ZA200701653B - Thiazolyl-dihydro indazoles - Google Patents
Thiazolyl-dihydro indazoles Download PDFInfo
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- ZA200701653B ZA200701653B ZA200701653A ZA200701653A ZA200701653B ZA 200701653 B ZA200701653 B ZA 200701653B ZA 200701653 A ZA200701653 A ZA 200701653A ZA 200701653 A ZA200701653 A ZA 200701653A ZA 200701653 B ZA200701653 B ZA 200701653B
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- 230000004060 metabolic process Effects 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- VMVNZNXAVJHNDJ-UHFFFAOYSA-N methyl 2,2,2-trifluoroacetate Chemical compound COC(=O)C(F)(F)F VMVNZNXAVJHNDJ-UHFFFAOYSA-N 0.000 description 1
- 230000002297 mitogenic effect Effects 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 125000006574 non-aromatic ring group Chemical group 0.000 description 1
- ZCYXXKJEDCHMGH-UHFFFAOYSA-N nonane Chemical compound CCCC[CH]CCCC ZCYXXKJEDCHMGH-UHFFFAOYSA-N 0.000 description 1
- 125000003518 norbornenyl group Chemical group C12(C=CC(CC1)C2)* 0.000 description 1
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 description 1
- BKIMMITUMNQMOS-UHFFFAOYSA-N normal nonane Natural products CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 1
- 125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004590 pyridopyridyl group Chemical group N1=C(C=CC2=C1C=CC=N2)* 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000004620 quinolinyl-N-oxide group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 230000008054 signal transmission Effects 0.000 description 1
- 102000009076 src-Family Kinases Human genes 0.000 description 1
- 108010087686 src-Family Kinases Proteins 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- JXZSWZVZQQAHKW-UHFFFAOYSA-N tert-butyl n-(4-pyrrolidin-1-ylcyclohexyl)carbamate Chemical compound C1CC(NC(=O)OC(C)(C)C)CCC1N1CCCC1 JXZSWZVZQQAHKW-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/84—Naphthothiazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Immunology (AREA)
- Ophthalmology & Optometry (AREA)
- Urology & Nephrology (AREA)
- Dermatology (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
®
Case 12-0238
THIAZOLYLDIHYDROINDAZOLES
The present invention relates to novel thiazolyldihydroindazoles of the general formula (1)
R3 aad
M S NN (1)
R!
R? where the radicals R' to R’ have the meanings given in the claims and the description, to their isomers, to processes for preparing these thiazolyl- dihydroindazoles, and to the use of the latter as pharmaceuticals.
The phosphorylation of proteins and lipids is an important cellular regulation mechanism which plays a role in many different biological processes such as cell proliferation, differentiation, apoptosis, metabolism, inflammation, immune reactions and angiogenesis. More than 500 kinases are encoded in the human genome. In general, tyrosine protein kinases are stimulated by growth factors or other mitogenic signals and phosphorylate proteins which initiate rapid signal transmissions. Serine/threonine protein kinases mostly ~~ phosphorylate proteins which crosslink and —amplifyp— intracellular signals. Lipid kinases are likewise important switching sites in intracellular signal pathways, with these sites linking various biological processes.
A number of protein kinases have already proved to be suitable target molecules for therapeutic intervention in a variety of indications, e.g. cancer and inflammatory and autoimmune diseases. Since a high percentage of the genes involved in the development of
®
Case 12-0238 - 2 - cancer which have been identified thus far encode kinases, these enzymes are attractive target molecules for the therapy of cancer in particular.
Phosphatidylinositol 3-kinases (PI3 kinases) are a subfamily of the lipid kinases and catalyse the transfer of a phosphate radical to the 3’ position of the inositol ring of phosphoinositides. They play a crucial role in a large number of cellular processes such as cell growth and differentiation processes, the regulation of cytoskeletal changes and the regulation : of intracellular transport processes. The PI3 kinases can be subdivided into different classes on the basis of their in-vitro specificity for particular phosphoinositide substrates.
Among the members of the class I PI3 kinases, the «, B and & PI3 kinases (class IA) are principally activated by receptor tyrosine kinases (RTKs) or soluble tyrosine kinases. On the other hand, the y PI3 kinase (class IB) is principally activated by GBy subunits which are released from heterotrimeric G proteins following activation of heptahelical receptors. As a result of these differences in the coupling to cell surface receptors, in combination with a more or less restricted expression, the 4 <class I PI3 kinases inevitably have very different tasks and functions in _
Many independent findings indicate that class IA PI3 kinases are involved in uncontrolled processes of cell growth and differentiation. Thus, the first PI3 kinase activity which was detected was associated with the transforming activity of viral oncogenes such as the middle T antigen of polyoma viruses, Src tyrosine kinases or activated growth factors (Workman, Biochem
Soc Trans. 2004; 32(Pt 2):393-6). Akt/PKB, which is
®
Case 12-0238 - 3 - activated directly by the lipid products of the class I
PI3 kinases and in this way transmits the signals into the cell, is found to be hyperactive in many tumours such as breast cancer and ovarian or pancreatic carcinoma. In addition, it has recently been found that the PIK3 CA gene, which encodes the pl1l0 subunit of
PI3Ka, exhibits a high frequency of mutation in many tumour types such as colon, mammary and lung carcinomas, with some of the mutations being representatively characterized as being activating mutations (Samuels et al., Science 2004; 304 (5670) :554).
It has now been found, surprisingly, that compounds of the general formula (I), in which the radicals R! to R3 have the meanings given below, act as inhibitors of specific cell cycle kinases. Consequently, the compounds according to the invention can be used, for example, for treating diseases which are connected to the activity of specific cell cycle kinases and are characterized by excessive or anomalous cell proliferation.
The present invention relates to compounds of the general formula (1)
R3 — Sr
MN Ni (1)
R! /
R2 in which
R' is selected from the group consisting of -NHRS, -NHC(O)R®, -NHC(O)ORS, -NHC(O)NR'R® and -NHC (0) SR;
R? is a radical which is optionally substituted by one or more R‘ and which is selected from the group
®
Case 12-0238 - 4 - consisting of C;salkyl, Ci.gcycloalkyl, 3-8-membered heterocycloalkyl, Ce-:caryl and 5-10-membered heteroaryl;
R® is a radical which is optionally substituted by one or more R° and/or R! and is selected from the group consisting of C4 jparyl and 5-10-membered heteroaryl;
R* is a radical selected from the group consisting of
R?*, R® and R* which is substituted by one or more, identical or different, RS and/or RP’; each R? is, independently of each other, selected from the group «consisting of Cj.calkyl, Ci.gcycloalkyl,
C4-11cycloalkylalkyl, Cg-10arvyl, Crasarylalkyl, 2-6- membered heteroalkyl, 3-8-membered heterocycloalkyl, 4-14 -membered heterocycloalkylalkyl, 5-10-membered heteroaryl and 6-16-membered heteroarylalkyl; each R° is a suitable radical and in each case selected, independently of each other, from the group consisting of =0, -OR®, C;.shaloalkyloxy, -OCF;, =§, -SR®, =NR®, =NOR®, -NR°R®, halogen, -CF3, -CN, -NC, -OCN, -SCN, -NO, -NO;, =N, -Ni;, -S(O)R°, -S(0),R°, -S(O).ORS, ~S(O)NR°R®, -S(0),NR°RS, -0S(0)R®, -0S(0),RS, -0S (0) ,0R", -0S (0) :NR°R®, -C(O)R", -C (0) ORS, -C(O) NR°RS, -C(O)N(R?)NRR®, -C(O)N(R%)OR®, -CN(RY)NR°RS, -OC(Q)R.
T -0C(0)OR°, -OC(O)NRR®, -OCN(R)NR°RS, -N(RY)C (ORC, -N(R%)C(0Q)RS®, -N(R?)C(S)RE, -N(R%) S(O) ,R®, -N(R%)S(0),NRR®, -N[S(0)2];R", -N(R%)C (0) OR, -N(R%)C(0O)NR°R®, and -N (RY) CN (RY) NR°R®; each R® is, independently of each other, hydrogen or a radical which is optionally substituted by one or more, identical or different, R® and/or R® and which is selected from the group consisting of CC; z;alkyl,
C;-gcycloalkyl, Cs.nicycloalkylalkyl, Cg.-caryl,
®
Case 12-0238 - 5 -
Cs.isarylalkyl, 2-6-membered heteroalkyl, 3-8-membered heterocycloalkyl, 4-l4-membered heterocycloalkylalkyl, 5-10-membered hetercaryl and 6-16-membered heteroarylalkyl, each RY is, independently of each other, hydrogen or a radical which is optionally substituted by one or more, identical or different, R® and/or Rf! and which is selected from the group consisting of C;.galkyl,
Cs;_scycloalkyl, Cs-11cycloalkylalkyl, Ce-10aryl,
C;.1sarylalkyl, 2-6-membered heteroalkyl, 3-8-membered heterocycloalkyl, 4-l4-membered heterocycloalkylalkyl, 5-10-membered heteroaryl and 6-16-membered heteroarylalkyl, each R® is a suitable radical and in each case selected, independently of each other, from the group consisting of =0, -OR®, C;jhaloalkyloxy, -OCF,, =S, -SR®, =NR®, =NOR’, -NR'Rf, halogen, -CF3, -CN, -NC, -OCN, -SCN, -NO, -NO;, =N;, -N;, -S(O)RY, -S(0),Rf, -S(0O),ORf, -S(O)NRR', -S5(0).NR'Rf, -0S(0)Rf, -0S(0),Rf, -0S(0),0R!, -0S (0) NR'R®, -C(O)Rf, -C(O)OR’, -C(O)NR'Rf, -CN(R?)NRRE, -0C (0) Rf, -0C (0) OR, -0C (0) NRR?, -OCN (R?) NRIR?, -N(R%)C(O)R", -N(R%)C(S)Rf, -N(RY9)S(O),Rf, -N(RY)C(O)OR', -N(R%)C(O)NR'Rf, and -N(RY)CN(RI)NRIRE; each RY is, independently of each other, hydrogen or a ~ radical which is optionally substituted by one or more, identical or different, RY and which is selected from the group consisting of CC, alkyl, Ci.gcycloalkyl,
Cq..:cycloalkylalkyl, Ce-1caryl, Cs-isarylalkyl, 2-6- membered heteroalkyl, 3-8-membered heterocycloalkyl, 4-14-membered heterocycloalkylalkyl, 5-10-membered heteroaryl and 6-16-membered hetercarylalkyl, each RY is, independently of each other, hydrogen,
Ci-salkyl, Ci.;cycloalkyl, Cs.::cycloalkylalkyl, CC; ;-aryl,
®
Case 12-0238 - 6 -
Cs.1sarylalkyl, 2-6-membered heteroalkyl, 3-8-membered heterocycleoalkyl, 4-l4-membered heterocycloalkylalkyl, 5-10-membered heteroaryl and 6-16 -membered heteroarylalkyl, where appropriate in the form of their tautomers, their racemates, their enantiomers, their diastereomers and their mixtures, as well as, where appropriate, their pharmacologically harmless acid addition salts.
One aspect of the invention relates to compounds of the general formula (1) where R? is a radical which is selected from the group consisting of phenyl, furyl, pyridyl, pyrimidinyl and pyrazinyl, where appropriate substituted by one or more R*.
Another aspect of the invention relates to compounds of the general formula (1) where R® is pyridyl.
Another aspect of the invention relates to compounds of the general formula (1) where R' is -NHC(O)RE.
Another aspect of the invention relates to compounds of the general formula (1) where R!' is -NHC(O)CHs.
One aspect of the invention relates to compounds of formula (A) 0
REN Sl -’ A a LL ;
S ~RY
Oo 0 where
X is -CH;, -OR® or -SR*, and
Y is phenyl, 5-10-membered heteroaryl or the group -C(0)0, and
RY is hydrogen, -NO, or C: alkyl and R! is defined as above.
Case 12-0238 - 7 -
Another aspect of the invention relates to compounds of the general formula (A) where R? is -C..¢alkyl.
Another aspect of the invention relates to the use of compounds of the formula (A) as synthesis intermediates.
One aspect of the invention relates to compounds of the general formula (1), or their pharmaceutically active salts, as pharmaceuticals.
One aspect of the invention relates to the use of compounds of the general formula (1), or their pharmaceutically active salts, for producing a pharmaceutical having an antiproliferative effect.
One aspect of the invention relates to a pharmaceutical composition which comprises, as the active compound, one or more compounds of the general formula (1) or their physiologically tolerated salts, where appropriate in combination with customary auxiliary substances and/or carrier substances.
Another aspect of the invention relates to the use of compounds of the general formula (1) for producing a pharmaceutical for treating and/or preventing cancer
One aspect of the invention relates to a pharmaceutical preparation which comprises a compound of the general formula (1) and at least one further cytostatic or cytotoxic active substance which differs from formula (1), where appropriate in the form of their tautomers, their racemates, their enantiomers, their diastereomers and their mixtures, as well as, where appropriate, their pharmacologically harmless acid addition salts.
®
Case 12-0238 - 8 -
As used herein, the following definitions apply unless otherwise described.
Alkyl substituents are in each case to be understood as being saturated, unsaturated, straight-chain or branched aliphatic hydrocarbon radicals (alkyl radicals) and comprise both saturated alkyl radicals and unsaturated alkenyl and alkynyl radicals. Alkenyl substituents are in each case straight-chain or branched, unsaturated alkyl radicals which possess at least one double bond. Alkynyl substituents are in each case to be understood as being straight-chain or branched, unsaturated alkyl radicals which possess at least one triple bond.
Heteroalkyl represents straight-chain or branched aliphatic hydrocarbon chains which are interrupted by from 1 to 3 heteroatoms, with it being possible for each of the available carbon and nitrogen atoms in the hetercalkyl chain to be optionally substituted, in each case independently of each other, and with the heteroatoms being selected, in each case independently of each other, from the group consisting of O, N and § (e.g. dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl, diethylaminomethyl, diethylamino- bis-2-methoxyethylamino, [2- (dimethylaminoethyl) - ethylamino]methyl, 3-[2-(dimethylaminoethyl)ethyl- aminolpropyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxy- propyl, methoxy, ethoxy, pPropoxy, methoxymethyl and 2-methoxyethyl).
Haloalkyl refers to alkyl radicals in which one or more hydrogen atom(s) has/have been replaced by halogen atoms. Haloalkyl includes both saturated alkyl radicals and unsaturated alkenyl and alkynyl radicals, such as
®
Case 12-0238 - 9 - ~CF3, ~CHF,, ~-CH,F, -CF,CF;, -CHFCF;, -CH,CF5, -CF,CH;, -CHFCH;, -CF.CF,CF;, -CF,CH,CH;, -CF=CF,, -CC1l=CH,, -CBr=CH,;, -CI=CH,, -C=C-CF3;, -CHFCH,CH; and -CHFCH,CF;.
Halogen refers to fluorine, chlorine, bromine and/or iodine atoms.
Cycloalkyl is to be understood as being a monocyclic or bicyclic ring where the ring system can be a saturated ring, or else an unsaturated, nonaromatic ring, which can, where appropriate, also contain double bonds, such as cyclopropyl, cyclopropenyl, cyclobutyl, cyclo- butenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclo- hexenyl, norbornyl and norbornenyl.
Cycloalkylalkyl comprises a noncyclic alkyl group in which a hydrogen atom which is bonded to a carbon atom, usually to a terminal C atom, has been replaced by a cycloalkyl group.
Aryl refers to monocyclic or bicyclic rings having 6-12 carbon atoms, such as phenyl and naphthyl.
Arylalkyl comprises a noncyclic alkyl group in which a hydrogen atom which is bonded to a carbon atom, usually to a terminal C atom, has been replaced by an aryl group. SE
Heteroaryl is to be understood as meaning monocyclic or bicyclic rings which contain one or more, identical or different heteroatoms, such as nitrogen, sulphur or oxygen atoms, in place of one or more carbon atoms.
Those which may be mentioned by way of example are furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl and
®
Case 12-0238 - 10 - triazinyl. Examples of bicyclic heteroaryl radicals are indolyl, isoindolyl, benzofuryl, benzothienyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, indazolyl, isoquinolinyl, quinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl and benzotriazinyl, indolizinyl, oxazolopyridyl, imidazopyridyl, naphthyridinyl, indolinyl, isochromanyl, chromanyl, tetrahydroisoquinolinyl, isoindolinyl, isobenzotetra- hydrofuryl, isobenzotetrahydrothienyl, isobenzothienyl, benzoxazolyl, pyridopyridyl, benzotetrahydrofuryl, benzotetrahydrothienyl, purinyl, benzodioxolyl, triazinyl, phenoxazinyl, phenothiazinyl, pteridinyl, benzothiazolyl, imidazopyridyl, imidazothiazolyl, dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl, dihydrobenzisothiazinyl, benzopyranyl, benzo- thiopyranyl, coumarinyl, isocoumarinyl, chromonyl, chromanonyl, pyridyl-N-oxide tetrahydroquinolinyl, dihydroquinolinyl, dihydroquinolinonyl, dihydroiso- quinolinonyl, dihydrocoumarinyl, dihydroisocoumarinyl, isoindolinonyl, benzodioxanyl, benzoxazolinonyl, pyrrolyl-N-oxide, pyrimidinyl-N-oxide, pyridazinyl-N- oxide, pyrazinyl-N-oxide, quinolinyl-N-oxide, indolyl-
N-oxide, indolinyl-N-oxide, isoquinolyl-N-oxide, quinazolinyl-N-oxide, quinoxalinyl-N-oxide, phthalazinyl-N-oxide, imidazolyl-N-oxide, isoxazolyl- ~~ N-oxide, = oxazolyl-N-oxide, __ thiazolyl-N-oxide, indolizinyl-N-oxide, indazolyl-N-oxide, benzothiazolyl-
N-oxide, benzimidazolyl-N-oxide, pyrrolyl-N-oxide, oxadiazolyl-N-oxide, thiadiazolyl-N-oxide, triazolyl-
N-oxide, tetrazolyl-N-oxide, benzothiopyranyl-S-oxide and benzothiopyranyl-S, S-dioxide.
Heteroarylalkyl comprises a noncyclic alkyl group in which a hydrogen atom which is bonded to a carbon atom, usually to a terminal C atom, has been replaced by a heteroaryl group.
®
Case 12-0238 - 11 -
Heterocycloalkyl refers to saturated or unsaturated, nonaromatic monocyclic, bicyclic or bridged bicyclic rings which comprise 3-12 carbon atoms and which carry heteroatoms, such as nitrogen, oxygen or sulphur, in place of one or more carbon atoms. Examples of these heterocycloalkyl radicals are tetrahydrofuryl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, indolinyl, isocindolinyl, morpholinyl, thiomorpholinyl, homomorpholinyl, homopiperidinyl, homopiperazinyl, homothiomorpholinyl, thiomorpholinyl-S-oxide, thio- morpholinyl-S, S-dioxide, tetrahydropyranyl, tetra- hydrothienyl, homothiomorpholinyl-s, S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridyl, dihydropyrimidinyl, dihydrofuryl, dihydropyranyl, tetrahydrothienyl-S- oxide, tetrahydrothienyl-S, s-dioxide, homothio- morpholinyl-S-oxide, 2-oxa-5-azabicyclo[2.2.1l]heptane, 8-oxa-3-azabicyclo[3.2.1]octane, 3,8-diazabicyclo- [3.2.1])octane, 2,5-diazabicyclo[2.2.1]heptane, 3,8-diazabicyclo(3.2.1]octane, 3,9-diazabicyclo{4.2.1]- nonane and 2,6-diazabicyclo(3.2.2])nonane.
Heterocycloalkylalkyl refers to a noncyclic alkyl group in which a hydrogen atom which is bonded to a carbon ~~ atom usually to a terminal C atom, has been replaced _ by a heterocycloalkyl group.
The following examples illustrate the present invention without, however, limiting its scope.
Synthesizing the reagents
R-1) cis-1-Methylamino-4-(pyrrolidin-1-yl)cyclohexane
LH,
Om
Case 12-0238 - 12 -
R-1a) tert-Butyl cis-4-(pyrrolidin-1-yl)cyclohexane- carbamate 0)
Yq =i 25 mg of potassium hydrogen carbonate are added to a solution of tert-butyl cis-4-aminocyclohexanecarbamate (10 g, 46 mmol) and 1,4-dibromobutane (12.1 g, 56 mmol) in 400 ml of DMF, and the mixture is stirred at RT for 24 h. The reaction mixture is then evaporated and the residue is taken up in diethyl ether: this solution is washed with water. The organic phase is dried and evaporated in vacuo. Yield: 12 g.
R-1Db) tert-Butyl N-methyl-cis-4-(pyrrolidin-1-yl)- cyclohexanecarbamate
Oo
So
N
=O
R-la (5 g, 18 mmol) is dissolved in 20 ml of
N,N-dimethylacetamide and this solution is added, at 37°C, to a suspension of sodium hydride (60% in liquid paraffin, 0.8 g, 20 mmol) in 20 ml of N,N-dimethyl- acetamide such that the temperature does not exceed 48°C. After the foam formation has come to an end, methyl iodide (2.9 g, 20 mmol) is added and the mixture the reaction mixture and the whole is washed with water. The organic phase is then treated with oxalic acid and washed with ethyl acetate. After that, the mixture is made alkaline with potassium hydrogen carbonate and extracted with ethyl acetate. The organic phases are evaporated and the residue is reacted without further purification. Yield: 1.4 g.
R-1b (1.4 g, 5 mmol) is dissolved in 50 ml of dichloromethane after which 25 ml of trifluoroacetic
®
Case 12-0238 - 13 - acid are added and the whole is stirred at RT for 4 h.
After the reaction mixture has been evaporated, the desired product is precipitated as the dihydrochloride using hydrochloric acid (1 N in diethyl ether).
Yield: 1 g
R-2) trans-1-Amino-4- (8-oxa-3-azabicyclo[3.2.1]oct- 3-yl)cyclohexane
NH, or oO
Triethylamine (21 g, 0.21 mol), benzyl trans-4-amino- cyclohexylcarbamate (24.8 g, 0.1 mol) and a catalytic quantity of DMAP are added consecutively to a solution of 2,5-bis(p-tosyloxymethyl) tetrahydrofuran (44 g, 0.1 mol) in 440 ml of toluene. The reaction mixture is heated under reflux for 6 d. After cooling down, the organic phase is decanted off from the insoluble resin and the residue is purified chromatographically. The : intermediate which is obtained in this way 1s suspended in 300 ml of methanol in an autoclave, after which 37 ml of hydrochloric acid (6 N in isopropanol) and 6 g of palladium on active charcoal are added. The reaction mixture is stirred under a hydrogen atmosphere (50 bar) at RT for 15 h. After filtering through Celite®, the filtrate is evaporated and the residue is taken up in isopropanol) are added to this solution. On cooling, the desired product precipitates as the hydrochloride salt, which is filtered and dried.
R-3) 1-Amino-4- (methylpropylamino) cyclohexane
NH, won {3 \
CH,
®
Case 12-0238 - 14 -
R-3a) tert-Butyl Cis-4-(2,2,2-trifluoroacetylamino)- cyclohexanecarbamate
H o N.__O
SY T
F°LH <
A solution of tert-butyl cis-4-aminocyclohexane- carbamate (22.1 g, 103 mmol) and methyl trifluoro- acetate (11 ml, 110 mmol) in 110 ml of methanol is stirred at RT for 4 h. After the reaction mixture has been cooled down to 0°C, the precipitate is filtered off, washed with diethyl ether and dried.
Yield: 17.6 g.
R-3b) tert-Butyl cis-4-methyl-(2,2,2-trifluoroacetyl)- aminocyclohexanecarbamate
H o N.__O
SALTY
SE
Sodium hydride (60% in liquid paraffin, 1.3 g, 32 mmol) is added, at RT and under a nitrogen atmosphere, to a suspension of R-3a (8.3 g, 27 mmol) in 100 ml of
N,N-dimethylacetamide. After 20 min, methyl iodide (4.5 g, 32 mmol) is added and the mixture is stirred at
RT for 15 h. Following hydrolysis with 800 ml of ice water, the precipitate is filtered off and washed with water and petroleum ether. The residue is recrystallized from 200 ml of diisopropyl ether to —————————Wwhich—318-mt—of acetonitrile have been added.
Yield: 11 g.
R-3c) tert-Butyl cis-4-methylaminocyclohexanecarbamate
Np
AT “<
In order to eliminate the trifluoroacetate group, 117 ml of sodium hydroxide solution (2 N) are added to
R-3b (39.7 g, 123 mmol) in 536 ml of methanol and the mixture is stirred at RT for 5 h. The reaction mixture is evaporated and the residue is extracted by shaking
Claims (16)
1.) Compounds of the general formula (1), R3 N 13x N 1 ~~ Ri S N (1) R2 in which R' is selected from the group consisting of -NHRS, -NHC(O)R®, -NHC(O)OR®, -NHC(O)NR°R®¢ and -NHC (0) SR; R®’ is a radical which is optionally substituted by one or more R* and which is selected from the group consisting of C;_salkyl, Ci gcycloalkyl, 3-8-membered heterocycloalkyl, C¢-1caryl, Cso1sarylalkyl and 5-10- membered hetercaryl; R’ is a radical which is optionally substituted by one or more R® and/or Rf and is selected from the group consisting of Cs.;paryl and 5-10-membered heteroaryl; R* is a radical selected from the group consisting of R*, R° and R® which is substituted by one or more, identical or different, RS andfor Rp — 0000 each R® is, independently of each other, selected from the group «consisting of CC. 4alkyl, Ca_gcycloalkyl,
C4.1:cycloalkylalkyl, Cs-10aryl, Cs.:sarylalkyl, 2-6- membered heteroalkyl, 3-8-membered heterocycloalkyl, 4-14-membered heterocycloalkylalkyl, 5-10-membered heteroaryl and 6-l6-membered heteroarylalkyl; each R” is a suitable radical and in each case selected, independently of each other, from the group
2 0e7 sores ® Case 12-0238 - 129 - consisting of =0, -OR®, CC. shaloalkyloxy, -OCF,, =8, -SR®, =NR®, =NOR®, -NR°R®, halogen, -CF3, -CN, -NC, -OCN, -SCN, -NO, -NO;, =N;, -N3, -S(O)R®, -S(O):R%, -S{0):0RS, -S(O)NR°R®, -S(0),;NR°R®, -0S(O)RS, -0S(0),RS, -0S(0),0RS, -0S(0):NR°R, -C (0) RS, -C(O)ORS, -C (O)NRRS, -C(O)N(R)NRR®, -C(O)N(RY)OR®, -CN(RY)NR°R®, ~OC(O)RS, -OC (0) ORS, -0C (0) NR°R®, -OCN (RY) NRRS, -N(R%)C(O)RS, -N(R?)C(O)RS, -N(R?)C(S)R", -N(R?) S(O) RF, ~-N(R®) S(O) NR°R®, -N[S(0)212R", -N(R%)C (0) ORS, -N(RY)C(O)NRR, and -N(R?)CN (RY)NR°R‘; each R® is, independently of each other, hydrogen or a radical which is optionally substituted by one or more, identical or different, R® and/or R® and which is selected from the group consisting of C;¢alkyl,
Ci.gcycloalkyl, C4-11cycloalkylalkyl, Ce-10aryl, Cro1earylalkyl, 2-6-membered heteroalkyl, 3-8-membered heterocycloalkyl, 4-l4-membered heterocycloalkylalkyl, 5-10-membered heteroaryl and 6-16-membered heterocarylalkyl, each R® is, independently of each other, hydrogen or a radical which is optionally substituted by one or more, identical or different, R® and/or RY and which is selected from the group «consisting of CC; alkyl,
Cy.gcycloalkyl, C4-1:cycloalkylalkyl, Cs-1caryl, - Chugarylalkyl, 2-6-membered hetercalkyl,— 3-8-membered— heterocyclecalkyl, 4-1l4-membered heterocycloalkylalkyl, 5-10-membered heteroaryl and 6-16-membered heterocarylalkyl, each R® 1s a suitable radical and in each case selected, independently of each other, from the group consisting of =0, -OR®, C.shaloalkyloxy, -OCF,, =S, -SR°, =NR’, =NOR’, -NR'Rf, halogen, -CF3, -CN, -NC, -OCN, -SCN, -NO, -NO;, =N;, -N;, -S(O)R°, -S(0):R*, -S(0).OR, -S(O)NR'Rf, -S(0).NR‘R®, -0S(0)R’, -0S(0):Rf, -0S(0);ORf,
® Case 12-0238 - 130 - -0S(0):NR'R’, -C(O)Rf, -C(O)ORf, -C{O)NR'R®, -CN(R%)NR'R%, -0C (0) RY, ~0C (0) OR*, -0C (0) NR'R", -OCN (R%) NR'R®, -N(R%)C(0)R", -N(RY)C(S)R®, -N(R%)S(O):Rf, -N(R®)C(0O)ORF, -N(R%)C(0)NR'Rf, and -N(RY)CN(R®)NR'R®; each R® is, independently of each other, hydrogen or a radical which is optionally substituted by one or more, identical or different, RY and is selected from the group consisting of Ci-salkyl, Cs.gcycloalkyl, Ci-11cycloalkylalkyl, Ce-10aryl, Ci1sarylalkyl, 2-6- membered heteroalkyl, 3-8-membered heterocycloalkyl, 4-14-membered heterocycloalkylalkyl, 5-10-membered heteroaryl and 6-l6-membered heterocarylalkyl, each R? is, independently of each other, hydrogen, C; salkyl, Ci.gcycloalkyl, C4.;icycloalkylalkyl, Ce_iparyl, Croied@rylalkyl, 2-6-membered heteroalkyl, 3-8-membered heterocycloalkyl, 4-l4-membered heterocycloalkylalkyl, 5-10-membered heteroaryl and 6-16-membered heteroarylalkyl, where appropriate in the form of their tautomers, their racemates, their enantiomers, their diastereomers and their mixtures, as well as, where appropriate, their pharmacologically harmless acid addition salts.
2.) Compounds according to Claim 1, wherein R® is a —_— radical selected from the group consisting of phenyl furyl, pyridyl, pyrimidinyl and pyrazinyl, optionally substituted by one or more R*.
3.) Compounds according to Claim 2, wherein R® is pyridyl.
4.) Compounds according to Claims 1 to 3, wherein R® is -NHC (O) RR".
5.) Compounds according to Claim 4, wherein R' is
@ Case 12-0238 - 131 - ~NHC (0) CH; .
6.) Compounds of the formula (A) Oo N/E i LL ; H S Y~g y 0 0 wherein X is -CH;, -OR! or -SR® and Y is phenyl, 5-10-membered heteroaryl or the group -C(0)0, and R’ is hydrogen, -NO, or C. alkyl and R' is defined as in claim 1..
7.) Compounds according to Claim 6, wherein R* is -Ci-salkyl.
8.) Compounds of the general formula (A) according to Claim 6 or 7 for use as synthesis intermediates.
9.) Compounds, or their pharmaceutically active salts, according to Claims 1 to 5 as pharmaceuticals.
10.) Compounds, or their pharmaceutically active salts, according to Claims 1 to 5 for producing a = pharmaceutical -having an antiproliferative effeet — — —
11.) Pharmaceutical preparations which comprise, as active compound, one or more compounds of the general formula (1) according to one of Claims 1 to 5, or their physiologically tolerated salts, where appropriate in combination with customary auxiliary substances and/or carrier substances.
12.) Use of compounds of the general formula (1) according to one of Claims 1 to 5 for producing a
[ Case 12-0238 - 132 - pharmaceutical for treating and/or preventing cancer.
13.) Pharmaceutical preparation which comprises a compound of the general formula (1) according to one of Claims 1 to 5 and at least one further cytostatic or cytotoxic active substance which differs from formula (1), where appropriate in the form of their tautomers, their racemates, their enantiomers, their diastereomers and their mixtures, as well as, where appropriate, their pharmacologically harmless acid addition salts. {
W02006/040281 PCT/EP2005/055021 -132a-
14.) Compounds according to any one of claims 1, or 8-10, substantially as herein described and exemplified.
15.) Pharmaceutical preparations according to claim 11 or 13, substantially as herein described and exemplified.
16.) Use according to claim 12, substantially as herein described and exemplified. AMENDED SHEET
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE102004048877A DE102004048877A1 (en) | 2004-10-07 | 2004-10-07 | New tricyclic thiazole derivatives useful as PI3 kinase inhibitors, for treating e.g. inflammatory and allergic airway and skin diseases, autoimmune and kidney disease |
Publications (1)
Publication Number | Publication Date |
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ZA200701653B true ZA200701653B (en) | 2008-07-30 |
Family
ID=36088804
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
ZA200701470A ZA200701470B (en) | 2004-10-07 | 2007-02-20 | PI3 kinases |
ZA200701653A ZA200701653B (en) | 2004-10-07 | 2007-02-26 | Thiazolyl-dihydro indazoles |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
ZA200701470A ZA200701470B (en) | 2004-10-07 | 2007-02-20 | PI3 kinases |
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---|---|
DE (1) | DE102004048877A1 (en) |
ZA (2) | ZA200701470B (en) |
Families Citing this family (5)
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WO2007113245A1 (en) | 2006-04-06 | 2007-10-11 | Boehringer Ingelheim International Gmbh | Thiazolyl dihydro-indazoles |
UY31700A (en) * | 2008-03-13 | 2009-11-10 | Boehringer Ingelheim Int | TIAZOLIL-DIHIDRO-INDAZOLES |
CA2766853A1 (en) | 2009-07-02 | 2011-01-06 | Novartis Ag | 2-carboxamide cycloamino ureas useful as pi3k inhibitors |
TW202043205A (en) | 2018-12-31 | 2020-12-01 | 美商拜歐米富士恩有限公司 | Inhibitors of menin-mll interaction |
SG11202106304RA (en) | 2018-12-31 | 2021-07-29 | Biomea Fusion Llc | Irreversible inhibitors of menin-mll interaction |
-
2004
- 2004-10-07 DE DE102004048877A patent/DE102004048877A1/en not_active Withdrawn
-
2007
- 2007-02-20 ZA ZA200701470A patent/ZA200701470B/en unknown
- 2007-02-26 ZA ZA200701653A patent/ZA200701653B/en unknown
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ZA200701470B (en) | 2009-05-27 |
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