I) in-R that the NH-group is connected
3Replace on the ring carbon atom, and not with heterocyclic radical (aa), (bb) or the R that Y group is connected (cc)
3Replace on the ring carbon atom;
Wherein work as R
3Be the optional monounsaturated C that replaces
5-7During cycloalkenyl group, then cycloalkenyl group is optional by 1 fluorine or C
1-2Alkyl substituent replace or by 2 be the substituting group replacement of fluorine or methyl independently, and with formula (I) in-R that the NH-group is connected
3Ring carbon atom does not participate in two keys of cycloalkenyl group;
Perhaps R
3Two cyclic groups for following formula (ee):
Y wherein
1, Y
2And Y
3Be CH independently
2Or oxygen (O), precondition is Y
1, Y
2And Y
3In maximum one be oxygen (O);
R
4Be hydrogen atom (H), methyl, ethyl, n-propyl, sec.-propyl, C
1-2Fluoro-alkyl, cyclopropyl ,-CH
2OR
4a,-CH (Me) OR
4aOr-CH
2CH
2OR
4aR wherein
4aBe hydrogen atom (H), methyl (Me) or C
1Fluoro-alkyl;
R
5Be hydrogen atom (H); C
1-8Alkyl; C
1-3Fluoro-alkyl; Optional by C
1-2The C that alkyl replaces
3-8Cycloalkyl; Or-(CH
2)
n 4-part or C
3-8Cycloalkyl moiety is optional by C
1-2Alkyl replaces-(CH
2)
n 4-C
3-8Cycloalkyl, wherein n
4Be 1 or 2;
Perhaps R
5For by a R
11The C that substituting group replaces
1-4Alkyl; R wherein
11Be hydroxyl (OH); C
1-6Alkoxyl group; C
1-2Fluoroalkyl; Phenoxy group; (single fluoro-or two fluoro-phenyl) the oxygen base; (monomethyl-or dimethyl-phenyl) the oxygen base; Benzyloxy;-NR
12R
13-NR
15-C (O) R
16-NR
15-C (O)-NH-R
15Or-NR
15-S (O)
2R
16
Perhaps R
5Be the C that on different carbon atoms, is replaced by two hydroxyls (OH) substituting group
2-4Alkyl;
Perhaps R
5For-(CH
2)
n 11-C (O) R
16-(CH
2)
n 11-C (O) NR
12R
13-CHR
19-C (O) NR
12R
13-(CH
2)
n 11-C (O) OR
16-(CH
2)
n 11-C (O) OH;-CHR
19-C (O) OR
16-CHR
19-C (O) OH;-(CH
2)
n 11-S (O)
2-NR
12R
13-(CH
2)
n 11-S (O)
2R
16Or-(CH
2)
n 11-CN; N wherein
11(each R wherein that is 0,1,2 or 3
5N in the group
11Value be independent of other R
5N in the group
11Value); R
19Be C
1-2Alkyl;
Perhaps R
5For-(CH
2)
n 13-Het, wherein n
13Be 0,1 or 2, Het removes-NR
12R
13In addition 4 yuan, 5 yuan, 6 yuan or 7 yuan of saturated or undersaturated heterocycles, this heterocycle contains 1-2 ring hetero atom that independently is selected from O, S and N; Wherein work as n
13Be 0 o'clock, any ring hetero atom of existence can not connect-(CH
2)
n 13-part; Not any non-undersaturated (promptly not the participating in two keys) that wherein exists and be not that (promptly this nitrogen-atoms does not connect-(CH connectivity nitrogen
2)
n 13-part or do not connect R
5The carbon atom that connects) ring nitrogen is NR
17Wherein 1-2 ring carbon atom is optional independently by C
1-2Alkyl replaces;
Perhaps R
5For phenyl (Ph) ,-CH
2-Ph ,-CHMe-Ph ,-CHEt-Ph, CMe
2Ph or-CH
2CH
2-Ph, wherein phenyl ring Ph is optional is that following substituting group replaces: halogen atom by 1-2 independently; C
1-4Alkyl; C
1-2Fluoro-alkyl; C
1-4Alkoxyl group; C
1-2Fluoroalkyl; Cyclopropyl; Cyclopropyl oxygen base;-C (O)-C
1-4Alkyl;-C (O) OH;-C (O)-OC
1-4Alkyl; C
1-4Alkyl-S (O)
2-; C
1-4Alkyl-S (O)
2-NR
8a-; R
7aR
8aN-S (O)
2-; R
7aR
8aN-C (O)-;-NR
8a-C (O)-C
1-4Alkyl; R
7aR
8aN; OH; Nitro (NO
2); Or cyano group (CN);
Perhaps R
4And R
5Formation-(CH combines
2)
p 1-or-(CH
2)
p 3-X
5-(CH
2)
p 4-, X wherein
5Be O or NR
17ap
1=2,3,4,5 or 6, p
3And p
4Be 1,2 or 3 independently, precondition is if p
3Be 3, p then
4Be 1 or 2, if p
4Be 3, p then
3Be 1 or 2;
Precondition is R at least
4And R
5One of be not hydrogen atom (H);
Wherein, in formula (x):
A is C-R
6A, nitrogen (N) or nitrogen-oxide compound (N
+-O
-),
B is C-R
6B, nitrogen (N) or nitrogen-oxide compound (N
+-O
-),
D is C-R
6D, nitrogen (N) or nitrogen-oxide compound (N
+-O
-),
E is C-R
6E, nitrogen (N) or nitrogen-oxide compound (N
+-O
-),
F is C-R
6F, nitrogen (N) or nitrogen-oxide compound (N
+-O-),
R wherein
6A, R
6B, R
6D, R
6EAnd R
6FBe hydrogen atom (H), halogen atom independently; C
1-6Alkyl; C
1-4Fluoro-alkyl; C
3-6Cycloalkyl; C
1-4Alkoxyl group; C
1-2Fluoroalkyl; C
3-6Cycloalkyl oxy;-C (O) R
16a-C (O) OR
30-S (O)
2-R
16aR
16a-S (O)
2-NR
15a-; R
7R
8N-S (O)
2-; C
1-2Alkyl-C (O)-R
15aN-S (O)
2-; C
1-4Alkyl-S (O)-, Ph-S (O)-, R
7R
8N-CO-;-NR
15a-C (O) R
16aR
7R
8N; Nitro (NO
2); OH (comprising its any tautomer); C
1-4Alkoxy methyl; C
1-4Alkoxyethyl; C
1-2Alkyl-S (O)
2-CH
2-; R
7R
8N-S (O)
2-CH
2-; C
1-2Alkyl-S (O)
2-NR
15a-CH
2-;-CH
2-OH;-CH
2CH
2-OH;-CH
2-NR
7R
8-CH
2-CH
2-NR
7R
8-CH
2-C (O) OR
30-CH
2-C (O)-NR
7R
8-CH
2-NR
15a-C (O)-C
1-3Alkyl;-(CH
2)
n 14-Het
1, n wherein
14Be 0 or 1; Cyano group (CN); Ar
5bPerhaps phenyl, pyridyl or pyrimidyl, wherein phenyl, pyridyl or pyrimidyl are optional independently by 1-2 following group replacement: fluorine, chlorine, C
1-2Alkyl, C
1Fluoro-alkyl, C
1-2Alkoxyl group or C
1Fluoroalkyl;
And/or two be selected from R
6A, R
6B, R
6D, R
6EAnd R
6FAdjacent group the formation :-CH=CH-CH=CH-that combines;-(CH
2)
n 14a-, n wherein
14aBe 3,4 or 5;-O-(CMe
2)-O-;-O-(CH
2)
n 14b-O-, wherein n
14bBe 1 or 2;-CH=CH-NR
15b-;-N=CH-NR
15b-;-CH=N-NR
15b-;-N=N-NR
15b-;-CH=CH-O-;-N=CH-O-;-CH=CH-S-; Or-N=CH-S-; R wherein
15bBe H or C
1-2Alkyl;
Precondition is:
Among A, B, D, E and the F is C-H (carbon-hydrogen), C-F (carbon-fluorine), nitrogen (N) or nitrogen-oxide compound (N independently more than two
+-O
-);
Be no more than two among A, B, D, E and the F and be nitrogen or nitrogen-oxide compound (N independently
+-O
-); With
Be no more than one among A, B, D, E and the F and be nitrogen-oxide compound (N
+-O
-);
Wherein, in formula (z):
G is O, S or NR
9, R wherein
9Be hydrogen atom (H), C
1-4Alkyl or C
1-2Fluoro-alkyl;
J is C-R
6J, C-[and formula (I) tie point] or nitrogen (N),
L is C-R
6L, C-[and formula (I) tie point] or nitrogen (N),
M is C-R
6M, C-[and formula (I) tie point] or nitrogen (N),
Q is C-R
6Q, C-[and formula (I) tie point] or nitrogen (N),
R wherein
6J, R
6L, R
6MAnd R
6QBe hydrogen atom (H), halogen atom independently; C
1-4Alkyl; C
1-3Fluoro-alkyl; C
3-6Cycloalkyl; C
1-4Alkoxyl group; C
1-2Fluoroalkyl; C
3-6Cycloalkyl oxy; OH (comprising its any tautomer); Or optional be the phenyl of following substituting group replacement independently by 1-2: fluorine, chlorine, C
1-2Alkyl, C
1Fluoro-alkyl, C
1-2Alkoxyl group or C
1Fluoroalkyl;
Precondition is:
Among J, L, M and the Q is C-H, C-F, C-C independently more than two
1-2The tie point of alkyl, C-[and formula (I)] or nitrogen (N); With
Be no more than three among J, L, M and the Q and be nitrogen (N);
Wherein:
R
7And R
8Be hydrogen atom (H) independently; C
1-4Alkyl; C
3-6Cycloalkyl; Or optional be the phenyl of following substituting group replacement independently by 1-2: fluorine, chlorine, C
1-2Alkyl, C
1Fluoro-alkyl, C
1-2Alkoxyl group or C
1Fluoroalkyl;
Perhaps R
7And R
8Formation-(CH together
2)
n 6-,-C (O)-(CH
2)
n 7-,-C (O)-(CH
2)
n 10-C (O)-,-(CH
2)
n 8-X
7-(CH
2)
n 9-or-C (O)-X
7-(CH
2)
n 10-, n wherein
6Be 3,4,5 or 6, n
7Be 2,3,4 or 5, n
8, n
9And n
10Be 2 or 3 independently, X
7Be O or NE
14
R
7aBe hydrogen atom (H) or C
1-4Alkyl;
R
8aBe hydrogen atom (H) or methyl;
R
12And R
13Be H independently; C
1-4Alkyl; C
3-6Cycloalkyl; Or optional be the phenyl of following substituting group replacement independently by 1-2: fluorine, chlorine, C
1-2Alkyl, C
1Fluoro-alkyl, C
1-2Alkoxyl group or C
1Fluoroalkyl;
Perhaps R
12And R
13Formation-(CH together
2)
n 6a,-C (O)-(CH
2)
n 7a-,-C (O)-(CH
2)
n 10a-C (O)-,-(CH
2)
n 8a-X
12-(CH
2)
n 9a-or-C (O)-X
12-(CH
2)
n 10a-, n wherein
6aBe 3,4,5 or 6, n
7aBe 2,3,4 or 5, n
8a, n
9aAnd n
10aBe 2 or 3 independently, X
12Be O or NR
14a
R
14, R
14a, R
17And R
17aBe hydrogen atom (H) independently; C
1-4Alkyl; C
1-2Fluoro-alkyl; Cyclopropyl;-C (O)-C
1-4Alkyl;-C (O) NR
7aR
8aOr-S (O)
2-C
1-4Alkyl;
Each R
15Be hydrogen atom (H) independently; C
1-4Alkyl; C
3-6Cycloalkyl; Or the optional phenyl that is replaced by 1-2 following group: halogen atom, C
1-2Alkyl, C
1Fluoro-alkyl, C
1-2Alkoxyl group or C
1Fluoroalkyl;
Each R
15aBe hydrogen atom (H) or C independently
1-4Alkyl;
R
16Be C
1-4Alkyl; C
3-6Cycloalkyl; C
3-6Cycloalkyl-CH
2-; Phenyl; Or benzyl, wherein phenyl and benzyl are chosen wantonly independently on their ring and are replaced for following substituting group independently by 1-2: fluorine, chlorine, methyl, C
1Fluoro-alkyl, methoxyl group or C
1Fluoroalkyl;
R
16aBe C
1-6Alkyl; C
3-6Cycloalkyl, optional by an oxo (=O), OH or C
1-2Alkyl substituent replaces; C
3-6Cycloalkyl-CH
2-; Pyridyl is chosen wantonly on ring carbon atom by a following group and is replaced: halogen atom, C
1-2Alkyl, C
1Fluoro-alkyl, C
1-2Alkoxyl group or C
1Fluoroalkyl; Ar
5cPhenyl, optional is that following substituting group replaces: halogen atom, C by 1-2 independently
1-2Alkyl, C
1Fluoro-alkyl, C
1-2Alkoxyl group or C
1Fluoroalkyl; Benzyl is chosen wantonly on its ring and is replaced for following substituting group independently by 1-2: halogen atom, C
1-2Alkyl, C
1Fluoro-alkyl, C
1-2Alkoxyl group or C
1Fluoroalkyl; Or on ring carbon atom, connect, and contain 1-2 4 yuan, 5 yuan, 6 yuan or 7 yuan of saturated heterocyclics that independently are selected from the ring hetero atom of O, S and N, wherein the ring nitrogen of any existence is NR
27, R wherein
27Be H, C
1-2Alkyl or-C (O) Me, and described heterocycle is chosen wantonly at carbon atom by a C
1-2Alkyl or oxo (=O) substituting group replaces, precondition be any oxo (=O) substituting group replaces on the ring carbon atom of shack nitrogen-atoms;
Each R
30Be hydrogen atom (H), C independently
1-4Alkyl or C
3-6Cycloalkyl;
Ar
5bAnd Ar
5cIndependently in 5 yuan of rings, containing 1 O, S or NR
15a5 yuan of aromatic heterocycles, wherein said 5 yuan of rings also can be chosen wantonly and contain 1-2 extra nitrogen-atoms, and described heterocycle is chosen wantonly and replaced by the group below on the ring carbon atom: halogen atom, C
1-2Alkyl, C
1Fluoro-alkyl ,-CH
2OH ,-CH
2-OC
1-2Alkyl, OH (comprising its keto tautomer) or-CH
2-NR
28R
29, R wherein
28And R
29Be H or methyl independently;
Het
1For on ring carbon atom, connecting, and contain 1-2 4 yuan, 5 yuan, 6 yuan or 7 yuan of saturated heterocyclics that independently are selected from the ring hetero atom of O, S and N; Wherein any ring nitrogen of Cun Zaiing is NR
31, R wherein
31Be H, C
1-2Alkyl or-C (O) Me; Described ring is chosen wantonly at carbon atom by a C
1-2Alkyl or oxo (=O) substituting group replaces, precondition be any oxo (=O) substituting group replaces on the ring carbon atom of shack nitrogen-atoms;
Precondition is:
Work as R
3Be formula (bb) heterocyclic radical, n
1Be 1, and Y is NR
10The time, R then
10Be not C
1-2Alkyl or C
1-2Fluoro-alkyl;
Work as R
3For formula (aa) heterocyclic radical and Y are NR
10The time, R then
10Be not C (O)-C
1-2Alkyl, C (O)-C
1Fluoro-alkyl or-C (O)-CH
2O-C
1Alkyl;
Work as R
3During for formula (cc) heterocyclic radical, then Y is O, S, SO
2Or NR
10, R wherein
10Be H;
Precondition is:
Work as R
3Be the optional C that replaces
3-8Cycloalkyl or the optional C that replaces
5-7During cycloalkenyl group, then any-C (O) OR
23,-C (O) NHR
24,-C (O) R
25,-CH
2OH or fluoro substituents are at R
33 of cyclobutyl ring; Or at R
3C
5Cycloalkyl (cyclopentyl) ring or cyclopentenes basic ring 3 or 4; Or at R
3C
6Cycloalkyl (cyclohexyl) ring or tetrahydrobenzene basic ring 4; Or at R
3Suberyl ring or suberene basic ring 3,4,5 or 6; Or at R
33,4,5,6 or 7 of ring octyl group ring, in this annexation, R
3Cycloalkyl ring or cyclenes basic ring 1 be considered to formula (I) in-tie point of NH-, promptly in the connection mode (I)-annular atoms of NH-;
Precondition is:
Work as R
3Be the optional C that replaces
3-8During cycloalkyl, then any OH, alkoxyl group, fluoroalkyl ,-CH
2CH
2OH or-CH
2NHR
22Substituting group is at R
33 of cyclobutyl ring; Or at R
3C
53 or 4 of cycloalkyl (cyclopentyl) ring; Or at R
3C
63,4 or 5 of cycloalkyl (cyclohexyl) ring; Or at R
33,4,5 or 6 of suberyl ring; Or at R
33,4,5,6 or 7 of ring octyl group ring;
Work as R
3During for formula (aa), (bb) or heterocyclic radical (cc), then any OH substituting group is at 6 yuan of R of formula (cc)
35 of heterocyclic radical, wherein n
2Be 1; Or at 7 yuan of R of formula (cc)
35 or 6 of heterocyclic radical, wherein n
2Be 2; Or at 7 yuan of R of formula (bb)
36 of heterocyclic radical, wherein n
1Be 2, in this annexation, R
31 of heterocyclic be considered to formula (I) in-tie point of NH-, promptly in the connection mode (I)-annular atoms of NH-, then all the other positions of heterocyclic are numbered, make the possible lowest number of being numbered of ring hetero atom.
2. the compound of claim 1 or salt, wherein R
1For ethyl, n-propyl or-CH
2CH
2OH.
3. the compound of claim 2 or salt, wherein R
1Be ethyl.
4. each compound or salt, wherein R in the claim 1,2 or 3
2Be hydrogen atom (H) or methyl.
5. the compound of claim 4 or salt, wherein R
2Be hydrogen atom (H).
6. each compound or salt, wherein R in the aforementioned claim
30-1 substituting group arranged.
7. each compound or salt, wherein R in the aforementioned claim
3Be the optional C that replaces
3-8Cycloalkyl or the optional formula (aa) that replaces, (bb) or (cc) heterocyclic radical.
8. each compound or salt are wherein worked as R in the aforementioned claim
3Be the optional C that replaces
3-8During cycloalkyl, R then
3Be the optional C that replaces
6-7Cycloalkyl or the optional cyclobutyl that replaces.
9. each compound or salt are wherein worked as R in the aforementioned claim
3Be the optional C that replaces
3-8During cycloalkyl, R then
3For choosing wantonly by 1-2 is the C that following substituting group replaces independently
3-8Cycloalkyl: oxo (=O); OH; C
1Alkoxyl group; C
1Fluoroalkyl; NHR
21, R wherein
21Be hydrogen atom (H); C
1-2Alkyl; C
1Fluoro-alkyl;-CH
2OH;-CH
2NHR
22, R wherein
22Be H;-C (O) OR
23, R wherein
23Be H;-C (O) NHR
24, R wherein
24Be H or methyl;-C (O) R
25, R wherein
25Be methyl; Fluorine; Oximido (=N-OH); Or=N-OR
26, R wherein
26Be C
1-2Alkyl; Wherein any OH, alkoxyl group, fluoroalkyl or NHR
21Substituting group not with formula (I) in-R that the NH-group is connected
3Replace on the ring carbon atom, and not with heterocyclic radical (aa), (bb) or the R that Y group is connected (cc)
3Replace on the ring carbon atom.
10. the compound of claim 9 or salt are wherein worked as R
3Be the optional C that replaces
3-8During cycloalkyl, R then
3For choosing wantonly by 1-2 is the C that following substituting group replaces independently
3-8Cycloalkyl: oxo (=O); OH; NHR
21, R wherein
21Be hydrogen atom (H); Methyl;-CH
2F;-CHF
2-C (O) OR
23, R wherein
23Be H;-C (O) NHR
24, R wherein
24Be H; Fluorine; Oximido (=N-OH); Or methoxyimino (=N-OR
26, R wherein
26Be methyl).
11. the compound of claim 10 or salt are wherein worked as R
3Be the optional C that replaces
3-8During cycloalkyl, R then
3Be the optional C that is replaced by the substituting group below
3-8Cycloalkyl: OH;-C (O) NHR
24, R wherein
24Be H; Oxo (=O) or oximido (=N-OH).
12. each compound or salt, wherein R in the aforementioned claim
3Not with formula (I) in-replace on the annular atoms that NH-is connected (except optional replaced by alkyl or fluoro-alkyl), and R
3On two annular atomses that connect the atom either side, do not replace (except choosing wantonly by alkyl, fluoro-alkyl or NHR
21Beyond replacing).
13. each compound or salt in the aforementioned claim are wherein for R
3, work as R
3When having the optional substituting group of 1-2, then described substituting group:
(a) at R
33 of cyclobutyl ring, or
(b) at R
3Cyclopentyl ring or cyclopentenes basic ring 3 and/or 4, or
(c) at R
3Cyclohexyl ring or tetrahydrobenzene basic ring 3,4 and/or 5, or
(d) at R
3Suberyl ring or suberene basic ring 3,4,5 and/or 6, or
(e) at R
33,4,5,6 and/or 7 of ring octyl group ring, and/or
(f) for substituting group alkyl or fluoro-alkyl, at R
31,2 and/or maximum numbered positions of cycloalkyl ring or cyclenes basic ring, and/or
(g) for substituting group NHR
21, at R
32 and/or maximum numbered positions of cycloalkyl ring or cyclenes basic ring.
14. each compound or salt in the aforementioned claim are wherein worked as R
3Be the optional monounsaturated C that replaces
5-7During cycloalkenyl group, R then
3Be the optional monounsaturated C that replaces
6Cycloalkenyl group (the promptly optional monounsaturated cyclohexenyl that replaces), wherein R
3Cyclohexenyl is optional to be replaced by a fluorine or methyl substituents.
15. each compound or salt in the aforementioned claim are wherein worked as R
3During for formula (aa), (bb) or heterocyclic radical (cc), then Y is O or NR
10
16. each compound or salt, wherein R in the aforementioned claim
10Be H, C (O) NH
2Or C (O) methyl.
17. the compound of claim 16 or salt, wherein R
10Be C (O) NH
2
18. each compound or salt in the aforementioned claim are wherein worked as R
3During for formula (aa), (bb) or heterocyclic radical (cc), R then
3Be formula (bb) heterocyclic radical, and n
1Be 1.
19. each compound or salt in the aforementioned claim are wherein at R
3Formula (aa), (bb) or (cc) in the heterocyclic radical, described 1-2 optional substituting group (being 1-2 optional ring carbon substituting group) is C independently
1-2Alkyl or oxo (=O).
20. each compound or salt in the aforementioned claim are wherein at R
3In, formula (aa), (bb) or heterocyclic radical (cc) are not substituted on ring carbon atom.
21. each compound or salt in the aforementioned claim are wherein worked as R
3During for formula (ee) two cyclic groups, Y then
1, Y
2And Y
3All be CH
2
22. each compound or salt, wherein NHR in the aforementioned claim
3Be following formula (a), (a1), (b), (c), (c1), (c2), (c3), (c4), (c5), (c6), (c7), (d), (e), (f), (g), (g1), (g2), (g3), (g4), (h), (i), (j), (k), (k1), (k2), (L), (m), (m1), (m2), (m3), (n), (o), (o1), (o2), (o3), (p), (p1), (p2), (p3), (p4), (p5), (p6), (p9), (p10), (p11) or (q):
23. the compound of claim 22 or salt, wherein NHR
3For formula (c), (c1), (c4), (c5), (h), (i), (j), (k), (k2), (m1), (n), (o), (o2), (o3), (p2), (p5), (p6), (p9), (p11) or (q).
24. the compound of claim 22 or salt, wherein NHR
3For formula (c), (h), (k2), (n), (o), (o2), (p9) or (p11).
25. each compound or salt in the claim 22,23 or 24, wherein:
Work as NHR
3During for formula (n), then it is cis-configuration, i.e. NHR
3Be suitable-(3-hydroxyl hexamethylene-1-yl) amino (comprising that cis-configuration is the mixture of the various configurations of main component);
Work as NHR
3During for formula (p9), then it is cis-configuration, i.e. NHR
3Be suitable-[4-(aminocarboxyl) hexamethylene-1-yl] amino (comprising that cis-configuration is the mixture of the various configurations of main component).
26. the compound of claim 22 or salt, wherein NHR
3For formula (h) or (k2), i.e. R
3Be tetrahydrochysene-2H-pyrans-4-base or 1-(aminocarboxyl)-4-piperidyl.
27. each compound or salt, wherein R in the aforementioned claim
4Be hydrogen atom (H); Methyl, ethyl, C
1Fluoro-alkyl ,-CH
2OH ,-CH (Me) OH ,-CH
2CH
2OH or-CH
2OMe.
28. the compound of claim 27 or salt, wherein R
4Be hydrogen atom (H), methyl, ethyl, CF
3,-CH
2OH or-CH
2OMe.
29. each compound or salt in the aforementioned claim, wherein:
R
5Be hydrogen atom (H); C
1-5Alkyl; C
1-2Fluoro-alkyl; C
3-6Cycloalkyl (unsubstituted); Or-(CH
2)
n 4-C
3-6Cycloalkyl (unsubstituted), wherein n
4Be 1 or 2;
Perhaps R
5For by a substituent R
11The C that replaces
1-3Alkyl; R wherein
11Be hydroxyl (OH); C
1-4Alkoxyl group; C
1Fluoroalkyl;-NR
12R
13-NR
15-C (O) R
16Or-NR
15-S (O)
2R
16
Perhaps R
5For-(CH
2)
n 11-C (O) NR
12R
13-(CH
2)
n 11-C (O) OR
16-(CH
2)
n 11-C (O) OH; Or-(CH
2)
n 11-CN; N wherein
11Be 0,1 or 2, for each R
5Group, n
11Be independent of other R
5N in the group
11Value;
Perhaps R
5For-(CH
2)
n 13-Het, wherein n
13Be 0 or 1, Het is:
Perhaps R
5For phenyl (Ph) or-CH
2-Ph, wherein phenyl ring Ph is optional is that following substituting group replaces: fluorine, chlorine, C by 1-2 independently
1-2Alkyl, C
1Fluoro-alkyl, C
1-2Alkoxyl group or C
1Fluoroalkyl;
Perhaps R
4And R
5Formation-(CH combines
2)
2-O-(CH
2)
2-or-(CH
2)
p 1-, p wherein
1Be 2,4 or 5.
30. each compound or salt, wherein R in the aforementioned claim
11Be OH, oxyethyl group, methoxyl group, NH
2, NHMe, NHEt, NMe
2, tetramethyleneimine-1-base or piperidines-1-base.
31. each compound or salt in the aforementioned claim, wherein:
R
7aBe H or methyl;
R
8aBe H;
R
7And R
8Be hydrogen atom (H) independently; C
1-2Alkyl; C
3-6Cycloalkyl; Or the optional phenyl that is replaced by the substituting group below: fluorine, chlorine, C
1-2Alkyl, C
1Fluoro-alkyl, C
1-2Alkoxyl group or C
1Fluoroalkyl; Wherein work as R
7During for cycloalkyl or the optional phenyl that replaces, R then
8Be not cycloalkyl and the optional phenyl that replaces;
Perhaps R
7And R
8Formation-(CH together
2)
n 6-or-(CH
2)
n 8-X
7-(CH
2)
n 9-, X wherein
7Be NR
14Or O, n
6Be 4 or 5, n
8And n
9Be 2;
R
12And R
13Be H independently; C
1-2Alkyl; C
3-6Cycloalkyl; Or the optional phenyl that is replaced by the substituting group below: fluorine, chlorine, C
1-2Alkyl, C
1Fluoro-alkyl, C
1-2Alkoxyl group or C
1Fluoroalkyl; Wherein work as R
12During for cycloalkyl or the optional phenyl that replaces, R then
13Be not cycloalkyl and the optional phenyl that replaces;
Perhaps R
12And R
13Formation-(CH together
2)
n 6a-or-(CH
2)
n 8a-X
12-(CH
2)
n 9a-, X wherein
12Be NR
14aOr O, n
6aBe 4 or 5, n
8aAnd n
9aBe 2;
R
14, R
14a, R
17And R
17aBe H, C independently
1-2Alkyl or-C (O) Me;
R
15Be hydrogen atom (H) or methyl;
Each R
15aBe H or C independently
1-2Alkyl;
R
15bBe H;
R
16Be C
1-4Alkyl;
R
16aBe C
1-4Alkyl; Unsubstituted C
3-6Cycloalkyl; Optional is the phenyl that following substituting group replaces by 1-2 independently: halogen atom, C
1-2Alkyl, C
1Fluoro-alkyl, C
1-2Alkoxyl group or C
1Fluoroalkyl; Or choose the benzyl that on its ring, is replaced independently wantonly: halogen atom, C for following substituting group by 1-2
1-2Alkyl, C
1Fluoro-alkyl, C
1-2Alkoxyl group or C
1Fluoroalkyl;
Each R
30Be hydrogen atom (H) or C independently
1-4Alkyl.
32. the compound of claim 31 or salt, wherein
R
7And R
8Be hydrogen atom (H) or C independently
1-2Alkyl;
R
12And R
13Be hydrogen atom (H) or C independently
1-2Alkyl;
R
16aBe C
1-4Alkyl.
33. each compound or salt in the aforementioned claim, wherein in formula (x):
Among A, B, D, E and the F is C-H (carbon-hydrogen) more than two; And among A, B, D, E and the F remaining one or more be C-H (carbon-hydrogen), C-F (carbon-fluorine), C-Cl (carbon-chlorine), C-Me, C-OMe or nitrogen (N) independently;
Be no more than one among A, B, D, E and the F and be nitrogen;
A, B, D, E and F are not nitrogen-oxide compound (N
+-O
-).
34. each compound or salt in the aforementioned claim, wherein Ar has formula (x) structure.
36. the compound of claim 35 or salt, wherein Ar has formula (x) structure, and formula (x) is formula (x1), (x8), (x13) or (x14).
37. the compound of claim 35 or salt, wherein Ar has formula (x) structure, and formula (x) is formula (x1).
38. the compound of claim 37 or salt, wherein Ar is formula (x1), and be monoalkyl-phenyl-, single (fluoro-alkyl)-phenyl-, single halo-phenyl-, monoalkoxy-phenyl-, single (fluoroalkyl)-phenyl-, dialkyl group-phenyl-, monoalkyl-single halo-phenyl-, dihalo-phenyl-or dihalo-monoalkyl-phenyl-.
39. the compound of claim 38 or salt, wherein Ar is single C
1-3Alkyl-phenyl; Single C
1Fluoro-alkyl-phenyl-; Single C
1-3Phenalkyloxy--; Single (C
1Fluoroalkyl)-phenyl-; Two C
1-2Alkyl-phenyl-; Single C
1-3Alkyl-single halo-phenyl-; Dihalo-phenyl-; Or dihalo-single C
1-2Alkyl-phenyl-.
40. each compound or salt in the aforementioned claim, wherein in formula (x), R
6A, R
6B, R
6D, R
6EAnd R
6FBe hydrogen atom (H), fluorine atom, chlorine atom, bromine atoms, iodine atom, methyl, ethyl, n-propyl, sec.-propyl, C independently of one another
4Alkyl, trifluoromethyl ,-CH
2OH, methoxyl group, oxyethyl group, positive propoxy, isopropoxy, C
1Fluoroalkyl, cyclohexyloxy; Cyclopentyloxy; Nitro (NO
2), OH, C
1-3Alkyl S (O)
2-, C
1-3Alkyl S (O)
2-NH-, Me
2N-S (O)
2-, H
2N-S (O)
2-,-CONH
2,-CONHMe ,-C (O) OH, cyano group (CN), NMe
2Or C
1-2Alkyl-S (O)
2-CH
2-.
41. the compound of claim 40 or salt, wherein R
6A, R
6B, R
6D, R
6EAnd R
6FBe independently of one another hydrogen atom (H), fluorine atom, chlorine atom, bromine atoms, methyl, ethyl, n-propyl, sec.-propyl, trifluoromethyl ,-CH
2OH, methoxyl group, oxyethyl group, positive propoxy, difluoro-methoxy, OH or MeS (O)
2-.
43. each compound or salt in the aforementioned claim, its Chinese style (I) compound or its salt is connecting R
4And R
5The carbon atom place be racemic, perhaps formula (I) compound or its salt is following formula (IA) compound or its salt:
Its Chinese style (IA) is meant that this compound or its salt more than 50% is connecting R
4And R
5The three-dimensional chemical configuration of carbon atom place shown in having.
44. the compound of claim 43 or salt, its Chinese style (I) compound or its salt are formula (IA) compound or its salt.
45. the compound of claim 44 or salt wherein in formula (IA), are with R
4And R
5It is (not consider the stereochemical structure of any other carbon atom) more than 50% that the stereochemical structure of the carbon atom of group should make it have enantiomer excessive (e.e.), and wherein " enantiomer is excessive " percentage ratio of (e.e.) being defined as the main isomer of existence deducts the percentage ratio of the less important isomer of existence.
46. each compound or salt in the claim 43,44 or 45, wherein in formula (IA), R
5Be hydrogen atom (H), R
4It is not hydrogen atom (H).
47. the compound of claim 46 or salt, wherein in formula (IA), R
5Be hydrogen atom (H); R
4Be methyl, ethyl, C
1Fluoro-alkyl ,-CH
2OH or-CH
2OMe.
48. the compound of claim 47 or salt, wherein in formula (IA), R
5Be hydrogen atom (H); R
4Be methyl or ethyl.
49. each compound or salt in the claim 46,47 or 48, wherein in formula (IA), Ar is a monocycle, and promptly in formula (IA), two are selected from R
6A, R
6B, R
6D, R
6EAnd R
6FAdjacent group can not combine and constitute second loop section.
50. each compound or salt in the aforementioned claim, it is following formula (XXVIII) compound or its salt:
Wherein:
R
X1Be hydrogen atom (H), C
1-2Alkyl or C
1Fluoro-alkyl;
R
Y1Be hydrogen atom (H) or C
1-2Alkyl;
R
Y2Be hydrogen atom (H); C
1-3Alkyl; Or-(CH
2)
n 7aa-OH; N wherein
7aaBe 1,2 or 3;
R
X2Be Ar
A, wherein:
(i) Ar
AFor choosing wantonly by 1-2 is the phenyl that following substituting group replaces independently: fluorine, chlorine, bromine, C
1-2Alkyl, C
1-2Fluoro-alkyl, C
1-2Alkoxyl group, C
1-2Fluoroalkyl; OH;-NR
11aaR
11bb(R wherein
11aaBe H or C
1-2Alkyl, R
11bbBe H, C
1-2Alkyl ,-C (O)-C
1-2Alkyl or-S (O)
2-C
1-2Alkyl); Cyano group;-C (O)-NR
11ccR
11dd(R wherein
11ccAnd R
11ddBe H or C independently
1-2Alkyl);-C (O)-OR
11ee, R wherein
11eeBe H or C
1-2Alkyl; Or-S (O)
2-R
11ff(R wherein
11ffBe C
1-2Alkyl, NH
2, NHMe or NMe
2); Perhaps described phenyl Ar
AChoose wantonly on two adjacent Ar annular atomses by the two ends of chain and replace, described chain is-(CH
2)
4-,-(CH
2)
3-or-CH=CH-CH=CH-; Perhaps
(ii) Ar
AFor containing 1-4 5 yuan of heteroaromatic rings that are selected from the heteroatomic optional replacement of O, N or S; Wherein as described heteroaromatic rings Ar
AWhen containing 2-4 heteroatoms, then a heteroatoms is selected from O, N and S, and remaining heteroatoms is N; Wherein said heteroaromatic rings Ar
AOptional is C by 1-2 independently
1-4The group of alkyl or OH (any keto tautomer that comprises the aromatic ring that OH replaces) replaces.
51. each compound or salt among the claim 1-49, they are not formula (XXVIII) compound or its salts of definition in the claim 50.
52. each formula (I) compound or its salt in the aforementioned claim, described compound is:
(1) 1-ethyl-N-[(1R)-1-phenyl propyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(2) 1-ethyl-N-(1-methyl isophthalic acid-phenylethyl)-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(3) 1-ethyl-N-{1-[4-(methyl sulphonyl) phenyl] ethyl }-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(4) N-(diphenyl methyl)-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(5) 1-ethyl-N-[1-(3-pyridyl) ethyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(6) 1-ethyl-N-[(1S)-1-phenyl propyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(7) 1-ethyl-N-[(1S)-1-phenylethyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(8) 1-ethyl-N-[(1R)-1-phenylethyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(9) 1-ethyl-N-[1-methyl isophthalic acid-(4-pyridyl) ethyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(10) 1-ethyl-N-[(1R)-1-phenylethyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(11) N-[1-(4-chloro-phenyl-) propyl group]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(12) 1-ethyl-N-{1-[4-(oxyethyl group) phenyl] ethyl }-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(13) 1-ethyl-N-(3-hydroxyl-1-phenyl propyl)-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(14) 1-ethyl-N-[1-(3-hydroxy phenyl) ethyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(15) N-[2-(dimethylamino)-1-phenylethyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(16) 1-ethyl-N-[1-phenyl-2-(1-pyrrolidyl) ethyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(17) 1-ethyl-N-[1-(hydroxymethyl)-1-phenyl propyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(18) 1-ethyl-N-{1-[4-(propoxy-) phenyl] ethyl }-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(19) 3-({ [1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-yl] carbonyl } amino)-3-phenylpropionic acid methyl esters
(20) 1-ethyl-N-[1-(4-fluorophenyl) ethyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(21) N-[1-(4-chloro-phenyl-) ethyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(22) ({ [1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-yl] carbonyl } amino) (phenyl) ethyl acetate
(23) 1-ethyl-N-{ (1R)-1-[3-(methoxyl group) phenyl] ethyl }-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(24) 1-ethyl-N-[(1S)-2-(methoxyl group)-1-phenylethyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(25) N-[(1R)-2-amino-2-oxo-1-phenylethyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(26) 1-ethyl-N-[(1R)-2-hydroxyl-1-phenylethyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(27) 1-ethyl-N-[(1R)-1-(4-nitrophenyl) ethyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(28) 1-ethyl-N-[(1S)-2-hydroxyl-1-phenylethyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(29) 1-ethyl-N-[(1R)-2-(methoxyl group)-1-phenylethyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(30) 1-ethyl-N-(2-hydroxyl-1,1-diphenyl-ethyl)-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(31) N-[1-(3-cyano-phenyl) ethyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(32) N-[cyano group (phenyl) methyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(33) N-{ cyclopropyl [4-(methoxyl group) phenyl] methyl }-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(34) 1-ethyl-N-[1-(1-naphthyl) ethyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(35) N-(1, the 2-diphenyl-ethyl)-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(36) 1-ethyl-N-{1-[4-(methoxyl group) phenyl] butyl }-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(37) 1-ethyl-N-[(1R)-1-(1-naphthyl) ethyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(38) 1-ethyl-N-[(1S)-1-(1-naphthyl) ethyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(39) N-[1-(aminocarboxyl)-1-phenyl propyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(40) 1-ethyl-N-(1-benzyl ring amyl group)-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(41) 1-ethyl-N-(4-phenyl tetrahydrochysene-2H-pyrans-4-yl)-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(42) 1-ethyl-N-(1-phenycyclopropyl)-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(43) N-{1-[4-(cyclohexyloxy)-3-aminomethyl phenyl] ethyl }-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(44) N-{1-[3-(cyclohexyloxy)-4-(methoxyl group) phenyl] ethyl }-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(45) N-[1-(2, the 3-dichlorophenyl) ethyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(46) N-{1-[4-(cyclohexyloxy)-3-hydroxy phenyl] ethyl }-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(47) N-{1-[4-(cyclopentyloxy) phenyl] ethyl }-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(48) 1-ethyl-N-[1-(4-aminomethyl phenyl) ethyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(49) N-{1-[4-(1, the 1-dimethyl ethyl) phenyl] suberyl }-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(50) N-[1-(4-bromophenyl) ethyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(51) 1-ethyl-N-[(1S)-1-(4-iodophenyl) ethyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(52) N-{1-[4-(amino-sulfonyl) phenyl] ethyl }-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(53) 1-ethyl-N-(1-methyl isophthalic acid-phenyl propyl)-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(54) N-[1-(1,3-benzodioxole-5-yl) cyclohexyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(55) 1-ethyl-N-{1-[4-(methoxyl group) phenyl] cyclohexyl }-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(56) 1-ethyl-N-[1-(4-fluorophenyl) cyclohexyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(57) N-[1-(3-chloro-phenyl-) cyclopentyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(58) N-[1-(2-chloro-phenyl-) cyclopentyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(59) N-{1-[4-(1, the 1-dimethyl ethyl) phenyl] cyclohexyl }-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(60) 1-ethyl-N-{1-[4-(1-methylethyl) phenyl] ethyl }-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(61) N-[1-(3, the 5-3,5-dimethylphenyl) ethyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(62) 1-ethyl-N-[(1S, 2R)-2-hydroxyl-1-phenyl propyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(63) 1-ethyl-N-{ (1R)-1-[4-(methoxyl group) phenyl] ethyl }-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(64) 1-ethyl-N-{ (1S)-1-[4-(methoxyl group) phenyl] ethyl }-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(65) 1-ethyl-N-(1-phenyl hexyl)-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(66) 1-ethyl-N-(1-phenylpentyl)-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(67) 1-ethyl-N-(2-methyl isophthalic acid-phenyl propyl)-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(68) 1-ethyl-N-(1-phenyl butyl)-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(69) 1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-N-(2,2,2-three fluoro-1-phenylethyls)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(70) N-[cyclopropyl (phenyl) methyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(71) 1-ethyl-N-[1-(4-fluorophenyl) propyl group]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(72) N-[1-(2, the 3-dichlorophenyl) propyl group]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(73) 1-ethyl-N-[(1R)-1-(4-aminomethyl phenyl) ethyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(74) 1-ethyl-N-(1-phenylethyl)-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(75) N-[(1R)-1-(4-bromophenyl) ethyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(76) N-[1-(4-chloro-phenyl-)-2-hydroxyethyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(77) N-[1-(3, the 4-dichlorophenyl)-2-hydroxyethyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(78) 1-ethyl-N-{1-[3-(methoxyl group) phenyl] propyl group }-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(79) 1-ethyl-N-{1-[4-(methoxyl group) phenyl] propyl group }-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(80) N-[1-(4-bromophenyl) propyl group]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(81) 1-ethyl-N-{1-[4-(propoxy-) phenyl] propyl group }-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(82) N-[1-(3, the 5-3,5-dimethylphenyl) propyl group]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(83) 1-ethyl-N-[1-(4-aminomethyl phenyl) propyl group]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(84) 1-ethyl-N-{1-[4-(1-methylethyl) phenyl] propyl group }-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(85) 1-ethyl-N-[1-(2-aminomethyl phenyl) ethyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(86) N-(1-{4-[(difluoromethyl) oxygen base] phenyl } ethyl)-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(87) 1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-N-{1-[4-(trifluoromethyl) phenyl] ethyl }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(88) 1-ethyl-N-[1-(2-aminomethyl phenyl) propyl group]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(89) 1-ethyl-N-{1-[4-(oxyethyl group) phenyl] propyl group }-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(90) N-(1-{4-[(difluoromethyl) oxygen base] phenyl } propyl group)-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(91) 1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-N-{1-[4-(trifluoromethyl) phenyl] propyl group }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(92) N-[1-(3, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(93) N-[1-(2, the 3-3,5-dimethylphenyl) ethyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(94) N-[1-(2, the 4-3,5-dimethylphenyl) ethyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(95) N-[1-(4-chloro-2-fluorophenyl) ethyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(96) N-[1-(3-chloro-4-aminomethyl phenyl) ethyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(97) N-[1-(2, the 3-3,5-dimethylphenyl) propyl group]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(98) N-[1-(2, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(99) N-[1-(4-chloro-2-fluorophenyl) propyl group]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(100) N-[1-(3-chloro-4-aminomethyl phenyl) propyl group]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(101) 1-ethyl-N-[1-(3-hydroxy phenyl) propyl group]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(102) N-[1-(2,3-dihydro-1H-indenes-5-yl) ethyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(103) 1-ethyl-N-[1-(5,6,7,8-tetrahydrochysene-2-naphthyl) ethyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(104) N-[1-(4-bromophenyl)-2,2, the 2-trifluoroethyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(105) 1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-N-{2,2,2-three fluoro-1-[3-(methoxyl group) phenyl] ethyl }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(106) 4-(cyclohexyl amino)-1-ethyl-N-{1-[4-(methyl sulphonyl) phenyl] ethyl }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(107) 4-(cyclohexyl amino)-1-ethyl-N-[(1R)-1-phenyl propyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(108) 4-(cyclohexyl amino)-N-(diphenyl methyl)-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(109) 4-(cyclohexyl amino)-1-ethyl-N-[(1R)-1-phenylethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(110) ({ [4-(cyclohexyl amino)-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-yl] carbonyl } amino) (phenyl) ethyl acetate
(111) N-[1-(4-chloro-phenyl-) ethyl]-4-(cyclohexyl amino)-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(112) 4-(cyclohexyl amino)-1-ethyl-N-(1-methyl isophthalic acid-phenylethyl)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(113) 4-(cyclohexyl amino)-1-ethyl-N-[1-(4-fluorophenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(114) N-[1-(4-chloro-phenyl-) propyl group]-4-(cyclohexyl amino)-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(115) 4-(cyclohexyl amino)-N-(1, the 2-diphenyl-ethyl)-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(116) 4-(cyclohexyl amino)-1-ethyl-N-{1-[4-(propoxy-) phenyl] ethyl }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(117) 3-({ [4-(cyclohexyl amino)-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-yl] carbonyl } amino)-3-phenylpropionic acid methyl esters
(118) 4-(cyclohexyl amino)-1-ethyl-N-[1-(hydroxymethyl)-1-phenyl propyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(119) 4-(cyclohexyl amino)-1-ethyl-N-(3-hydroxyl-1-phenyl propyl)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(120) 4-(cyclohexyl amino)-1-ethyl-N-{1-[4-(oxyethyl group) phenyl] ethyl }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(121) 4-(cyclohexyl amino)-1-ethyl-N-[1-(3-hydroxy phenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(122) 4-(cyclohexyl amino)-1-ethyl-N-[1-phenyl-2-(1-pyrrolidyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(123) 4-(cyclohexyl amino)-N-[2-(dimethylamino)-1-phenylethyl]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(124) 4-(cyclohexyl amino)-1-ethyl-N-[(1R)-2-(methoxyl group)-1-phenylethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(125) N-[(1R)-2-amino-2-oxo-1-phenylethyl]-4-(cyclohexyl amino)-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(126) 4-(cyclohexyl amino)-1-ethyl-N-[(1R)-2-hydroxyl-1-phenylethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(127) 4-(cyclohexyl amino)-1-ethyl-N-[(1S)-2-hydroxyl-1-phenylethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(128) 4-(cyclohexyl amino)-1-ethyl-N-{ (1R)-1-[3-(methoxyl group) phenyl] ethyl }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(129) 4-(cyclohexyl amino)-1-ethyl-N-[(1S)-2-(methoxyl group)-1-phenylethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(130) 4-(cyclohexyl amino)-1-ethyl-N-[(1R)-1-(4-nitrophenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(131) 4-(cyclohexyl amino)-1-ethyl-N-[(1S)-1-(1-naphthyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(132) 4-(cyclohexyl amino)-1-ethyl-N-[phenyl (4-phenyl-1,3-thiazoles-2-yl) methyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(133) N-[cyano group (phenyl) methyl]-4-(cyclohexyl amino)-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(134) 4-(cyclohexyl amino)-1-ethyl-N-[1-(1-naphthyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(135) 4-(cyclohexyl amino)-1-ethyl-N-(2-hydroxyl-1,1-diphenyl-ethyl)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(136) 4-(cyclohexyl amino)-1-ethyl-N-{ (1R)-1-[4-(methoxyl group) phenyl] ethyl }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(137) 4-(cyclohexyl amino)-1-ethyl-N-[1-(4-fluorophenyl) propyl group]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(138) 4-(cyclohexyl amino)-N-[1-(2, the 3-dichlorophenyl) propyl group]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(139) 4-(cyclohexyl amino)-1-ethyl-N-[(1R)-1-(4-aminomethyl phenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(140) 4-(cyclohexyl amino)-1-ethyl-N-(1-phenylethyl)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(141) N-[(1R)-1-(4-bromophenyl) ethyl]-4-(cyclohexyl amino)-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(142) 4-(cyclohexyl amino)-N-[1-(2, the 3-dichlorophenyl) ethyl]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(143) 4-(cyclohexyl amino)-1-ethyl-N-{1-[3-(methoxyl group) phenyl] propyl group }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(144) 4-(cyclohexyl amino)-1-ethyl-N-{1-[4-(methoxyl group) phenyl] propyl group }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(145) N-[1-(4-bromophenyl) propyl group]-4-(cyclohexyl amino)-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(146) 4-(cyclohexyl amino)-1-ethyl-N-{1-[4-(propoxy-) phenyl] propyl group }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(147) 4-(cyclohexyl amino)-N-[1-(3, the 5-3,5-dimethylphenyl) propyl group]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(148) 4-(cyclohexyl amino)-1-ethyl-N-[1-(4-aminomethyl phenyl) propyl group]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(149) 4-(cyclohexyl amino)-1-ethyl-N-{1-[4-(1-methylethyl) phenyl] propyl group }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(150) 4-(cyclohexyl amino)-1-ethyl-N-[1-(2-aminomethyl phenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(151) 4-(cyclohexyl amino)-N-(1-{4-[(difluoromethyl) oxygen base] phenyl } ethyl)-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(152) 4-(cyclohexyl amino)-1-ethyl-N-{1-[4-(trifluoromethyl) phenyl] ethyl }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(153) 4-(cyclohexyl amino)-1-ethyl-N-[1-(2-aminomethyl phenyl) propyl group]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(154) 4-(cyclohexyl amino)-1-ethyl-N-{1-[4-(oxyethyl group) phenyl] propyl group }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(155) 4-(cyclohexyl amino)-N-(1-{4-[(difluoromethyl) oxygen base] phenyl } propyl group)-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(156) 4-(cyclohexyl amino)-1-ethyl-N-{1-[4-(trifluoromethyl) phenyl] propyl group }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(157) 4-(cyclohexyl amino)-N-[1-(3, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(158) 4-(cyclohexyl amino)-N-[1-(2, the 3-3,5-dimethylphenyl) ethyl]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(159) 4-(cyclohexyl amino)-N-[1-(2, the 4-3,5-dimethylphenyl) ethyl]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(160) N-[1-(4-chloro-2-fluorophenyl) ethyl]-4-(cyclohexyl amino)-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(161) N-[1-(3-chloro-4-aminomethyl phenyl) ethyl]-4-(cyclohexyl amino)-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(162) 4-(cyclohexyl amino)-N-[1-(2, the 3-3,5-dimethylphenyl) propyl group]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(163) 4-(cyclohexyl amino)-N-[1-(2, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(164) N-[1-(4-chloro-2-fluorophenyl) propyl group]-4-(cyclohexyl amino)-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(165) N-[1-(3-chloro-4-aminomethyl phenyl) propyl group]-4-(cyclohexyl amino)-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(166) 4-(cyclohexyl amino)-1-ethyl-N-[1-(3-hydroxy phenyl) propyl group]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(167) N-[1-(4-chloro-phenyl-)-2-hydroxyethyl]-4-(cyclohexyl amino)-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(168) 4-(cyclohexyl amino)-N-[1-(2,3-dihydro-1H-indenes-5-yl) ethyl]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(169) 4-(cyclohexyl amino)-1-ethyl-N-[1-(5,6,7,8-tetrahydrochysene-2-naphthyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(170) amino 4-[(1-ethanoyl-4-piperidyl)]-the 1-ethyl-N-[(1S)-the 1-phenyl propyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(171) amino 4-[(1-ethanoyl-4-piperidyl)]-the 1-ethyl-N-[(1R)-the 1-phenylethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(172) amino 4-[(1-ethanoyl-4-piperidyl)]-N-(diphenyl methyl)-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(173) amino 4-[(1-ethanoyl-4-piperidyl)]-1-ethyl-N-{1-[4-(methyl sulphonyl) phenyl] ethyl }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(174) amino 4-[(1-ethanoyl-4-piperidyl)]-the 1-ethyl-N-[(1R)-the 1-phenyl propyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(175) N-[1-(4-chloro-phenyl-) ethyl]-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(176) N-[1-(4-chloro-phenyl-) propyl group]-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(177) 1-ethyl-N-[(1S)-1-(4-nitrophenyl) ethyl]-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(178) 1-ethyl-N-[(1R)-1-(4-nitrophenyl) ethyl]-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(179) 1-ethyl-N-{1-[4-(oxyethyl group) phenyl] ethyl }-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(180) amino 1-ethyl-4-[(4-oxo cyclohexyl)]-N-{1-[4-(propoxy-) phenyl] ethyl }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(181) 1-ethyl-N-[1-(4-fluorophenyl) ethyl]-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(182) 1-ethyl-N-[(1R)-2-hydroxyl-1-phenylethyl]-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(183) amino 1-ethyl-4-[(4-oxo cyclohexyl)]-N-(1-phenyl propyl)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(184) (2R)-[(1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-yl } carbonyl) amino] [3-(methoxyl group) phenyl] acetate
(185) 1-ethyl-N-{1-[4-(1-methylethyl) phenyl] ethyl }-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(186) 1-ethyl-N-[1-(2-aminomethyl phenyl) ethyl]-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(187) N-[1-(3, the 5-3,5-dimethylphenyl) ethyl]-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(188) 1-ethyl-N-{ (1R)-1-[4-(methoxyl group) phenyl] ethyl }-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(189) 1-ethyl-N-[1-(4-fluorophenyl) propyl group]-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(190) N-[1-(2, the 3-dichlorophenyl) propyl group]-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(191) 1-ethyl-N-[(1R)-1-(4-aminomethyl phenyl) ethyl]-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(192) amino 1-ethyl-4-[(4-oxo cyclohexyl)]-N-(1-phenylethyl)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(193) N-[(1R)-1-(4-bromophenyl) ethyl]-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(194) 1-ethyl-N-[(1S)-2-hydroxyl-1-phenylethyl]-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(195) N-[1-(4-chloro-phenyl-)-2-hydroxyethyl]-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(196) N-(1-{4-[(difluoromethyl) oxygen base] phenyl } ethyl)-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(197) amino 1-ethyl-4-[(4-oxo cyclohexyl)]-N-{1-[4-(trifluoromethyl) phenyl] ethyl }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(198) 1-ethyl-N-[1-(2-aminomethyl phenyl) propyl group]-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(199) 1-ethyl-N-{1-[4-(oxyethyl group) phenyl] propyl group }-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(200) N-(1-{4-[(difluoromethyl) oxygen base] phenyl } propyl group)-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(201) amino 1-ethyl-4-[(4-oxo cyclohexyl)]-N-{1-[4-(trifluoromethyl) phenyl] propyl group }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(202) N-[1-(3, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(203) amino 1-ethyl-4-[(4-oxo cyclohexyl)]-N-[(1R)-the 1-phenyl propyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(204) 1-ethyl-N-{ (1R)-1-[3-(methoxyl group) phenyl] ethyl }-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(205) N-[1-(2, the 3-3,5-dimethylphenyl) ethyl]-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(206) N-[1-(2, the 4-3,5-dimethylphenyl) ethyl]-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(207) N-[1-(4-chloro-2-fluorophenyl) ethyl]-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(208) N-[1-(3-chloro-4-aminomethyl phenyl) ethyl]-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(209) N-[1-(2, the 3-3,5-dimethylphenyl) propyl group]-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(210) N-[1-(2, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(211) N-[1-(4-chloro-2-fluorophenyl) propyl group]-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(212) N-[1-(3-chloro-4-aminomethyl phenyl) propyl group]-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(213) 1-ethyl-N-[1-(3-hydroxy phenyl) ethyl]-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(214) 1-ethyl-N-[1-(3-hydroxy phenyl) propyl group]-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(215) N-[1-(2, the 3-dichlorophenyl) ethyl]-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(216) 1-ethyl-N-{1-[3-(methoxyl group) phenyl] propyl group }-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(217) 1-ethyl-N-{1-[4-(methoxyl group) phenyl] propyl group }-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(218) N-[1-(4-bromophenyl) propyl group]-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(219) amino 1-ethyl-4-[(4-oxo cyclohexyl)]-N-{1-[4-(propoxy-) phenyl] propyl group }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(220) N-[1-(3, the 5-3,5-dimethylphenyl) propyl group]-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(221) 1-ethyl-N-[1-(4-aminomethyl phenyl) propyl group]-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(222) 1-ethyl-N-{1-[4-(1-methylethyl) phenyl] propyl group }-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(223) 1-ethyl-N-(1-{4-[(1-methylethyl) oxygen base] phenyl } ethyl)-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(224) amino 1-ethyl-4-[(4-oxo cyclohexyl)]-N-[1-(5,6,7,8-tetrahydrochysene-2-naphthyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(225) N-[1-(4-bromophenyl)-2,2, the 2-trifluoroethyl]-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(226) amino 1-ethyl-4-[(4-oxo cyclohexyl)]-N-{2,2,2-three fluoro-1-[3-(methoxyl group) phenyl] ethyl }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(227) 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-[1-(5,6,7,8-tetrahydrochysene-2-naphthyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(228) 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-[(1S)-2-hydroxyl-1-phenylethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(229) N-[1-(2,3-dihydro-1H-indenes-5-yl) ethyl]-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(230) N-[1-(4-chloro-phenyl-)-2-hydroxyethyl]-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(231) 1-ethyl-N-{1-[4-(oxyethyl group) phenyl] ethyl }-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(232) 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-{1-[4-(propoxy-) phenyl] ethyl }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(233) 1-ethyl-N-[1-(4-fluorophenyl) ethyl]-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(234) 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-[(1R)-2-hydroxyl-1-phenylethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(235) 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-(1-phenyl propyl)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(236) 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-{1-[4-(1-methylethyl) phenyl] ethyl }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(237) N-[1-(3, the 5-3,5-dimethylphenyl) ethyl]-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(238) 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-{ (1R)-1-[4-(methoxyl group) phenyl] ethyl }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(239) 1-ethyl-N-[1-(4-fluorophenyl) propyl group]-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(240) N-[1-(2, the 3-dichlorophenyl) propyl group]-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(241) 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-[(1R)-1-(4-aminomethyl phenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(242) 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-(1-phenylethyl)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(243) N-[(1R)-1-(4-bromophenyl) ethyl]-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(244) N-[1-(2, the 3-dichlorophenyl) ethyl]-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(245) N-[1-(4-chloro-phenyl-) propyl group]-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(246) N-[1-(4-chloro-phenyl-) ethyl]-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(247) 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-{1-[3-(methoxyl group) phenyl] propyl group }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(248) 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-{1-[4-(methoxyl group) phenyl] propyl group }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(249) N-[1-(4-bromophenyl) propyl group]-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(250) 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-{1-[4-(propoxy-) phenyl] propyl group }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(251) N-[1-(3, the 5-3,5-dimethylphenyl) propyl group]-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(252) 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-[1-(4-aminomethyl phenyl) propyl group]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(253) 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-{1-[4-(1-methylethyl) phenyl] propyl group }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(254) 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-[1-(2-aminomethyl phenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(255) N-(1-{4-[(difluoromethyl) oxygen base] phenyl } ethyl)-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(256) 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-{1-[4-(trifluoromethyl) phenyl] ethyl }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(257) 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-[1-(2-aminomethyl phenyl) propyl group]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(258) 1-ethyl-N-{1-[4-(oxyethyl group) phenyl] propyl group }-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(259) N-(1-{4-[(difluoromethyl) oxygen base] phenyl } propyl group)-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(260) 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-{1-[4-(trifluoromethyl) phenyl] propyl group }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(261) N-[1-(3, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(262) 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-[(1R)-the 1-phenyl propyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(263) 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-{ (1R)-1-[3-(methoxyl group) phenyl] ethyl }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(264) N-[1-(2, the 3-3,5-dimethylphenyl) ethyl]-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(265) N-[1-(2, the 4-3,5-dimethylphenyl) ethyl]-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(266) N-[1-(4-chloro-2-fluorophenyl) ethyl]-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(267) N-[1-(3-chloro-4-aminomethyl phenyl) ethyl]-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(268) N-[1-(2, the 3-3,5-dimethylphenyl) propyl group]-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(269) N-[1-(2, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(270) N-[1-(4-chloro-2-fluorophenyl) propyl group]-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(271) N-[1-(3-chloro-4-aminomethyl phenyl) propyl group]-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(272) 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-[1-(3-hydroxy phenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(273) 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-[1-(3-hydroxy phenyl) propyl group]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(274) N-[1-(2, the 4-3,5-dimethylphenyl) ethyl]-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(275) N-[1-(2, the 4-3,5-dimethylphenyl) ethyl]-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(276) N-[1-(3, the 5-3,5-dimethylphenyl) ethyl]-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(277) N-[1-(3, the 5-3,5-dimethylphenyl) ethyl]-1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(278) 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-(1-{4-[(1-methylethyl) oxygen base] phenyl } ethyl)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(279) 1-ethyl-4-{[4-(oximido) cyclohexyl] amino }-N-(1-{4-[(1-methylethyl) oxygen base] phenyl } ethyl)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(280) 1-ethyl-N-[1-(4-fluorophenyl) ethyl]-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(281) 1-ethyl-N-[1-(4-fluorophenyl) ethyl]-4-{[4-(oximido) cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(282) N-[1-(4-chloro-phenyl-) propyl group]-1-ethyl-4-{[(1S, 3R)-and/or (1R, 3S)-the 3-hydroxy-cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(283) 1-ethyl-4-{[(1S, 3R)-and/or (1R, 3S)-the 3-hydroxy-cyclohexyl] amino }-N-[(1R)-1-(4-aminomethyl phenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(284) N-[1-(2, the 4-3,5-dimethylphenyl) ethyl]-1-ethyl-4-{[(1S, 3R)-and/or (1R, 3S)-the 3-hydroxy-cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide, isomer 1
(285) N-[1-(2, the 4-3,5-dimethylphenyl) ethyl]-1-ethyl-4-{[(1S, 3R)-and/or (1R, 3S)-the 3-hydroxy-cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide, isomer 2
(286) N-[1-(3, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-4-{[(1S, 3R)-and/or (1R, 3S)-the 3-hydroxy-cyclohexyl] amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(287) N-[1-(4-chloro-phenyl-) propyl group]-1-ethyl-6-methyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(288) N-[1-(4-chloro-phenyl-) ethyl]-1-ethyl-6-methyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(289) N-[1-(4-chloro-phenyl-) ethyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide, enantiomer 1
(290) N-[1-(4-chloro-phenyl-) ethyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide, enantiomer 2
(291) N-[1-(4-chloro-phenyl-) propyl group]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide, enantiomer 1
(292) N-[1-(4-chloro-phenyl-) propyl group]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide, enantiomer 2
(293) 1-ethyl-N-{1-[4-(oxyethyl group) phenyl] ethyl }-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide, enantiomer 1
(294) 1-ethyl-N-{1-[4-(oxyethyl group) phenyl] ethyl }-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide, enantiomer 2
(295) N-[1-(2, the 4-3,5-dimethylphenyl) ethyl]-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide, enantiomer 1
(296) N-[1-(2, the 4-3,5-dimethylphenyl) ethyl]-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide, enantiomer 2
(297) N-[1-(3, the 5-3,5-dimethylphenyl) ethyl]-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide, enantiomer 1
(298) N-[1-(3, the 5-3,5-dimethylphenyl) ethyl]-1-ethyl-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide, enantiomer 2
(299) 1-ethyl-N-(1-{4-[(1-methylethyl) oxygen base] phenyl } ethyl)-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide, enantiomer 1
(300) 1-ethyl-N-(1-{4-[(1-methylethyl) oxygen base] phenyl } ethyl)-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide, enantiomer 2
(301) 1-ethyl-N-[1-(4-fluorophenyl) ethyl]-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide, enantiomer 1
(302) 1-ethyl-N-[1-(4-fluorophenyl) ethyl]-4-[(4-oxo cyclohexyl) amino]-1H-pyrazolo [3,4-b] pyridine-5-methane amide, enantiomer 2
(303) N-[1-(2, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide, enantiomer 1
(304) N-[1-(2, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide, enantiomer 2
(305) 1-ethyl-4-{[(1S, 3R)-and/or (1R, 3S)-the 3-hydroxy-cyclohexyl] amino }-N-[(1R)-1-(4-aminomethyl phenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide, diastereomer 1
(306) 1-ethyl-4-{[(1S, 3R)-and/or (1R, 3S)-the 3-hydroxy-cyclohexyl] amino }-N-[(1R)-1-(4-aminomethyl phenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide, diastereomer 2
(307) N-[1-(2, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide (enantiomer 2) hydrochloride
(308) 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-the 1-ethyl-N-[(1R)-1-(4-aminomethyl phenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(309) 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-the 1-ethyl-N-[(1R)-the 1-phenylethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(310) 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-N-[(1R)-1-(4-bromophenyl) ethyl]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(311) 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-N-[1-(2, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(312) 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-N-[1-(3-chloro-4-aminomethyl phenyl) propyl group]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(313) 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-N-[1-(4-chloro-2-fluorophenyl) propyl group]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide, or
(314) 4-{[4-(aminocarboxyl) cyclohexyl] amino }-the 1-ethyl-N-[(1R)-the 1-phenylethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide;
Or its salt.
53. each formula (I) compound or its salt among the claim 1-51, described compound is:
(1) N-[(1S)-1-(2, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(2) N-[(1R)-1-(2, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(3) N-[(1R)-1-(2, the 5-3,5-dimethylphenyl) ethyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(4) 1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-N-[(1R)-1-(2,4, the 6-trimethylphenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(5) 1-ethyl-N-[(1R)-1-(2-ethylphenyl) ethyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(6) 1-ethyl-N-[(1R)-1-(4-ethylphenyl) ethyl]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(7) 1-ethyl-N-[(1R)-1-(4-aminomethyl phenyl) propyl group]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(8) 1-ethyl-N-[(1R)-1-(4-ethylphenyl) propyl group]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(9) 1-ethyl-N-{ (1R)-1-[4-(1-methylethyl) phenyl] propyl group }-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(10) N-[(1R)-1-(4-chloro-2-fluorophenyl) propyl group]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(11) N-[(1R)-1-(2, the 6-3,5-dimethylphenyl) propyl group]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(12) N-[(1R)-1-(2, the 5-3,5-dimethylphenyl) propyl group]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(13) 1-ethyl-N-[(1R)-1-(2-ethylphenyl) propyl group]-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(14) 1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-N-[(1R)-1-(2,4, the 6-trimethylphenyl) propyl group]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(15) 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-N-[(1R)-1-(2, the 5-3,5-dimethylphenyl) ethyl]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(16) 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-the 1-ethyl-N-[(1R)-1-(4-ethylphenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(17) 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-the 1-ethyl-N-[(1R)-1-(2-ethylphenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(18) 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-the 1-ethyl-N-[(1R)-1-(2,4, the 6-trimethylphenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(19) 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-N-[(1R)-1-(2, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(20) 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-N-[1-(4-chloro-phenyl-) ethyl]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(21) 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-the 1-ethyl-N-[(1R)-the 1-phenyl propyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(22) 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-N-[1-(4-chloro-phenyl-) propyl group]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(23) 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-1-ethyl-N-[1-(4-fluorophenyl) propyl group]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(24) 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-the 1-ethyl-N-[(1R)-1-(4-aminomethyl phenyl) propyl group]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(25) 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-the 1-ethyl-N-[(1R)-1-(4-ethylphenyl) propyl group]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(26) 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-1-ethyl-N-{ (1R)-1-[4-(1-methylethyl) phenyl] propyl group }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(27) 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-N-[(1R)-1-(4-chloro-2-fluorophenyl) propyl group]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(28) 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-N-[(1R)-1-(2, the 6-3,5-dimethylphenyl) propyl group]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(29) 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-N-[(1R)-1-(2, the 5-3,5-dimethylphenyl) propyl group]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(30) 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-the 1-ethyl-N-[(1R)-1-(2-ethylphenyl) propyl group]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(31) 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-the 1-ethyl-N-[(1R)-1-(2,4, the 6-trimethylphenyl) propyl group]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(32) 4-{[4-(aminocarboxyl) cyclohexyl] amino }-N-[1-(4-chloro-phenyl-) propyl group]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(33) 4-{[4-(aminocarboxyl) cyclohexyl] amino }-the 1-ethyl-N-[(1R)-the 1-phenyl propyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(34) 4-{[4-(aminocarboxyl) cyclohexyl] amino }-N-(1-{4-[(difluoromethyl) oxygen base] phenyl } ethyl)-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(35) 4-{[4-(aminocarboxyl) cyclohexyl] amino }-N-[1-(4-chloro-phenyl-) ethyl]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(36) 4-{[4-(aminocarboxyl) cyclohexyl] amino }-1-ethyl-N-[1-(4-fluorophenyl) propyl group]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(37) 4-{[4-(aminocarboxyl) cyclohexyl] amino }-N-[(1R)-1-(4-bromophenyl) ethyl]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(38) 4-{[suitable-4-(aminocarboxyl) cyclohexyl] amino-N-[(1R)-1-(2, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(39) 4-{[suitable-4-(aminocarboxyl) cyclohexyl] amino-1-ethyl-N-[(1R)-1-(4-aminomethyl phenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(40) 4-{[suitable-4-(aminocarboxyl) cyclohexyl] amino-1-ethyl-N-[(1R)-1-phenylethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(41) 4-{[suitable-4-(aminocarboxyl) cyclohexyl] amino-N-[(1R)-1-(4-bromophenyl) ethyl]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(42) 4-{[anti--4-(aminocarboxyl) cyclohexyl] amino-N-[(1R)-1-(2, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(43) 4-{[anti--4-(aminocarboxyl) cyclohexyl] amino-1-ethyl-N-[(1R)-1-(4-aminomethyl phenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(44) 4-{[anti--4-(aminocarboxyl) cyclohexyl] amino-1-ethyl-N-[(1R)-1-phenylethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(45) 4-{[anti--4-(aminocarboxyl) cyclohexyl] amino-N-[(1R)-1-(4-bromophenyl) ethyl]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(46) 4-{[(3S)-and 1-(aminocarboxyl) tetramethyleneimine-3-yl] amino }-N-[1-(2, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(47) 4-{[(3S)-and 1-(aminocarboxyl) tetramethyleneimine-3-yl] amino }-the 1-ethyl-N-[(1R)-1-(4-aminomethyl phenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(48) 4-{[(3S)-and 1-(aminocarboxyl) tetramethyleneimine-3-yl] amino }-N-[1-(3, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(49) 4-{[(3S)-and 1-(aminocarboxyl) tetramethyleneimine-3-yl] amino }-N-[(1R)-1-(4-bromophenyl) ethyl]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(50) 4-{[(3R)-and 1-(aminocarboxyl) tetramethyleneimine-3-yl] amino }-N-[1-(2, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(51) 4-{[(3R)-and 1-(aminocarboxyl) tetramethyleneimine-3-yl] amino }-the 1-ethyl-N-[(1R)-1-(4-aminomethyl phenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(52) 4-{[(3R)-and 1-(aminocarboxyl) tetramethyleneimine-3-yl] amino }-N-[1-(3, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(53) 4-{[(3R)-and 1-(aminocarboxyl) tetramethyleneimine-3-yl] amino }-N-[(1R)-1-(4-bromophenyl) ethyl]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(54) 4-{[suitable-3-(aminocarboxyl) cyclobutyl] amino-1-ethyl-N-[(1R)-1-(4-aminomethyl phenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(55) 4-{[suitable-3-(aminocarboxyl) cyclobutyl] amino-N-[1-(2, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(56) 4-[(anti--4-ethanoyl cyclohexyl) amino]-1-ethyl-N-[(1R)-1-(4-aminomethyl phenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(57) amino 4-[(4-ethanoyl cyclohexyl)]-N-[(1R)-1-(2, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(58) 4-[(suitable-4-ethanoyl cyclohexyl) amino]-1-ethyl-N-[(1R)-1-(4-aminomethyl phenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(59) 1-ethyl-4-{[anti--the 3-hydroxy-cyclohexyl] amino-N-[(1R)-1-(4-aminomethyl phenyl) ethyl]-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(60) N-[(1S)-1-(2, the 4-3,5-dimethylphenyl) ethyl]-1-ethyl-4-{[is anti--the 3-hydroxy-cyclohexyl] and amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(61) N-[(1R)-1-(2, the 4-3,5-dimethylphenyl) ethyl]-1-ethyl-4-{[is anti--the 3-hydroxy-cyclohexyl] and amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(62) N-[(1R)-1-(4-bromophenyl) ethyl]-1-ethyl-4-{[is anti--the 3-hydroxy-cyclohexyl] and amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(63) N-[1-(3, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-4-{[is anti--the 3-hydroxy-cyclohexyl] and amino }-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(64) N-[4-(dimethylamino)-1-(3-aminomethyl phenyl)-4-oxo butyl]-1-ethyl-4-(tetrahydrochysene-2H-pyrans-4-base is amino)-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(65) 4-{[1-(aminocarboxyl)-4-piperidyl] amino }-N-[4-(dimethylamino)-1-(3-aminomethyl phenyl)-4-oxo butyl]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide
(66) 1-ethyl-N-[(1R)-1-(4-aminomethyl phenyl) ethyl]-4-(4-piperidyl amino)-1H-pyrazolo [3,4-b] pyridine-5-carboxamide hydrochloride, or
(67) N-[1-(2, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-4-(4-piperidyl amino)-1H-pyrazolo [3,4-b] pyridine-5-carboxamide hydrochloride;
Or its salt.
54. each formula (I) compound or its salt among the claim 1-51, described compound is by structure described herein and/or the embodiment 73,75,98,283,304,306,307,310 of name definition or 311 compound or its pharmacy acceptable salt, or by structure described herein and/or the embodiment 316,321,324,326,327,328,330,331,332,333,334,335,336,337,338,339,343,344 of name definition or 345 compound or its pharmacy acceptable salt.
55. each compound or salt among the claim 1-53, it is described compound or its pharmacy acceptable salt.
56. each compound or salt in the aforementioned claim, described compound or salt are particulate form, the compound of wherein said particulate form or the size definition of salt are about 0.5 micron to about 10 microns for its D50 value.
57. each compound or salt in the aforementioned claim, described compound or salt are as mammiferous active treatment material.
58. a pharmaceutical composition, described composition comprise formula (I) compound or its pharmacy acceptable salt of each definition among the claim 1-56, and one or more pharmaceutically acceptable carrier and/or vehicle.
59. the pharmaceutical composition of claim 58, described composition are fit to suck administration of human.
60. the pharmaceutical composition of claim 58, described composition are used for the treatment of and/or prevent mammiferous inflammatory diseases and/or allergic disease, cognitive decline or dysthymia disorders.
61. the formula of each definition (I) compound or its pharmacy acceptable salt are used for the treatment of and/or prevent purposes in the medicine of mammiferous inflammatory diseases and/or allergic disease in preparation among the claim 1-56.
62. the purposes of claim 61, wherein said inflammatory diseases and/or allergic disease are mammiferous chronic obstructive pulmonary disease (COPD), asthma, rheumatoid arthritis, rhinallergosis or atopic dermatitis.
63. the formula of each definition (I) compound or its pharmacy acceptable salt are used for the treatment of and/or prevent purposes in the medicine of mammiferous following disease in preparation among the claim 1-56: asthma, chronic obstructive pulmonary disease (COPD), atopic dermatitis, urticaria, rhinallergosis, allergic conjunctivitis, vernal conjunctivitis, eosinophilic granuloma, psoriasis, rheumatoid arthritis, septic shock, ulcerative colitis, Crohn disease, the reperfusion injury of cardiac muscle and brain, chronic glomerulonephritis, endotoxin shock, adult respiratory distress syndrome, multiple sclerosis, cognitive decline, dysthymia disorders or pain.
64. one kind treats and/or prevents the method that needs this mammiferous inflammatory diseases that treats and/or prevents and/or allergic disease, cognitive decline or dysthymia disorders, this method comprises formula (I) compound or its pharmacy acceptable salt of each definition among the claim 1-56 that gives described Mammals treatment significant quantity.
65. the method for claim 64, this method is to treat and/or prevent to need this mammiferous inflammatory diseases that treats and/or prevents and/or the method for allergic disease, and wherein said inflammatory diseases and/or allergic disease are mammiferous chronic obstructive pulmonary disease (COPD), asthma, rheumatoid arthritis, rhinallergosis or atopic dermatitis.
66. combination medicine, described combination medicine comprises formula (I) compound or its pharmacy acceptable salt of each definition among the claim 1-56, and beta-2-adrenoreceptor agonists, antihistaminic, anti-allergic drug, antiphlogiston or muscarine (M) receptor antagonist.
A 67. following formula (IB) compound or its salt:
Wherein:
R
1aBe C
2-3Alkyl, C
2Fluoro-alkyl or-CH
2CH
2OH;
R
2aBe hydrogen atom (H) or methyl;
NHR
3aBe formula (p14), wherein NHR
3aIn group and the formula (IB) 4 of Pyrazolopyridine-the NH-tie point is following underscore part:
R
4aaBe methyl, ethyl, C
1Fluoro-alkyl ,-CH
2OH or-CH
2OMe;
R
6Aa, R
6Ba, R
6Da, R
6EaAnd R
6FaBe independently of one another hydrogen atom (H), fluorine atom, chlorine atom, bromine atoms, iodine atom, methyl, ethyl, n-propyl, sec.-propyl, isobutyl-, trifluoromethyl ,-CH
2OH, methoxyl group, oxyethyl group, positive propoxy, isopropoxy, C
1Fluoroalkyl, nitro (NO
2), OH, C
1-3Alkyl S (O)
2-, C
1-2Alkyl S (O)
2-NH-,-CONH
2, cyano group (CN) or C
1-2Alkyl S (O)
2-CH
2-; Precondition is R
6Aa, R
6Ba, R
6Da, R
6EaAnd R
6FaIn be hydrogen atom (H) more than two;
And in formula (IB), the described compound of 50% above volumetric molar concentration or salt are connecting R
4aaThree-dimensional chemical configuration shown in the carbon atom place of group has.
68. the compound of claim 67 or salt, wherein:
R
1aBe ethyl;
R
2aBe H;
R
4aaBe methyl or ethyl;
R
6Aa, R
6Ba, R
6Da, R
6EaAnd R
6FaBe independently of one another hydrogen atom (H), fluorine atom, chlorine atom, bromine atoms, methyl, ethyl, n-propyl, sec.-propyl, trifluoromethyl ,-CH
2OH, methoxyl group, oxyethyl group, positive propoxy, difluoro-methoxy, OH or MeS (O)
2-; Precondition is R
6Aa, R
6Ba, R
6Da, R
6EaAnd R
6FaIn be hydrogen atom (H) more than three.
69. the compound of claim 67 or 68 or salt, the NHR of its Chinese style (p14)
3aGroup is a cis-configuration, is [suitable-4-(1-hydroxyethyl) cyclohexyl] amino (comprising that cis-configuration is the mixture of the various configurations of main component).
70. each compound or salt in the claim 67,68 or 69, wherein in formula (IB), the described compound of 70% above volumetric molar concentration or salt are connecting R
4aaThree-dimensional chemical configuration shown in the carbon atom place of group has.
71. each compound or salt in the claim 67,68,69 or 70, its be 4-[suitable-4-(1-hydroxyethyl) cyclohexyl] amino-N-[1-(2, the 4-3,5-dimethylphenyl) propyl group]-1-ethyl-1H-pyrazolo [3,4-b] pyridine-5-methane amide or its salt, and the described compound of 50% above volumetric molar concentration or salt are (R) three-dimensional chemical configuration at the benzylic carbon atoms place.
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
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EPPCT/EP03/14867 | 2003-12-19 | ||
PCT/EP2003/014867 WO2004056823A1 (en) | 2002-12-23 | 2003-12-19 | PYRAZOLO[3,4-b]PYRIDINE COMPOUNDS, AND THEIR USE AS PHOSPHODIESTERASE INHIBITORS |
GB0405899.6 | 2004-03-16 | ||
GB0405936.6 | 2004-03-16 | ||
GB0406754.2 | 2004-03-25 |
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Cited By (3)
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CN107501258A (en) * | 2017-09-14 | 2017-12-22 | 刘双伟 | A kind of thiazolyl nicotinamide compound and its application in antiallergy and asthmatic medicament is prepared |
CN113056270A (en) * | 2018-09-18 | 2021-06-29 | 梅塔科林公司 | Crystalline forms of farnesoid X receptor agonists |
CN113563319A (en) * | 2020-07-21 | 2021-10-29 | 中国药科大学 | Indazole heterocycles having phosphodiesterase 4B inhibitory activity |
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2004
- 2004-12-17 CN CNA2004800416577A patent/CN1914205A/en active Pending
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
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CN107501258A (en) * | 2017-09-14 | 2017-12-22 | 刘双伟 | A kind of thiazolyl nicotinamide compound and its application in antiallergy and asthmatic medicament is prepared |
CN107501258B (en) * | 2017-09-14 | 2018-08-28 | 刘双伟 | A kind of thiazolyl nicotinamide compound and its application in preparing antiallergy and asthmatic medicament |
CN107501258B8 (en) * | 2017-09-14 | 2018-10-16 | 青岛大学附属医院 | A kind of thiazolyl nicotinamide compound and its application in preparing antiallergy and asthmatic medicament |
CN113056270A (en) * | 2018-09-18 | 2021-06-29 | 梅塔科林公司 | Crystalline forms of farnesoid X receptor agonists |
CN113563319A (en) * | 2020-07-21 | 2021-10-29 | 中国药科大学 | Indazole heterocycles having phosphodiesterase 4B inhibitory activity |
CN113563319B (en) * | 2020-07-21 | 2024-01-12 | 中国药科大学 | Indazole heterocyclic compounds having phosphodiesterase 4B inhibitory activity |
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