®
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.
Background to the inventionThe 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).
Detailed description of the inventionIt 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 -
DEFINITIONSAs 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