CN116547280A - Benzo [ h ] quinazolin-4-amine and thieno [3,2-h ] quinazolin-4-amine derivatives for the treatment of cancer - Google Patents
Benzo [ h ] quinazolin-4-amine and thieno [3,2-h ] quinazolin-4-amine derivatives for the treatment of cancer Download PDFInfo
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- CN116547280A CN116547280A CN202180082479.6A CN202180082479A CN116547280A CN 116547280 A CN116547280 A CN 116547280A CN 202180082479 A CN202180082479 A CN 202180082479A CN 116547280 A CN116547280 A CN 116547280A
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Abstract
The present invention provides compounds having formula (IA) and compounds having formula (IB) and pharmaceutically acceptable salts thereof; wherein A is selected from the group (A1) and the group (A2): wherein #1 is attached to a carbon atom forming an oxime moiety, and wherein group (A1) is optionally substituted with one or two R10 and group (A2) is optionally substituted with one R10, and wherein R1, X, R2 and R10 are as definedAs defined in the claims, and methods of using the compounds in the treatment of neoplastic diseases, particularly cancer.
Description
The present invention relates to compounds targeting the CDC 2-like kinase (CLK) family and their use in the treatment of neoplastic diseases such as cancer.
Frequent mutations in splice machinery elements have been reported in diseases such as cancer. CLK belongs to the CMGC kinase group and includes four family members: CLK1, CLK2, CLK3, and CLK4. CLK is known to play a key role in regulating Alternative Splicing (AS) through phosphorylation of splicing factors rich in the serine-arginine (SR) family. Alternative splicing of transcripts is an important regulatory mechanism in eukaryotes that allows a single gene to produce multiple protein isoforms with different functions. CLK mediated phosphorylation of SR proteins is associated with their redistribution from speckle to diffuse nuclear matrix distribution patterns (Colwill et al, EMBO J. [ J. European molecular biology) 1996,15 (2): 265-75). Phosphorylation of SR proteins must be tightly regulated to achieve nuclear import, assembly of the spliceosome, and ultimately correct splicing, particularly to promote exon inclusion. Increased expression levels of CLK have been reported in a variety of cancers, and small molecule inhibitors of CLK have been described as effective in preclinical animal models of Cancer (Yoshida T et al, cancer Res. [ Cancer research ]2015,75 (7): 1516-26; iwai K et al, EMBO Mol Med [ European molecular biology institute molecular medicine ].2018 10 (6): e8289; zhu D et al, mol Cancer Ther. [ molecular Cancer therapeutics ]2018,17 (8): 1727-1738). Thus, targeting CLK offers potential for anti-cancer therapies, for example in splicing factor mutant cancers, where there is a convincing theory that aberrant splicing can be exploited as a leak and treatment opportunity.
In a first aspect, the present invention provides compounds having the formula (IA) and formula (IB)
And pharmaceutically acceptable salts thereof; wherein the method comprises the steps of
A is selected from the group (A1) and the group (A2):
wherein #1 is attached to a carbon atom forming an oxime moiety, and wherein group (A1) is optionally substituted with one or two R10 and group (A2) is optionally substituted with one R10;
each R10 is independently halogen or-NH 2 ；
X is-O-, -C (=O) -, -C (=CH) 2 )-、-CH 2 -, -NH-or-N (C1-C4 alkyl) -,
and wherein when R2 is halogen or-CN, X is a bond, and wherein when X is-C (=o) -R2 is not hydrogen;
or X-R2 is hydrogen;
ra and Rb together form-CH 2 -CH 2 -CH 2 -or-CH 2 -CH 2 -CH 2 -CH 2 -a bridging portion;
r1 is-Y-R3;
y is a bond or C1-C6 alkylene, one of which is not terminal-CH 2 -part may be replaced by-O-;
r3 is hydrogen, -CN, -OH, C1-C4 haloalkyl, C2-C4 alkenylene-R4C 2-C4 alkynylene-R4, -O-C1-C4 alkylene-R4, -O-C1-C4 haloalkyl, -NH 2 -NH (C1-C4 alkylene-R4), -N (C1-C4 alkylene-R4) 2 、-C (=o) -OH, -C (=o) -O-C1-C4 alkylene-R4, -C (=o) -NH 2 -C (=o) -NH (C1-C4 alkylene-R4), -C (=o) -N (C1-C4 alkylene-R4) 2 Ring P, ring Q, -O-ring P, -O-ring Q or-S (O) 2 ) -C1-C4 alkyl;
r4 is hydrogen, -NH 2 -NH (C1-C2 alkyl) or-N (C1-C2 alkyl) 2 ；
Ring P is a 5-6 membered saturated or partially unsaturated carbocyclic ring optionally substituted with one to three R5, or a 5-6 membered saturated or partially unsaturated heterocyclic ring containing one to two heteroatoms selected from N and O optionally substituted with one to three R5;
each R5 is independently-NH 2 -OH, -CN, C1-C4 alkyl (e.g. C1-C2 alkyl), C1-C4 alkylene-R11 (e.g. C1-C2 alkylene-R11), -O-C1-C2 alkyl or oxo;
each R11 is independently halogen, -NH 2 -OH, -CN or-O-C1-C2 alkyl;
ring Q is phenyl optionally substituted with one to three R6, or is 5-6 membered heteroaryl optionally substituted with one to three R6 containing one to two heteroatoms selected from N, S and O;
each R6 is independently-NH 2 -OH, -CN, C1-C2 alkyl or-O-C1-C2 alkyl;
r2 is hydrogen, halogen, -CN, C1-C4 alkyl optionally substituted by one or two R7, or a 4-to 7-membered saturated carbocyclic ring optionally substituted by one or two R8, or a 4-to 7-membered saturated heterocyclic ring containing one-N (R9) -moiety as ring member and additionally containing only carbon atoms as ring members;
each R7 is independently-OH, halogen, -NH 2 -NH (C1-C2 alkyl), -N (C1-C2 alkyl) 2 or-NH (-C (=o) -C1-C2 alkyl);
each R8 is independently-OH, halogen, -NH 2 -NH (C1-C2 alkyl), -N (C1-C2 alkyl) 2 -NH (-C (=o) -C1-C2 alkyl) or C1-C2 alkyl; and is also provided with
R9 is hydrogen, C1-C4 alkyl or-C (=O) -C1-C2 alkyl.
In another aspect, the present invention provides compounds having formula (IA) and compounds having formula (IB) and pharmaceutically acceptable salts thereof, for use in treating a neoplastic disease in a subject selected from the group consisting of mammals, particularly humans.
In a further aspect, the present invention provides the use of a compound of formula (IA) and a compound of formula (IB) and pharmaceutically acceptable salts thereof in the manufacture of a medicament for the treatment of a neoplastic disease in a subject selected from the group consisting of mammals, particularly humans.
In another aspect, the invention provides a method of treating a neoplastic disease in a subject selected from a mammal, particularly a human, the method comprising administering to the subject, for example, a therapeutically acceptable amount of a compound of formula (IA) or a compound of formula (IB) or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention provides a pharmaceutical composition comprising a compound having formula (IA) or a compound having formula (IB) or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients.
Each alkyl moiety, alone or as part of a larger group such as an alkoxy group, is linear or branched. Examples include methyl, ethyl, n-propyl, propan-2-yl, n-butyl, butan-2-yl, 2-methyl-propan-1-yl or 2-methyl-propan-2-yl.
Each alkylene moiety alone or as part of a larger group is linear or branched and is, for example, -CH 2 -、-CH 2 -CH 2 -、-CH(CH 3 )-、-CH 2 -CH 2 -CH 2 -、-CH(CH 3 )-CH 2 -、-CH(CH 2 CH 3 ) -or-CH 2 CH(CH 3 )CH 2 -。
Each alkenyl moiety, alone or as part of a larger group such as an alkenyloxy group, is linear or branched. Each moiety may be in the (E) -configuration or the (Z) -configuration. Examples include vinyl and allyl.
Each alkenylene moiety alone or as part of a larger group, e.g. alkenyloxy, is linear or branched and is, for example, -CH 2 -ch=ch-. Each part may be (E)-configuration or (Z) -configuration.
Each alkynyl moiety, alone or as part of a larger group such as alkynyloxy, is straight or branched and is preferably a C2-C4 alkynyl. Examples are ethynyl and propargyl.
Each alkynylene moiety alone or as part of a larger group is linear or branched and is, for example, -CH 2 -C≡C-。
Each haloalkyl moiety, alone or as part of a larger group such as haloalkoxy, is an alkyl group substituted with one or more halogen atoms, which may be the same or different. Examples include difluoromethyl, trifluoromethyl, chlorodifluoromethyl and 2, 2-trifluoroethyl. The haloalkyl moiety includes, for example, 1 to 5 halo substituents or 1 to 3 halo substituents.
Each cycloalkyl moiety (also referred to as a carbocycle moiety) may be saturated or partially unsaturated (unless otherwise indicated) and may be in a monocyclic or bicyclic form, preferably in a monocyclic form. Examples of monocyclic cycloalkyl groups include cyclobutyl, cyclopentyl and cyclohexyl. An example of a bicyclocycloalkyl group is bicyclo [2.2.1] hept-2-yl.
Halogen is fluorine, chlorine, bromine or iodine.
Heteroaryl means an aromatic ring system containing the stated number of heteroatoms selected from nitrogen, oxygen and sulfur as ring members. Heteroaryl rings do not contain adjacent oxygen atoms, adjacent sulfur atoms, or adjacent oxygen and sulfur atoms within the ring, or together with atoms that connect the ring and other parts of the molecule outside the ring.
The term "heterocycle" refers to a saturated or partially unsaturated carbocyclic ring (unless otherwise specified) that additionally contains the stated number of heteroatoms selected from nitrogen, oxygen and sulfur as ring members. Such rings do not contain adjacent oxygen atoms, adjacent sulfur atoms, or adjacent oxygen and sulfur atoms within the ring, or together with atoms that connect the ring and other parts of the molecule outside the ring.
Oxo is an =o group. When a moiety is said to be "substituted with oxo", it is considered to be substituted with one substituent, for example when ring P may be substituted with one to three R5 and R5 may be oxo, ring P may be substituted with oxo and two additional R5 groups.
When a group is said to be optionally substituted, it may be unsubstituted or substituted with the indicated number of substituents.
When a ring nomenclature is provided for a particular moiety, it is applied to assume that there are no substituents on the ring. For example, piperidin-1-yl places the nitrogen atom at the attachment point, independent of the identity of any substituents that may be present on the piperidine moiety.
The compounds of the invention include all (E) and (Z) isomers and mixtures thereof in any ratio. In particular, the oxime moiety may be in the (E) or (Z) configuration, which yields the following isomers:
both the (Z) and (E) isomers are included within the scope of the compounds of formula (IA) and the compounds of formula (IB), with Z isomers being preferred. Also, where cis and trans isomers are possible, for example when R2 is cyclohex-4-ylamine, both cis and trans isomers are included within the scope of formulas (IA) and (IB). Whenever a compound of formula (IA) or a compound of formula (IB) contains one or two or more chiral centers (e.g. when Y is a branched alkylene), such compounds may be provided as pure enantiomers or pure diastereomers and mixtures thereof in any ratio, and all such isomers are included within the scope of compounds of formula (IA) and compounds of formula (IB). Such compounds of the invention also include all tautomeric forms of the compounds of formula (IA) and of the compounds of formula (IB), wherein such possibilities exist, for example, when the saturated ring is substituted with oxo. Isotopically-labeled compounds (including deuterium substitution and carbon-13 and/or carbon-14 labeling) are also included within the scope of compounds having formula (IA) and compounds having formula (IB).
The compounds of formula (IA) and compounds of formula (IB) may also be solvated, in particular hydrated, which is also included in the compounds of formula (IA) and compounds of formula (IB). Solvation and hydration may occur during the preparation process. References to the compounds of the present invention include pharmaceutically acceptable salts of the compounds. Such salts may also exist as hydrates and solvates. Examples of pharmacologically acceptable salts of the compounds having formula (IA) and of the compounds having formula (IB) are salts of physiologically acceptable inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid, or salts of organic acids such as methanesulfonic acid, p-toluenesulfonic acid, lactic acid, formic acid, acetic acid, trifluoroacetic acid, citric acid, succinic acid, fumaric acid, maleic acid and salicylic acid. Other examples of compounds of formula (IA) and pharmacologically acceptable salts of compounds of formula (IB) are alkali metal and alkaline earth metal salts, such as, for example, sodium, potassium, lithium, calcium or magnesium salts; ammonium salts or salts of organic bases, such as, for example, methylamine, dimethylamine, triethylamine, piperidine, ethylenediamine, lysine, choline hydroxide, meglumine, morpholine or arginine salts.
Examples of substituent definitions below and embodiments may be combined in any combination where possible.
A is selected from the group consisting of group (A1) and group (A2), wherein #1 is attached to a carbon atom forming an oxime moiety, wherein group (A1) is optionally substituted with one or two R10 and group (A2) is optionally substituted with one R10. The carbon atom forming the oxime moiety is the carbon atom described as "C" in the unit > C (=n-O-R1).
Preferably, a is selected from the group (A1) optionally substituted with one R10, and the group (A2) which is unsubstituted.
More preferably, a is a group (A1) optionally substituted with one R10.
Preferably, when a is the group (A1), X is attached to a carbon atom located in para position relative to #2, i.e. in the position described in the compounds of formula (IAa and IBa) below.
Preferably, when a is a group (A2), X is attached to a carbon atom adjacent to the S atom, i.e. in the position described in the compound of formula (IAb) below.
Each R10 is independently halogen or-NH 2 。
Preferably, each R10 is independently fluorine, chlorine or-NH 2 More preferred are chlorine or-NH 2 。
Specific examples of R10 are fluorine, chlorine and-NH 2 。
X is-O-, -C (=O) -, -C (=CH) 2 )-、-CH 2 -, -NH-or-N (C1-C4 alkyl) -, and wherein when R2 is halogen or-CN, X is a bond, and wherein when X is-C (=o) -R2 is not hydrogen; or X-R2 is hydrogen.
Specific examples of X are-O-, -C (=o) -, -C (=ch 2 )-、-CH 2 -, -NH-and-N (CH) 3 ) - (and X is a bond when R2 is halogen such as chlorine, bromine or iodine or-CN).
Ra and Rb together form-CH 2 -CH 2 -CH 2 -or-CH 2 -CH 2 -CH 2 -CH 2 -a bridging portion.
Preferably, ra and Rb together form-CH 2 -CH 2 -CH 2 -CH 2 A bridging moiety, i.e. producing a five membered fused carbocyclic ring as described in formula (IBa) below.
R1 is-Y-R3.
Preferably, R1 is hydrogen, C1-C6 alkylene-R3, one of which is not terminal-CH 2 Part may be replaced by-O-, or R1 is a ring P. Mention of "non-terminal-CH 2 Moiety "means-CH not at either end of the alkylene moiety 2 A moiety (i.e. not the proximal end relative to the oxime moiety-CH 2 -part, not the distal end relative to the oxime part, -CH 2 -part).
More preferably, R1 is hydrogen or C1-C6 alkylene-R3.
Even more preferably, R1 is hydrogen or C1-C6 alkylene-R3, wherein there are no more than three carbon atom spacers between the oxime oxygen atom and R3. In other more preferred embodiments, R1 may be C1-C3 alkylene-R3.
Specific examples of R1 are hydrogen, -CH 3 、-CH(CH 3 )CH 3 、-CH 2 CH(CH 3 )CH 3 、-CH 2 CH＝CH 2 、-CH 2 C≡CH、-CH 2 CH 2 CH 2 CN、-CH 2 CH 2 CH 2 N(CH 2 CH 3 )CH 2 CH 3 、-CH 2 CH 2 CH 2 O-benzyl, -CH 2 CH(CH 3 )OH、-CH 2 CH 2 CH 2 OH、-CH 2 CH 2 NH 2 、-CH 2 CH 2 CH 2 NH 2 、-CH 2 CH 2 C(＝O)OCH 2 CH 3 、-CH 2 CH 2 C(＝O)OCH 3 、-CH 2 CH 2 N(CH 2 CH 3 )CH 2 CH 3 、-CH 2 CH 2 N(CH 3 )CH 3 、-CH 2 CH 2 OH、-CH 2 CH 2 OCH 3 、-CH 2 CH 3 、-CH 2 CN、-CH 2 CH 2 CN、-CH 2 C(＝O)NH 2 、-CH 2 C(＝O)NHCH 3 、-CH 2 C(＝O)NHCH 2 CH 2 NH 2 、-CH 2 C(＝O)OH、-CH 2 C(＝O)OCH 3 4-aminocyclohexyl, -CH 2 CH 2 Piperidinyl (e.g. -CH 2 CH 2 -piperidin-1-yl), -CH 2 CH 2 Pyrrolidinyl (e.g. -CH 2 CH 2 -pyrrolidin-1-yl), 4-cyanobenzyl, benzyl, -CH 2 -3, 5-dimethyl-isoxazolyl (e.g. -CH 2 -3, 5-dimethyl-isoxazol-4-yl), -CH 2 -4-aminocyclohexyl, -CH 2 Oxazolidin-2-ones (e.g. -CH 2 -oxazolidin-5-yl-2-one), -CH 2 -N-methyl-oxazolidin-2-ones, e.g. (-CH) 2 -N-methyl-oxazolidin-5-yl-2-one), -CH 2 -N- (1-hydroxyethyl-2-yl) -oxazolidin-2-one (e.g. -CH) 2 -N- (1-hydroxyethyl-2-yl) -oxazolidin-5-yl-2-one), -CH 2 -N- (1-methoxyethyl-2-yl) -oxazolidin-2-one (e.g. -CH 2 -N- (1-methoxyethyl-2-yl) -oxazolidin-5-yl-2-one), -CH 2 -N-methyl-pyrrolidinyl (e.g. -CH 2 -N-methyl-pyrrolidin-3-yl), -CH 2 -N-methyl-pyrrolidin-2-one (e.g. -CH 2 -N-Methyl-pyrrolidin-4-yl-2-one), -CH 2 Pyrrolidinyl (e.g. -CH 2 -pyrrolidin-3-yl), -CH 2 Pyrrolidinyl-2-ones (e.g. -CH 2 -pyrrolidin-4-yl-2-one), -CH 2 CH 2 OCF 3 、-CH 2 CH 2 CF 3 、-CH 2 CH 2 -phenyl, -CH 2 CH 2 O-phenyl, -CH 2 CH 2 CH 2 Pyridyl (e.g. -CH 2 CH 2 CH 2 -pyridin-3-yl), -CH 2 CH 2 OCH 2 CH 3 、-CH 2 CH 2 CH 2 S(O 2 )CH 3 、-CH 2 CH 2 C(CH 3 ) 2 CN、-CH 2 CH 2 OCH 2 CF 3 、-CH 2 CH 2 CF 2 CH 3 、-CH 2 CH 2 CH 2 CH 2 F and-CH 2 CH 2 CH 2 CF 3 。
In general, it is preferred that at least two carbon spacer units (e.g. -CH) be present between the oxime oxygen atom and any oxygen atom present in R1 2 CH 2 -)。
Y is a bond or C1-C6 alkylene, one of which is not terminal-CH 2 Part may be replaced by-O-. Mention of "non-terminal-CH 2 Moiety "means-CH not at either end of the alkylene moiety 2 A moiety (i.e. not the proximal end relative to the oxime moiety-CH 2 -part, not the distal end relative to the oxime part, -CH 2 -part).
Preferably, Y is a bond or a C1-C6 alkylene group, more preferably Y is a bond or a C1-C6 alkylene group, wherein there are no more than three carbon atom spacers between the oxime oxygen atom and R3. In other preferred embodiments, Y is a C1-C3 alkylene group.
Specific examples of Y are bond, -CH 2 -、-CH 2 CH 2 -、-CH 2 CH 2 CH 2 -、-CH(CH 3 )CH 2 -、-CH 2 CH(CH 3 )-、-CH 2 CH(CH 3 )CH 2 -、-CH 2 CH 2 C(CH 3 )(CH 3 )-、-CH 2 CH 2 OCH 2 -、-CH 2 CH 2 OCH 2 CH 2 -and-CH 2 CH 2 CH 2 OCH 2 -。
R3 is hydrogen, -CN, -OH, C1-C4 haloalkyl, C2-C4 alkenylene-R4C 2-C4 alkynylene-R4, -O-C1-C4 alkylene-R4, -O-C1-C4 haloalkyl, -NH 2 -NH (C1-C4 alkylene-R4), -N (C1-C4 alkylene-R4) 2 -C (=o) -OH, -C (=o) -O-C1-C4 alkylene-R4, -C (=o) -NH 2 -C (=o) -NH (C1-C4 alkylene-R4), -C (=o) -N (C1-C4 alkylene-R4) 2 Ring P, ring Q, -O-ring P, -O-ring Q or-S (O) 2 ) -C1-C4 alkyl.
It is preferred that the composition of the present invention, R3 is hydrogen, -CN, -OH, C1-C4 haloalkyl, C2-C4 alkenyl C2-C4 alkynyl, -O-C1-C4 alkyl, -O-C1-C4 haloalkyl, -NH 2 -C (=o) -OH, -C (=o) -O-C1-C4 alkyl, -C (=o) -NH 2 -C (=o) -NH (C1-C4 alkylene-R4), ring P, ring Q, -O-ring P, -O-ring Q or-S (O) 2 ) -C1-C4 alkyl.
It is more preferable that the method further comprises the steps of, R3 is hydrogen, -CN, -OH, C1-C4 haloalkyl, -O-C1-C4 alkyl, -O-C1-C4 haloalkyl, -C2-C4 alkynyl, -C (=O) -OH, -C (=O) -O-C1-C4 alkyl, -C (=O) -NH 2 -C (=o) -NH (C1-C4 alkyl), phenyl, or oxazolidin-2-one optionally substituted with one R5 (e.g. oxazolidin-5-yl-2-one) (e.g. substituted with one methyl (e.g. N-methyl-oxazolidin-5-yl-2-one), by one-CH 2 CH 2 OH substitution (e.g. N- (1-hydroxyethyl-2-yl) -oxazolidin-5-yl-2-one) or by a-CH 2 CH 2 OCH 3 Substituted (e.g., N- (1-methoxyethyl-2-yl) -oxazolidin-5-yl-2-one)).
Preferably, when Y is a bond, R3 is hydrogen or a ring P.
Specific examples of R3 are hydrogen, -CN, -OH, -NH 2 、-CH＝CH 2 、-C≡CH、-N(CH 2 CH 3 ) 2 、-N(CH 3 )CH 3 、-OCH 3 、-C(＝O)NHCH 2 CH 2 NH 2 、-C(＝O)NH 2 、-C(＝O)NHCH 3 、-C(＝O)OCH 2 CH 3 、-C(＝O)OH、-C(＝O)OCH 3 4-amino-cyclohexyl, piperidinyl (e.g., piperidin-1-yl), pyrrolidinyl (e.g., pyrrolidin-1-yl, pyrrolidin-3-yl), N-methylpyrrolidinyl (e.g., N-methylpyrrolidin-3-yl), pyrrolidin-2-one (e.g., pyrrolidin-4-yl-2-one), N-methyl-pyrrolidin-2-one (e.g., N-methylpyrrolidin-4-yl-2-one), 3, 5-dimethyl-isoxazolyl (e.g., 3, 5-dimethyl-isoxazol-4-yl), and oxazolidin-2-ones (e.g. oxazolidin-5-yl-2-one), oxazolidin-2-ones substituted with one methyl group (e.g. N-methyl-oxazolidin-5-yl-2-one), N- (1-methoxyethyl-2-yl) -oxazolidin-2-ones (e.g. N- (1-methoxyethyl-2-yl) -oxazolidin-5-yl-2-one), N- (1-hydroxyethyl-2-yl) -oxazolidin-2-ones (e.g. N- (1-hydroxyethyl-2-yl) -oxazolidin-5-yl-2-one), and, 4-CN-phenyl, -OCF 3 、-CF 3 -O-phenyl, -pyridinyl (e.g. pyridin-3-yl), -OCH 2 CH 3 、-S(O) 2 CH 3 、-OCH 2 CF 3 、-CF 2 CH 3 、CH 2 F。
R4 is hydrogen, -NH 2 -NH (C1-C2 alkyl) or-N (C1-C2 alkyl) 2 。
Preferably, R4 is hydrogen, -NH 2 or-NH (CH) 3 )。
Specific examples of R4 are hydrogen and-NH 2 。
Ring P is a 5-6 membered saturated or partially unsaturated carbocyclic ring optionally substituted with one to three R5, or a 5-6 membered saturated or partially unsaturated heterocyclic ring containing one to two heteroatoms selected from N and O, optionally substituted with one to three R5.
Preferably, ring P is a 6 membered saturated carbocyclic ring optionally substituted with one to two R5, or a 5 membered saturated heterocyclic ring containing one to two heteroatoms selected from N and O optionally substituted with one to two R5.
More preferably, ring P is an oxazolidinyl optionally substituted with one or two R5, especially oxazolidinyl-2-one optionally substituted with one R5, preferably wherein R5 is not oxo.
Specific examples of the ring P are aminocyclohexyl (e.g. 4-amino-cyclohexyl), piperidinyl (e.g. piperidin-1-yl), pyrrolidinyl (e.g. pyrrolidin-1-yl, pyrrolidin-3-yl, N-methyl-pyrrolidin-3-yl), pyrrolidin-2-one (e.g. pyrrolidin-4-yl-2-one, N-methyl-pyrrolidin-4-yl-2-one) and oxazolidin-2-one (e.g. oxazolidin-5-yl-2-one, N- (1-hydroxyethyl-2-yl) -oxazolidin-5-yl-2-one, N- (1-methoxyethyl-2-yl) -oxazolidin-5-yl-2-one, N-methyl-oxazolidin-5-yl-2-one).
Each R5 is independently-NH 2 -OH, -CN, C1-C4 alkyl (e.g. C1-C2 alkyl), C1-C4 alkylene-R11 (e.g. C1-C2 alkylene-R11), -O-C1-C2 alkyl or oxo.
Preferably, each R5 is independently-NH 2 C1-C2 alkyl, -C1-C2 alkyl-R11 or oxo. More preferably, each R5 is independently C1-C2 alkyl, -C1-C2 alkyl-R11 or oxo. Preferably, when a moiety is substituted with R5, no more than one R5 is oxo. In particular, it is preferred that the oxazolidinyl-2-one moiety is not further substituted with oxo.
Specific examples of R5 are-NH 2 、-CH 3 Oxo, CH 2 CH 2 OH and-CH 2 CH 2 OCH 3 。
Each R11 is independently halogen, -NH 2 -OH, -CN or-O-C1-C2 alkyl.
Specific examples of R11 are-OH and-OCH 3 。
Ring Q is phenyl optionally substituted with one to three R6, or is 5-6 membered heteroaryl optionally substituted with one to three R6 containing one to two heteroatoms selected from N, S and O.
Preferably, ring Q is phenyl optionally substituted with one or two R6, or is a 6 membered heteroaryl optionally substituted with one or two R6, containing one to two heteroatoms selected from N, S and O, e.g. pyridinyl, e.g. pyridin-3-yl.
Specific examples of ring Q are phenyl, 4-CN-phenyl, 3, 5-dimethylisoxazolyl (e.g., 3, 5-dimethylisoxazol-4-yl) and pyridinyl (e.g., pyridin-3-yl).
Each R6 is independently-NH 2 -OH, -CN, C1-C2 alkyl or-O-C1-C2 alkyl.
Preferably, each R6 is independently-NH 2 、-OH、-CN、-CH 3 or-OCH 3 . Specific examples of R6 are-CN and-CH 3 。
R2 is hydrogen, halogen, -CN, C1-C4 alkyl optionally substituted by one or two R7, or a 4-to 7-membered saturated carbocyclic ring optionally substituted by one or two R8, or a 4-to 7-membered saturated heterocyclic ring containing one-N (R9) -moiety as ring member and additionally containing only carbon atoms as ring member, wherein X is a bond when R2 is halogen.
Preferably, R2 is hydrogen, halogen, C1-C4 alkyl optionally substituted by one or two R7, or is optionally substituted by one or two R8 (preferably by at least one is-NH) 2 R8 substituted) or a 6 membered saturated heterocyclic ring containing one-N (R9) -moiety as a ring member and additionally containing only carbon atoms as ring members.
More preferably, R2 is bromo, iodo, -CH 3 C1-C4 alkylene-R7, or a 6-membered saturated carbocyclic ring substituted by one or two R8 groups, wherein at least one R8 is-NH 2 And is located para to X (e.g., 4-aminocyclohexyl (e.g., selected from cis-4-amino-cyclohexyl and trans-4-amino-cyclohexyl), 4-amino-3-fluoro-cyclohexyl (e.g., trans-4-amino-3-fluoro-cyclohexyl), 4-amino-4-methyl-cyclohexyl (e.g., cis-4-amino-4-methyl-cyclohexyl)) or piperidin-4-yl.
Specific examples of R2 are hydrogen, -CN, chlorine, bromine, iodine, -CH 3 、-CH 2 CH 2 OH, 4-amino-cyclohexyl (e.g., selected from cis-4-amino-cyclohexyl and trans-4-amino-cyclohexyl), 4-amino-3-fluoro-cyclohexyl (e.g., trans-4-amino-3-fluoro-cyclohexyl), piperidin-4-yl, and 4-amino-4-methyl-cyclohexyl (e.g., cis-4-amino-4-methyl-cyclohexyl).
Specific examples of-X-R2 are-O- (4-amino-cyclohexyl) (e.g. selected from-O- (cis-4-amino-cyclohexyl) and-O- (trans-4-amino-cyclohexyl)), -C (=ch 2 ) - (4-amino-cyclohexyl) (e.g. -C (=ch) 2 ) - (trans-4-amino-ring)Hexyl)), -O-CH 3 、-N(CH 3 ) - (4-amino-cyclohexyl) (e.g. -N (CH) 3 ) - (trans-4-amino-cyclohexyl)), bromo, -O- (4-amino-3-fluoro-cyclohexyl) (e.g. O- (trans-4-amino-3-fluoro-cyclohexyl)), -O-piperidin-4-yl, -N (CH) 3 ) -piperidin-4-yl, -CH 2 - (4-amino-cyclohexyl) (e.g. -CH 2 - (trans-4-amino-cyclohexyl)), chlorine, -OH, -CH 2 Piperidin-4-yl, -CN, iodine, -O-CH 2 CH 2 OH, OH-NH- (4-amino-cyclohexyl) (e.g. selected from the group consisting of-NH- (cis-4-amino-cyclohexyl) and-NH- (trans-4-amino-cyclohexyl)); -C (=o) -CH 3 and-O- (4-amino-4-methyl-cyclohexyl) (e.g., -O- (cis-4-amino-4-methyl-cyclohexyl)).
Each R7 is independently-OH, halogen, -NH 2 -NH (C1-C2 alkyl), -N (C1-C2 alkyl) 2 or-NH (-C (=O) -C1-C2 alkyl).
Preferably, each R7 is independently halogen, -NH 2 or-OH (e.g. halogen or-NH) 2 )。
More preferably, each R7 is independently fluorine, -NH 2 or-OH (e.g. fluorine or-NH) 2 )。
A specific example of R7 is-OH.
Each R8 is independently-OH, halogen, -NH 2 -NH (C1-C2 alkyl), -N (C1-C2 alkyl) 2 -NH (-C (=o) -C1-C2 alkyl) or C1-C2 alkyl.
Preferably, each R8 is independently halogen, -NH 2 or-CH 3 (e.g. halogen or-NH) 2 ) And preferably at least one R8 is-NH 2 。
More preferably, each R8 is independently fluorine, -NH 2 or-CH 3 (e.g. fluorine or-NH) 2 ) And preferably at least one R8 is-NH 2 。
Specific examples of R8 are fluorine, -NH 2 And CH (CH) 3 (e.g. fluorine and-NH) 2 )。
R9 is hydrogen, C1-C4 alkyl or-C (=O) -C1-C2 alkyl.
Preferably, R9 is hydrogen or-CH 3 . A specific example of R9 is hydrogen.
In some embodiments, the compounds of the present invention are compounds having formula (IA).
In some embodiments, the compounds of the present invention are compounds having formula (IB).
In some embodiments, the compounds of the present invention are compounds having formula (IB-1)
In some embodiments, a is a group (A1).
In some embodiments, a is a group (A2).
In some embodiments, X is-O-.
In some embodiments, X is-C (=ch 2 )-。
In some embodiments, X is-CH 2 -。
In some embodiments, X is-N (CH 3 )-。
In some embodiments, X is-C (=o) -.
In some embodiments, X is-NH-.
In some embodiments, X is a bond and R2 is halogen (e.g., chlorine, bromine, or iodine).
In some embodiments, X is a bond and R2 is —cn.
In some embodiments, A is a group (A1) and X is-O-.
In some embodiments, a is a group (A1) and X is-C (=ch 2 )-。
In some embodiments, A is a group (A1) and X is-CH 2 -。
In some embodiments, A is a group (A1) and X is-N (CH) 3 )-。
In some embodiments, a is a group (A1) and X is-C (=o) -.
In some embodiments, A is a group (A1) and X is-NH-.
In some embodiments, a is a group (A1), X is a bond and R2 is-CN.
In some embodiments, a is a group (A1), X is a bond and R2 is halogen (e.g., chlorine, bromine, or iodine).
In some embodiments, A is a group (A2) and X is-O-.
In some embodiments, a is a group (A2) and X is-C (=ch 2 )-。
In some embodiments, A is a group (A2) and X is-CH 2 -。
In some embodiments, A is a group (A2) and X is-N (CH) 3 )-。
In some embodiments, a is a group (A2), X is a bond and R2 is halogen.
In some embodiments, R1 is hydrogen or C1-C6 alkylene-R3, and R3 is hydrogen, -CN, -OH, C1-C4 haloalkyl, C2-C4 alkenyl C2-C4 alkynyl, -O-C1-C4 alkyl, -O-C1-C4 haloalkyl, -NH 2 -C (=o) -OH, -C (=o) -O-C1-C4 alkyl, -C (=o) -NH 2 -C (=o) -NH (C1-C4 alkylene-R4), ring P, ring Q, -O-ring P, -O-ring Q or-S (O) 2 ) -C1-C4 alkyl.
In some embodiments, R1 is hydrogen or C1-C6 alkylene-R3, wherein there are no more than three carbon atom spacers between the oxime oxygen atom and R3, and R3 is hydrogen, -CN, -OH, C1-C4 haloalkyl, -O-C1-C4 alkyl, -O-C1-C4 haloalkyl, -C2-C4 alkynyl, -C (=O) -OH, -C (=O) -O-C1-C4 alkyl, -C (=O) -NH 2 -C (=o) -NH (C1-C4 alkyl), phenyl, or oxazolidin-2-one optionally substituted with one R5 (e.g. oxazolidin-5-yl-2-one) (e.g. substituted with one methyl (e.g. N-methyl-oxazolidin-5-yl-2-one), with one-CH 2 CH 2 OH substitution (e.g. N- (1-hydroxyethyl-2-yl) -oxazolidin-5-yl-2-one) or by a-CH 2 CH 2 OCH 3 Substituted (e.g., N- (1-methoxyethyl-2-yl) -oxazolidin-5-yl-2-one)).
In some embodiments, R1 is hydrogen or C1-C3 alkylene-R3, and R3 is hydrogen, -CN, -OH, C1-C4 haloalkyl, -O-C1-C4 alkyl, -O-C1-C4 haloalkyl, C2-C4 alkynyl, -C (=O) -OH, -C (=O) and/orO-C1-C4 alkyl, -C (=O) -NH 2 -C (=o) -NH (C1-C4 alkyl), phenyl, or oxazolidin-2-one optionally substituted with one R5 (e.g. oxazolidin-5-yl-2-one) (e.g. substituted with one methyl (e.g. N-methyl-oxazolidin-5-yl-2-one), with one-CH 2 CH 2 OH substitution (e.g. N- (1-hydroxyethyl-2-yl) -oxazolidin-5-yl-2-one) or by a-CH 2 CH 2 OCH 3 Substituted (e.g., N- (1-methoxyethyl-2-yl) -oxazolidin-5-yl-2-one)).
In some embodiments, R1 is hydrogen.
In some embodiments, R1 is C1-C6 alkylene-R3, wherein one is not terminal-CH 2 Part may be replaced by-O-and wherein R3 is hydrogen, -CN, -OH, C1-C4 haloalkyl, C2-C4 alkenylene-R4C 2-C4 alkynylene-R4, -O-C1-C4 alkylene-R4, -O-C1-C4 haloalkyl, -NH 2 -NH (C1-C4 alkylene-R4), -N (C1-C4 alkylene-R4) 2 -C (=o) -OH, -C (=o) -O-C1-C4 alkylene-R4, -C (=o) -NH 2 -C (=o) -NH (C1-C4 alkylene-R4), -C (=o) -N (C1-C4 alkylene-R4) 2 or-S (O) 2 ) -C1-C4 alkyl, and R4 has the meaning as described herein.
In some embodiments, R1 is C1-C6 alkylene-R3, and wherein R3 is hydrogen, -CN, -OH, C1-C4 haloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, -O-C1-C4 alkyl, -O-C1-C4 haloalkyl, -C (=O) -OH, -C (=O) -O-C1-C4 alkyl, -C (=O) -NH 2 -C (=O) -NH (C1-C4 alkylene-R4) or-S (O) 2 ) -C1-C4 alkyl, and R4 has the meaning as described herein.
In some embodiments, R1 is C1-C6 alkylene-R3, wherein there are no more than three carbon atom spacers between the oxime oxygen atom and R3, and wherein R3 is hydrogen, -CN, -OH, C1-C4 haloalkyl, -O-C1-C4 alkyl, -O-C1-C4 haloalkyl, C2-C4 alkynyl, -C (=O) -OH, -C (=O) -O-C1-C4 alkyl, -C (=O) -NH 2 or-C (=O) -NH (C1-C4 alkyl). In some embodiments, R1 is C1-C3 alkylene-R3, and wherein R3 is hydrogen, -CN, -OH, C1-C4 haloalkyl, -O-C1-C4 alkyl, -O-C1-C4 haloalkyl, C2-C4 alkynyl, -C (=O) -OH, -C (=O) -O-C1-C4 alkyl, -C(＝O)-NH 2 or-C (=O) -NH (C1-C4 alkyl).
In some embodiments, R1 is C2-C3 alkylene-R3, and wherein R3 is-CN, -OH or-O-C1-C4 alkyl.
In some embodiments, R1 is C1-C6 alkylene-R3, wherein one is not terminal-CH 2 Part may be replaced by-O-, and wherein R3 is ring P, ring Q, -O-ring P or-O-ring Q.
In some embodiments, R1 is C1-C6 alkylene-R3, and wherein R3 is a ring P, a ring Q, -O-ring P, or-O-ring Q.
In some embodiments, R1 is C1-C6 alkylene-R3, wherein there are no more than three carbon atom spacers between the oxime oxygen atom and R3, and wherein R3 is ring P or ring Q.
In some embodiments, R1 is C1-C3 alkylene-R3, and wherein R3 is a ring P or a ring Q.
In some embodiments, R1 is C1-C3 alkylene-R3, wherein there are no more than three carbon atom spacers between the oxime oxygen atom and R3, and wherein R3 is phenyl or oxazolidin-2-one optionally substituted with one R5 (preferably C1-C4 alkyl or C1-C4 alkylene-R11), and preferably R5 is attached to the nitrogen atom of the oxazolidin-2-one and R11 has the meaning as described herein.
In some embodiments, R1 is C1-C3 alkylene-R3, and wherein R3 is phenyl or oxazolidin-2-one optionally substituted with one R5 (preferably C1-C4 alkyl or C1-C4 alkylene-R11), and preferably R5 is attached to the nitrogen atom of the oxazolidin-2-one and R11 has the meaning as described herein.
In some embodiments, R1 is-CH optionally substituted with one R5 2 -oxazolidin-2-ones, and R5 has the meaning as described herein, preferably wherein R5 is not oxo.
In some embodiments, R1 is-CH optionally substituted with one R5 2 -oxazolidin-2-one, and wherein when R5 is present, it has the meaning as described herein, but is not oxo, and is attached to the nitrogen atom of the oxazolidin-2-one moiety.
In some embodiments, R1 is-CH 2 CH 2 CN、-CH 2 CH 2 OH、-CH 2 CH 2 OCH 3 Or CH optionally substituted with one R5 2 -oxazolidin-2-one, and wherein when R5 is present, it is attached to the nitrogen atom of the oxazolidin-2-one moiety, and wherein R5 is-CH 2 CH 2 OH or-CH 2 CH 2 OCH 3 。
In one embodiment (embodiment A1), the compound is a compound having formula (IA) or a compound having formula (IB), wherein
A is selected from the group consisting of group (A1) and group (A2), and wherein group (A1) is optionally substituted with one or two R10, and group (A2) is optionally substituted with one R10;
each R10 is independently fluorine, chlorine or-NH 2 ；
X is-O-, -C (=O) -, -C (=CH) 2 )-、-CH 2 -, -NH-or-N (C1-C4 alkyl) -,
and wherein when R2 is halogen or-CN, X is a bond, and wherein when X is-C (=o) -R2 is not hydrogen;
Ra and Rb together form-CH 2 -CH 2 -CH 2 -CH 2 -a bridging portion;
r1 is-Y-R3;
y is a bond or C1-C6 alkylene, one of which is not terminal-CH 2 -part may be replaced by-O-;
r3 is hydrogen, -CN, -OH, C1-C4 haloalkyl, C2-C4 alkenyl C2-C4 alkynyl, -O-C1-C4 alkyl, -O-C1-C4 haloalkyl, -NH 2 -C (=o) -OH, -C (=o) -O-C1-C4 alkyl, -C (=o) -NH 2 -C (=o) -NH (C1-C4 alkylene-R4), ring P, ring Q, -O-ring P, -O-ring Q or-S (O) 2 ) -C1-C4 alkyl;
r4 is hydrogen, -NH 2 or-NH (CH) 3 )；
Ring P is a 6 membered saturated carbocyclic ring optionally substituted with one to two R5, or a 5 membered saturated heterocyclic ring containing one to two heteroatoms selected from N and O optionally substituted with one to two R5;
each R5 is independently-NH 2 -OH, -CN, C1-C2 alkyl (e.g. -CH 3 ) -C1-C2 alkyl-R11, -O-C1-C2 alkyl (e.g. -OCH) 3 ) Or oxo;
each R11 is independently halogen, -NH 2 -OH, -CN or-O-C1-C2 alkyl;
ring Q is phenyl optionally substituted with one or two R6, or is 6 membered heteroaryl optionally substituted with one or two R6 containing one to two heteroatoms selected from N, S and O;
each R6 is independently-NH 2 、-OH、-CN、-CH 3 or-OCH 3 ；
R2 is hydrogen, halogen, C1-C4 alkyl optionally substituted by one or two R7, or is optionally substituted by one or two R8 (preferably by at least one being-NH) 2 R8 substituted) or a 6 membered saturated heterocyclic ring containing one-N (R9) -moiety as a ring member and additionally containing only carbon atoms as ring members;
each R7 is independently halogen, -NH 2 or-OH (e.g. halogen or-NH) 2 )；
Each R8 is independently halogen, -NH 2 or-CH 3 (e.g. halogen or-NH) 2 ) The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with
R9 is hydrogen or-CH 3 。
Examples of the substituent definitions above and the compounds of formula (IA) and the embodiments given for the compounds of formula (IB) may be combined with embodiment A1 in any combination where possible.
In one embodiment (embodiments A1-a), the compounds of the invention are compounds of formula (IA) as defined for embodiment A1.
In one embodiment (embodiments A1-B), the compounds of the invention are compounds of formula (IB) as defined for embodiment A1.
In one embodiment (embodiment A2), the compound is a compound having formula (IA) or a compound having formula (IB), wherein
A is selected from the group consisting of group (A1) and group (A2), and wherein group (A1) is optionally substituted with one or two R10, and group (A2) is optionally substituted with one R10;
each R10 is independently fluorine, chlorine or-NH 2 ；
Preferably, X is attached to a carbon atom located in para position relative to # 2;
x is-O-, -C (=O) -, -C (=CH) 2 )-、-CH 2 -, -NH-or-N (C1-C4 alkyl) -, and wherein when R2 is halogen or-CN, X is a bond, and wherein when X is-C (=o) -R2 is not hydrogen;
ra and Rb together form-CH 2 -CH 2 -CH 2 -CH 2 -a bridging portion;
r1 is hydrogen, C1-C6 alkylene-R3, one of which is not terminal-CH 2 -part may be replaced by-O-, or R1 is a ring P;
r3 is hydrogen, -CN, -OH, C1-C4 haloalkyl, C2-C4 alkenyl C2-C4 alkynyl, -O-C1-C4 alkyl, -O-C1-C4 haloalkyl, -NH 2 -C (=o) -OH, -C (=o) -O-C1-C4 alkyl, -C (=o) -NH 2 -C (=o) -NH (C1-C4 alkylene-R4), ring P, ring Q, -O-ring P, -O-ring Q or-S (O) 2 ) -C1-C4 alkyl;
r4 is hydrogen, -NH 2 or-NH (CH) 3 )；
Ring P is a 6 membered saturated carbocyclic ring optionally substituted with one to two R5, or a 5 membered saturated heterocyclic ring containing one to two heteroatoms selected from N and O optionally substituted with one to two R5;
each R5 is independently-NH 2 -OH, -CN, C1-C2 alkyl (e.g. -CH 3 ) -C1-C2 alkyl-R11, -O-C1-C2 alkyl (e.g. -OCH) 3 ) Or oxo;
ring Q is phenyl optionally substituted with one or two R6, or is 6 membered heteroaryl optionally substituted with one or two R6 containing one to two heteroatoms selected from N, S and O;
Each R6 is independently-NH 2 、-OH、-CN、-CH 3 or-OCH 3 ；
R2 is hydrogen, halogen, C1-C4 alkane optionally substituted with one or two R7A radical, or optionally substituted by one or two R8 radicals (preferably by at least one being-NH 2 R8 substituted) or a 6 membered saturated heterocyclic ring containing one-N (R9) -moiety as a ring member and additionally containing only carbon atoms as ring members;
each R7 is independently halogen, -NH 2 or-OH (e.g. halogen or-NH) 2 )；
Each R8 is independently halogen, -NH 2 or-CH 3 (e.g. halogen or-NH) 2 ) The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with
R9 is hydrogen or-CH 3 。
Examples of the substituent definitions above and the compounds of formula (IA) and the embodiments given for the compounds of formula (IB) may be combined with embodiment A2 in any combination where possible.
In one embodiment (embodiment A2-a), the compound of the invention is a compound of formula (IA) as defined for embodiment A2.
In one embodiment (embodiments A2-B), the compounds of the invention are compounds of formula (IB) as defined for embodiment A2.
In one embodiment (embodiment B1), the compound is a compound having the formula (IA) or a compound having the formula (IB), wherein
A is a group (A1) optionally substituted with one R10;
r10 is chlorine or-NH 2 ；
Preferably, X is attached to a carbon atom located in para position relative to # 2;
x is-O-, -C (=O) -, -C (=CH) 2 )-、-CH 2 -or-N (CH) 3 ) -, and wherein when R2 is halogen, X is a bond, and wherein when X is-C (=o) -R2 is not hydrogen;
ra and Rb together form-CH 2 -CH 2 -CH 2 -CH 2 -a bridging portion;
r1 is-Y-R3;
y is a bond or a C1-C6 alkylene group, preferably wherein there are no more than three carbon atom spacers between the oxime oxygen atom and R3, more preferably a bond or a C1-C3 alkylene group;
r3 is hydrogen, -CN, -OH, C1-C4 haloalkyl, -O-C1-C4 alkyl, -O-C1-C4 haloalkyl, -C2-C4 alkynyl, -C (=O) -OH, -C (=O) -O-C1-C4 alkyl, -C (=O) -NH 2 -C (=o) -NH (C1-C4 alkyl), phenyl, oxazolidin-2-one (e.g. oxazolidin-3-yl-2-one, oxazolidin-5-yl-2-one), or oxazolidin-2-one substituted by one R5 (e.g. substituted by one methyl (e.g. N-methyl-oxazolidin-5-yl-2-one), by one-CH 2 CH 2 OH substitution (e.g. N- (1-hydroxyethyl-2-yl) -oxazolidin-5-yl-2-one) or by a-CH 2 CH 2 OCH 3 Substituted (e.g., N- (1-methoxyethyl-2-yl) -oxazolidin-5-yl-2-one)), and preferably wherein when Y is a bond, R3 is hydrogen;
R5 is C1-C2 alkyl or-C1-C2 alkyl-R11;
r11 is halogen, -NH 2 -OH, -CN or-O-C1-C2 alkyl;
r2 is fluorine, chlorine, bromine, iodine, -CH 3 C1-C4 alkyl-R7, a 6 membered saturated carbocyclic ring substituted by one or two R8 groups, wherein at least one R8 is-NH 2 And is located para (e.g., 4-amino-cyclohexyl, 4-amino-3-fluoro-cyclohexyl, 4-amino-4-methyl-cyclohexyl) or piperidin-4-yl relative to X;
r7 is fluorine, -NH 2 or-OH; and is also provided with
Each R8 is independently halogen, -NH 2 or-CH 3 。
Examples of the substituent definitions above and the embodiments given for the compounds of formula (IA) and the compounds of formula (IB) may be combined with embodiment B1 in any combination where possible.
In one embodiment (embodiment B1-a), the compound of the invention is a compound of formula (IA) as defined for embodiment B1.
In one embodiment (embodiments B1-B), the compounds of the invention are compounds of formula (IB) as defined for embodiment B1.
In one embodiment (embodiment B2), the compound is a compound having formula (IA) or a compound having formula (IB), wherein
A is a group (A1) optionally substituted with one R10;
R10 is chlorine or-NH 2 ；
Preferably, X is attached to a carbon atom located in para position relative to # 2;
x is-O-, -C (=O) -, -C (=CH) 2 )-、-CH 2 -or-N (CH) 3 ) -, and wherein when R2 is halogen, X is a bond, and wherein when X is-C (=o) -R2 is not hydrogen;
ra and Rb together form-CH 2 -CH 2 -CH 2 -CH 2 -a bridging portion;
r1 is hydrogen or C1-C6 alkylene-R3, preferably wherein there are no more than three carbon atom spacers between the oxime oxygen atom and R3, more preferably hydrogen or C1-C3 alkylene-R3;
r3 is hydrogen, -CN, -OH, C1-C4 haloalkyl, -O-C1-C4 alkyl, -O-C1-C4 haloalkyl, -C2-C4 alkynyl, -C (=O) -OH, -C (=O) -O-C1-C4 alkyl, -C (=O) -NH 2 -C (=o) -NH (C1-C4 alkyl), phenyl, oxazolidin-2-one (e.g. oxazolidin-3-yl-2-one, oxazolidin-5-yl-2-one), or oxazolidin-2-one substituted by one R5 (e.g. by one methyl group (e.g. N-methyl-oxazolidin-5-yl-2-one), by one-CH 2 CH 2 OH substitution (e.g. N- (1-hydroxyethyl-2-yl) -oxazolidin-5-yl-2-one) or by a-CH 2 CH 2 OCH 3 Substitution (e.g., N- (1-methoxyethyl-2-yl) -oxazolidin-5-yl-2-one));
r5 is C1-C2 alkyl or-C1-C2 alkyl-R11;
r11 is halogen, -NH 2 -OH, -CN or-O-C1-C2 alkyl;
R2 is fluorine, chlorine, bromine, iodine, -CH 3 C1-C4 alkyl-R7, a 6 membered saturated carbocyclic ring substituted by one or two R8 groups, wherein at least one R8 is-NH 2 And is located para (e.g., 4-amino-cyclohexyl, 4-amino-3-fluoro-cyclohexyl, 4-amino-4-methyl-cyclohexyl) or piperidin-4-yl relative to X;
r7 is fluorine, -NH 2 or-OH; and is also provided with
Each R8 is independently halogen, -NH 2 or-CH 3 。
Examples of the substituent definitions above and the embodiments given for the compounds of formula (IA) and the compounds of formula (IB) may be combined with embodiment B2 in any combination where possible.
In one embodiment (embodiment B2-a), the compound of the invention is a compound of formula (IA) as defined for embodiment B2.
In one embodiment (embodiments B2-B), the compounds of the invention are compounds of formula (IB) as defined for embodiment B2.
In one embodiment (embodiment C1), the compound is a compound having formula (IA) or a compound having formula (IB), wherein
A is selected from the group consisting of group (A1) and group (A2) and wherein group (A1) is optionally substituted with one R10 and group (A2) is unsubstituted;
r10 is chlorine or-NH 2 ；
Preferably, when a is a group (A1), X is attached to a carbon atom located in para position relative to #2, and preferably when a is a group (A2), X is attached to a carbon atom adjacent to the S atom;
x is-O-, -C (=O) -, -C (=CH) 2 )-、-CH 2 -, -NH-or-N (CH) 3 ) -, wherein when R2 is halogen, X is a bond, and wherein when X is-C (=o) -R2 is not hydrogen;
ra and Rb together form-CH 2 -CH 2 -CH 2 -CH 2 -a bridging portion;
r1 is-Y-R3;
y is a bond, -CH 2 -、-CH 2 CH 2 -、-CH 2 CH 2 CH 2 -、-CH(CH 3 )CH 2 -、-CH 2 CH(CH 3 )-、-CH 2 CH(CH 3 )CH 2 -、-CH 2 CH 2 C(CH 3 )(CH 3 )-、-CH 2 CH 2 OCH 2 -、-CH 2 CH 2 OCH 2 CH 2 -or-CH 2 CH 2 CH 2 OCH 2 -；
R3 is hydrogen, -CN, -OH, -NH 2 、-CH＝CH 2 、-C≡CH、-N(CH 2 CH 3 ) 2 、-N(CH 3 )CH 3 、-OCH 3 、-C(＝O)NHCH 2 CH 2 NH 2 、-C(＝O)NH 2 、-C(＝O)NHCH 3 、-C(＝O)OCH 2 CH 3 、-C(＝O)OH、-C(＝O)OCH 3 4-amino-cyclohexyl, piperidinyl (e.g., piperidin-1-yl), pyrrolidinyl (e.g., pyrrolidin-1-yl, pyrrolidin-3-yl), pyrrolidin-2-one (e.g., pyrrolidin-4-yl-2-one), N-methylpyrrolidinyl (e.g., N-methylpyrrolidin-3-yl), N-methyl-pyrrolidin-2-one (e.g., N-methylpyrrolidin-4-yl-2-one), 3, 5-dimethyl-isoxazolyl (e.g., 3, 5-dimethyl-isoxazol-4-yl), oxazolidin-2-one (e.g., oxazolidin-3-yl-2-one, oxazolidin-5-yl-2-one), oxazolidin-2-one substituted with one methyl (e.g., N-methyl-oxazolidin-5-yl-2-one), N- (1-methoxyethyl-2-yl) -oxazolidin-2-one (e.g., N- (1-methoxyethyl-2-yl) -oxazolidin-5-yl-2-one), N- (1-hydroxyethyl-2-yl) -oxazolidin-2-one (e.g., N- (1-hydroxyethyl-2-yl) -oxazolidin-5-yl-2-one), 4-CN-phenyl, -OCF 3 、-CF 3 -O-phenyl, -pyridinyl (e.g. pyridin-3-yl), -OCH 2 CH 3 、-S(O) 2 CH 3 、-OCH 2 CF 3 、-CF 2 CH 3 or-CH 2 F, performing the process; and is also provided with
R2 is hydrogen, -CN, chlorine, bromine, iodine, -CH 3 、-CH 2 CH 2 OH, 4-amino-cyclohexyl, 4-amino-3-fluoro-cyclohexyl, piperidin-4-yl or 4-amino-4-methyl-cyclohexyl.
Examples of the substituent definitions above and the compounds of formula (IA) and the embodiments given for the compounds of formula (IB) may be combined with embodiment C1 in any combination where possible.
In one embodiment (embodiment C1-a), the compound of the invention is a compound of formula (IA) as defined for embodiment C1.
In one embodiment (embodiments C1-B), the compounds of the present invention are compounds of formula (IB) as defined for embodiment C1.
In one embodiment (embodiment C2), the compound is a compound having formula (IA) or a compound having formula (IB), wherein
A is selected from the group consisting of group (A1) and group (A2) and wherein group (A1) is optionally substituted with one R10 and group (A2) is unsubstituted;
r10 is chlorine or-NH 2 ；
Preferably, when a is a group (A1), X is attached to a carbon atom located in para position relative to #2, and preferably when a is a group (A2), X is attached to a carbon atom adjacent to the S atom;
X is-O-, -C (=O) -, -C (=CH) 2 )-、-CH 2 -or-N (CH) 3 ) -, and wherein when R2 is halogen, X is a bond, and wherein when X is-C (=o) -R2 is not hydrogen;
ra and Rb together form-CH 2 -CH 2 -CH 2 -CH 2 -a bridging portion;
r1 is hydrogen, -CH 3 、-CH(CH 3 )CH 3 、-CH 2 CH(CH 3 )CH 3 、-CH 2 CH＝CH 2 、-CH 2 C≡CH、-CH 2 CH 2 CH 2 CN、-CH 2 CH 2 CH 2 N(CH 2 CH 3 )CH 2 CH 3 、-CH 2 CH 2 CH 2 O-benzyl, -CH 2 CH(CH 3 )OH、-CH 2 CH 2 CH 2 OH、-CH 2 CH 2 NH 2 、-CH 2 CH 2 CH 2 NH 2 、-CH 2 CH 2 C(＝O)OCH 2 CH 3 、-CH 2 CH 2 C(＝O)OCH 3 、-CH 2 CH 2 N(CH 2 CH 3 )CH 2 CH 3 、-CH 2 CH 2 N(CH 3 )CH 3 、-CH 2 CH 2 OH、-CH 2 CH 2 OMe、-CH 2 CH 3 、-CH 2 CN、-CH 2 CH 2 CN、-CH 2 C(＝O)NH 2 、-CH 2 C(＝O)NHCH 3 、-CH 2 C(＝O)NHCH 2 CH 2 NH 2 、-CH 2 C(＝O)OH、-CH 2 C(＝O)OCH 3 4-aminocyclohexyl, -CH 2 CH 2 Piperidinyl (e.g. -CH 2 CH 2 -piperidin-1-yl), -CH 2 CH 2 Pyrrolidinyl (e.g. -CH 2 CH 2 -pyrrolidin-1-yl), 4-cyanobenzyl, benzyl, -CH 2 -3, 5-dimethyl-isoxazolyl (e.g. -CH 2 -3, 5-dimethyl-isoxazol-4-yl), -CH 2 -4-aminocyclohexyl, -CH 2 Oxazolidin-2-ones (e.g. -CH 2 -oxazolidin-5-yl-2-one), -CH 2 -N-methyl-oxazolidin-2-ones, e.g., (-CH) 2 -N-methyl-oxazolidin-5-yl-2-one), -CH 2 -N- (1-hydroxyethyl-2-yl) -oxazolidin-2-one (e.g. -CH) 2 -N- (1-hydroxyethyl-2-yl) -oxazolidin-5-yl-2-one), -CH 2 -N- (1-methoxyethyl-2-yl) -oxazolidin-2-one (e.g. -CH 2 -N- (1-methoxyethyl-2-yl) -oxazolidin-5-yl-2-one), -CH 2 -N-methyl-pyrrolidinyl (e.g. -CH 2 -N-methyl-pyrrolidin-3-yl), -CH 2 -N-methyl-pyrrolidin-2-one (e.g. -CH 2 -N-methyl-pyrrolidin-4-yl-2-one), -CH 2 Pyrrolidinyl (e.g. -CH 2 -pyrrolidin-3-yl), -CH 2 Pyrrolidinyl-2-ones (e.g. -CH 2 -pyrrolidin-4-yl-2-one), -CH 2 CH 2 OCF 3 、-CH 2 CH 2 CF 3 、-CH 2 CH 2 -phenyl, -CH 2 CH 2 O-phenyl, -CH 2 CH 2 CH 2 Pyridyl (e.g. -CH 2 CH 2 CH 2 -pyridin-3-yl), -CH 2 CH 2 OCH 2 CH 3 、-CH 2 CH 2 CH 2 S(O 2 )CH 3 、-CH 2 CH 2 C(CH 3 ) 2 CN、-CH 2 CH 2 OCH 2 CF 3 、-CH 2 CH 2 CF 2 CH 3 、-CH 2 CH 2 CH 2 CH 2 F or-CH 2 CH 2 CH 2 CF 3 The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with
R2 is hydrogen, -CN, chlorine, bromine, iodine, -CH 3 、-CH 2 CH 2 OH, 4-amino-cyclohexyl, 4-amino-3-fluoro-cyclohexyl, piperidin-4-yl or 4-amino-4-methyl-cyclohexyl.
Examples of the substituent definitions above and the compounds of formula (IA) and the embodiments given for the compounds of formula (IB) may be combined with embodiment C2 in any combination where possible.
In one embodiment (embodiment C2-a), the compound of the invention is a compound of formula (IA) as defined for embodiment C2.
In one embodiment (embodiment C2-B), the compound of the invention is a compound of formula (IB) as defined for embodiment C2.
In one embodiment (embodiment D), the compound is a compound having the formula (IAa)
Wherein R1, X, R2 and R10 are as defined for compounds having formula (IA) and n is 0, 1 or 2, preferably 0 or 1.
Examples of the substituent definitions above and the embodiments given for the compounds of formula (IA) may be combined with embodiment D in any combination where possible.
In one embodiment (embodiment D1), the compound is a compound having formula (IAa), wherein R1, X, R2 and R10 are as defined in embodiments A1-a or embodiments A2-a, and n is 0, 1 or 2.
Examples of the substituent definitions above and the embodiments given for the compounds of formula (IA) may be combined with embodiment D1 in any combination where possible.
In one embodiment (embodiment D2), the compound is a compound having formula (IAa), wherein R1, X, R2 and R10 are as defined in embodiment B1-a or embodiment B2-a, and n is 0 or 1.
Examples of the substituent definitions above and the embodiments given for the compounds of formula (IA) may be combined with embodiment D2 in any combination where possible.
In one embodiment (embodiment D3), the compound is a compound having formula (IAa), wherein R1, X, R2 and R10 are as defined in embodiment C1-a or embodiment C2-a, and n is 0 or 1.
Examples of the substituent definitions above and the embodiments given for the compounds of formula (IA) may be combined with embodiment D3 in any combination where feasible.
In one embodiment (embodiment E), the compound is a compound having formula (IAb)
Wherein R1, X and R2 are as defined for compounds having formula (IA).
Examples of the substituent definitions above and the embodiments given for the compounds of formula (IA) may be combined with embodiment E in any combination where possible.
In one embodiment (embodiment E1), the compound is a compound having formula (IAb), wherein R1, X and R2 are as defined in embodiments A1-A or embodiments A2-A.
Examples of the substituent definitions above and the embodiments given for the compounds of formula (IA) may be combined with embodiment E1 in any combination where possible.
In one embodiment (embodiment E2), the compound is a compound having formula (IAb), wherein R1, X and R2 are as defined in embodiment B1-A or embodiment B2-A.
Examples of the substituent definitions above and the embodiments given for the compounds of formula (IA) may be combined with embodiment E2 in any combination where possible.
In one embodiment (embodiment E3), the compound is a compound having formula (IAb), wherein R1 and R2 are as defined in embodiment C1-A or embodiment C2-A.
Examples of the substituent definitions above and the embodiments given for the compounds of formula (IA) may be combined with embodiment E3 in any combination where possible.
In one embodiment (embodiment F), the compound is a compound having the formula (IBa)
Wherein R1, X, R2 and R10 are as defined for the compound of formula (IB) and n is 0, 1 or 2, preferably 0 or 1.
Examples of the substituent definitions above and the embodiments given for the compounds of formula (IB) may be combined with embodiment F in any combination where possible.
In one embodiment (embodiment F1), the compound is a compound having the formula (IBa), wherein R1, X, and R2 are as defined in embodiments A1-B or embodiments A2-B, and n is 0, 1, or 2.
Examples of the substituent definitions above and the embodiments given for the compounds of formula (IB) may be combined with embodiment F1 in any combination where possible.
In one embodiment (embodiment F2), the compound is a compound having formula (IBa) wherein R1, X and R2 are as defined in embodiments B1-B or embodiments B2-B, and n is 0 or 1.
Examples of the substituent definitions above and the embodiments given for the compounds of formula (IB) may be combined with embodiment F2 in any combination where possible.
In one embodiment (embodiment F3), the compound is a compound having the formula (IBa), wherein R1, X, and R2 are as defined in embodiments C1-B or embodiments C2-B, and n is 0 or 1.
Examples of the substituent definitions above and the embodiments given for the compounds of formula (IB) may be combined with embodiment F3 in any combination where possible.
In some embodiments, the invention may be described by the following paragraphs, which may be combined with any of the above substituent definitions and embodiments, where applicable, in any combination:
paragraph 1A: a compound having formula (IA), or a pharmaceutically acceptable salt thereof; wherein the method comprises the steps of
Wherein #1 is attached to a carbon atom forming an oxime moiety, and wherein group (A1) is optionally substituted with one or two R10 and group (A2) is optionally substituted with one R10;
each R10 is independently halogen or-NH 2 ；
X is-O-, -C (=CH 2 )-、-CH 2 -, -NH-or-N (C1-C4 alkyl) -;
r1 is-Y-R3;
y is a bond or C1-C6 alkylene, one of which is not terminal-CH 2 -part may be replaced by-O-;
r3 is hydrogen, -CN, -OH, -C2-C4 alkenylene-R4C 2-C4 Alkylene-R4, -O-C1-C4 alkylene-R4, -NH 2 -NH (C1-C4 alkylene-R4), -N (C1-C4 alkylene-R4) 2 -C (=o) -OH, -C (=o) -O-C1-C4 alkylene-R4, -C (=o) -NH 2 -C (=o) -NH (C1-C4 alkylene-R4), -C (=o) -N (C1-C4 alkylene-R4) 2 Ring P, ring Q, -O-ring P, or-O-ring Q;
r4 is hydrogen, -NH 2 -NH (C1-C2 alkyl) or-N (C1-C2 alkyl) 2 ；
Ring P is a 5-6 membered saturated or partially unsaturated carbocyclic ring optionally substituted with one to three R5, or a 5-6 membered saturated or partially unsaturated heterocyclic ring containing one to two heteroatoms selected from N and O optionally substituted with one to three R5;
each R5 is independently-NH 2 -OH, -CN, C1-C2 alkyl, -O-C1-C2 alkyl or oxo;
ring Q is phenyl optionally substituted with one to three R6, or is 5-6 membered heteroaryl optionally substituted with one to three R6 containing one to two heteroatoms selected from N, S and O;
each R6 is independently-NH 2 -OH, -CN, C1-C2 alkyl or-O-C1-C2 alkyl;
r2 is hydrogen, C1-C4 alkyl optionally substituted by one or two R7, or a 4-to 7-membered saturated carbocyclic ring optionally substituted by one or two R8, or a 4-to 7-membered saturated heterocyclic ring containing one-N (R9) -moiety as ring member and additionally containing only carbon atoms as ring members;
Each R7 is independently-OH, halogen, -NH 2 -NH (C1-C2 alkyl), -N (C1-C2 alkyl) 2 or-NH (-C (=o) -C1-C2 alkyl);
each R8 is independently-OH, halogen, -NH 2 -NH (C1-C2 alkyl), -N (C1-C2 alkyl) 2 or-NH (-C (=o) -C1-C2 alkyl); and is also provided with
R9 is hydrogen, C1-C4 alkyl or-C (=O) -C1-C2 alkyl.
The compound of paragraph 2A, paragraph 1A, or a pharmaceutically acceptable salt thereof, wherein when a is a group (A1), X is attached to a carbon atom located para to #2, and when a is a group (A2), X is attached to a carbon atom adjacent to the S atom.
Paragraph 3A. The compound of paragraph 1A or paragraph 2A, or a pharmaceutically acceptable salt thereof, wherein A is a group (A1).
Paragraph 4A. The compound of paragraph 1A or paragraph 2A, or a pharmaceutically acceptable salt thereof, wherein A is a group (A2).
Paragraph 5A the compound of any one of paragraphs 1A to 4A or a pharmaceutically acceptable salt thereof, wherein X is-O-, -C (=CH) 2 ) -or-N (CH) 3 )-。
Paragraph 6A the compound of any one of paragraphs 1A to 5A or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen, C1-C6 alkylene-R3, wherein one is not terminal-CH 2 The moiety may be replaced by-O-, or R1 is ring P or ring Q.
Paragraph 7A the compound of any one of paragraphs 1A to 6A or a pharmaceutically acceptable salt thereof, wherein R3 is hydrogen, -CN, -OH, C2-C4 alkenyl, C2-C4 alkynyl, -O-C1-C4 alkyl, -C (=O) -OH, -C (=O) -O-C1-C4 alkyl, -C (=O) -NH 2 -C (=o) -NH (C1-C4 alkylene-R4), ring P, ring Q, -O-ring P or-O-ring Q.
The compound of any one of paragraphs 1A to 7A, or a pharmaceutically acceptable salt thereof, wherein R2 is C1-C4 alkyl optionally substituted with one or two R7, or a 6 membered saturated carbocyclic ring optionally substituted with one or two R8.
Paragraph 9A the compound of paragraph 1A or a pharmaceutically acceptable salt thereof, wherein
A is selected from the group consisting of group (A1) and group (A2), and wherein group (A1) is optionally substituted with one or two R10, and group (A2) is optionally substituted with one R10;
each R10 is independently fluorine, chlorine or-NH 2 ；
X is-O-, -C (=CH 2 )-、-CH 2 -, -NH-or-N (C1-C4 alkyl) -;
r1 is-Y-R3;
y is a bond or C1-C6 alkylene, one of which is not terminal-CH 2 -part may be replaced by-O-;
r3 is hydrogen, -CN, -OH, C2-C4 alkenyl, C2-C4 alkynyl, -O-C1-C4 alkyl, -C (=O) -OH, -C (=O) -O-C1-C4 alkyl, -C (=O) -NH 2 -C (=o) -NH (C1-C4 alkylene-R4), ring P, ring Q, -O-ring P or-O-ring Q;
r4 is hydrogen, -NH 2 or-NH (CH) 3 )；
Ring P is a 6 membered saturated carbocyclic ring optionally substituted with one to two R5, or a 5 membered saturated heterocyclic ring containing one to two heteroatoms selected from N and O optionally substituted with one to two R5;
Each R5 is independently-NH 2 、-OH、-CN、-CH 3 、-OCH 3 Or oxo;
ring Q is phenyl optionally substituted with one to three R6, or is 5 membered heteroaryl optionally substituted with one to three R6 containing one to two heteroatoms selected from N, S and O;
each R6 is independently-NH 2 、-OH、-CN、-CH 3 or-OCH 3 ；
R2 is C1-C4 alkyl optionally substituted with one or two R7, or is a 6 membered saturated carbocyclic ring optionally substituted with one or two R8;
each R7 is independently halogen or-NH 2 The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with
Each R8 is independently halogen or-NH 2 。
Paragraph 10A the compound of paragraph 1A or a pharmaceutically acceptable salt thereof, wherein
A is a group (A1) optionally substituted with one R10;
r10 is chlorine or-NH 2 ；
X is-O-, -C (=CH 2 ) -or-N (CH) 3 )-；
R1 is hydrogen or C1-C6 alkylene-R3;
r3 is hydrogen, -CN, -OH, -O-C1-C4 alkyl, C2-C4 alkynyl, -C (=O) -OH, -C (=O) -O-C1-C4 alkyl, -C (=O) -NH 2 -C (=o) -NH (C1-C4 alkyl) or oxazolidin-2-one optionally substituted with one methyl group; and is also provided with
R2 is-CH 3 Or 4-amino-cyclohexyl.
Paragraph 11A the compound of any one of paragraphs 1A to 10A or a pharmaceutically acceptable salt thereof, wherein the compound having formula (IA) is the Z isomer of the oxime moiety.
Paragraph 1B. A compound having formula (IA), or a pharmaceutically acceptable salt thereof; wherein the method comprises the steps of
A is selected from the group consisting of group (A1) and group (A2), wherein #1 is attached to a carbon atom forming an oxime moiety, wherein group (A1) is optionally substituted with one or two R10 and group (A2) is optionally substituted with one R10;
each R10 is independently halogen or-NH 2 ；
X is-O-, -C (=CH 2 )-、-CH 2 -, -NH-or-N (C1-C4 alkyl) -, wherein when R2 is halogen, X is a bond;
r1 is-Y-R3;
y is a bondOr C1-C6 alkylene, one of which is not terminal-CH 2 -part may be replaced by-O-;
r3 is hydrogen, -CN, -OH, -C2-C4 alkenylene-R4C 2-C4 Alkylene-R4, -O-C1-C4 alkylene-R4, -NH 2 -NH (C1-C4 alkylene-R4), -N (C1-C4 alkylene-R4) 2 -C (=o) -OH, -C (=o) -O-C1-C4 alkylene-R4, -C (=o) -NH 2 -C (=o) -NH (C1-C4 alkylene-R4), -C (=o) -N (C1-C4 alkylene-R4) 2 Ring P, ring Q, -O-ring P, or-O-ring Q;
r4 is hydrogen, -NH 2 -NH (C1-C2 alkyl) or-N (C1-C2 alkyl) 2 ；
Ring P is a 5-6 membered saturated or partially unsaturated carbocyclic ring optionally substituted with one to three R5, or a 5-6 membered saturated or partially unsaturated heterocyclic ring containing one to two heteroatoms selected from N and O optionally substituted with one to three R5;
each R5 is independently-NH 2 -OH, -CN, C1-C2 alkyl, -O-C1-C2 alkyl or oxo;
Ring Q is phenyl optionally substituted with one to three R6, or is 5-6 membered heteroaryl optionally substituted with one to three R6 containing one to two heteroatoms selected from N, S and O;
each R6 is independently-NH 2 -OH, -CN, C1-C2 alkyl or-O-C1-C2 alkyl;
r2 is hydrogen, halogen, C1-C4 alkyl optionally substituted by one or two R7, or a 4-to 7-membered saturated carbocyclic ring optionally substituted by one or two R8, or a 4-to 7-membered saturated heterocyclic ring containing one-N (R9) -moiety as ring member and additionally containing only carbon atoms as ring members;
each R7 is independently-OH, halogen, -NH 2 -NH (C1-C2 alkyl), -N (C1-C2 alkyl) 2 or-NH (-C (=o) -C1-C2 alkyl);
each R8 is independently-OH, halogen, -NH 2 -NH (C1-C2 alkyl), -N (C1-C2 alkyl) 2 or-NH (-C (=o) -C1-C2 alkyl); and is also provided with
R9 is hydrogen, C1-C4 alkyl or-C (=O) -C1-C2 alkyl.
The compound of paragraph 2B, paragraph 1B, or a pharmaceutically acceptable salt thereof, wherein when a is a group (A1), X is attached to a carbon atom located para to #2, and when a is a group (A2), X is attached to a carbon atom adjacent to the S atom.
The compound of paragraph 1B or paragraph 2B, or a pharmaceutically acceptable salt thereof, wherein a is a group (A1).
The compound of paragraph 1B or paragraph 2B, or a pharmaceutically acceptable salt thereof, wherein a is a group (A2).
Paragraph 5B the compound of any one of paragraphs 1B to 4B or a pharmaceutically acceptable salt thereof, wherein X is-O-, -C (=CH) 2 ) -or-N (CH) 3 ) -, and wherein when R2 is halogen, X is a bond.
Paragraph 6B the compound of any one of paragraphs 1B to 5B or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen, C1-C6 alkylene-R3, wherein one is not terminal-CH 2 The moiety may be replaced by-O-, or R1 is ring P or ring Q.
Paragraph 7B the compound of any one of paragraphs 1B to 6B or a pharmaceutically acceptable salt thereof, wherein R3 is hydrogen, -CN, -OH, C2-C4 alkenyl, C2-C4 alkynyl, -O-C1-C4 alkyl, -C (=O) -OH, -C (=O) -O-C1-C4 alkyl, -C (=O) -NH 2 -C (=o) -NH (C1-C4 alkylene-R4), ring P, ring Q, -O-ring P or-O-ring Q.
The compound of any one of paragraphs 1B to 7B, or a pharmaceutically acceptable salt thereof, wherein R2 is halogen, C1-C4 alkyl optionally substituted with one or two R7, or a 6 membered saturated carbocyclic ring optionally substituted with one or two R8.
Paragraph 9B the compound of paragraph 1B or a pharmaceutically acceptable salt thereof, wherein
A is selected from the group consisting of group (A1) and group (A2), and wherein group (A1) is optionally substituted with one or two R10, and group (A2) is optionally substituted with one R10;
Each R10 is independently fluorine, chlorine or-NH 2 ；
X is-O-, -C (=CH 2 )-、-CH 2 -, -NH-or-N (C1-C4 alkyl) -, wherein when R2 is halogen, X is a bond;
r1 is-Y-R3;
y is a bond or C1-C6 alkylene, one of which is not terminal-CH 2 -part may be replaced by-O-;
r3 is hydrogen, -CN, -OH, C2-C4 alkenyl, C2-C4 alkynyl, -O-C1-C4 alkyl, -C (=O) -OH, -C (=O) -O-C1-C4 alkyl, -C (=O) -NH 2 -C (=o) -NH (C1-C4 alkylene-R4), ring P, ring Q, -O-ring P or-O-ring Q;
r4 is hydrogen, -NH 2 or-NH (CH) 3 )；
Ring P is a 6 membered saturated carbocyclic ring optionally substituted with one to two R5, or a 5 membered saturated heterocyclic ring containing one to two heteroatoms selected from N and O optionally substituted with one to two R5;
each R5 is independently-NH 2 、-OH、-CN、-CH 3 、-OCH 3 Or oxo;
ring Q is phenyl optionally substituted with one to three R6, or is 5 membered heteroaryl optionally substituted with one to three R6 containing one to two heteroatoms selected from N, S and O;
each R6 is independently-NH 2 、-OH、-CN、-CH 3 or-OCH 3 ；
R2 is halogen, C1-C4 alkyl optionally substituted with one or two R7, or a 6 membered saturated carbocyclic ring optionally substituted with one or two R8;
each R7 is independently halogen or-NH 2 The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with
Each R8 is independently halogen or-NH 2 。
Paragraph 10B the compound of paragraph 1B or a pharmaceutically acceptable salt thereof, wherein
A is a group (A1) optionally substituted with one R10;
r10 is chlorine or-NH 2 ；
X is-O-, -C (=CH 2 ) -or-N (CH) 3 ) -wherein when R2 is halogen, X is a bond;
r1 is hydrogen or C1-C6 alkylene-R3;
r3 is hydrogen, -CN, -OH, -O-C1-C4 alkyl, C2-C4 alkynyl, -C (=O) -OH, -C (=O) -O-C1-C4 alkyl, -C (=o) -NH 2 -C (=o) -NH (C1-C4 alkyl) or oxazolidin-2-one optionally substituted with one methyl group; and is also provided with
R2 is fluorine, chlorine, bromine, -CH 3 4-amino-cyclohexyl or 4-amino-3-fluoro-cyclohexyl.
Paragraph 11B the compound of any one of paragraphs 1B to 10B or a pharmaceutically acceptable salt thereof, wherein the compound having formula (IA) is the Z isomer of the oxime moiety.
Paragraph 1℃ A compound having formula (IA), or a pharmaceutically acceptable salt thereof; wherein the method comprises the steps of
A is selected from the group consisting of group (A1) and group (A2), wherein #1 is attached to a carbon atom forming an oxime moiety, wherein group (A1) is optionally substituted with one or two R10 and group (A2) is optionally substituted with one R10;
each R10 is independently halogen or-NH 2 ；
X is-O-, -C (=CH 2 )-、-CH 2 -, -NH-or-N (C1-C4 alkyl) -, wherein when R2 is halogen or-CN, X is a bond;
R1 is-Y-R3;
y is a bond or C1-C6 alkylene, one of which is not terminal-CH 2 -part may be replaced by-O-;
r3 is hydrogen, -CN, -OH, -C2-C4 alkenylene-R4C 2-C4 Alkylene-R4, -O-C1-C4 alkylene-R4, -NH 2 -NH (C1-C4 alkylene-R4), -N (C1-C4 alkylene-R4) 2 -C (=o) -OH, -C (=o) -O-C1-C4 alkylene-R4, -C (=o) -NH 2 -C (=o) -NH (C1-C4 alkylene-R4), -C (=o) -N (C1-C4 alkylene-R4) 2 Ring P, ring Q, -O-ring P, or-O-ring Q;
r4 is hydrogen, -NH 2 -NH (C1-C2 alkyl) or-N (C1-C2 alkyl) 2 ；
Ring P is a 5-6 membered saturated or partially unsaturated carbocyclic ring optionally substituted with one to three R5, or a 5-6 membered saturated or partially unsaturated heterocyclic ring containing one to two heteroatoms selected from N and O optionally substituted with one to three R5;
each R5 is independently-NH 2 -OH, -CN, C1-C2 alkyl-R11, -O-C1-C2 alkyl or oxo;
each R11 is independently halogen, -NH 2 -OH, -CN or-O-C1-C2 alkyl;
ring Q is phenyl optionally substituted with one to three R6, or is 5-6 membered heteroaryl optionally substituted with one to three R6 containing one to two heteroatoms selected from N, S and O;
each R6 is independently-NH 2 -OH, -CN, C1-C2 alkyl or-O-C1-C2 alkyl;
r2 is hydrogen, halogen, -CN, C1-C4 alkyl optionally substituted by one or two R7, or a 4-to 7-membered saturated carbocyclic ring optionally substituted by one or two R8, or a 4-to 7-membered saturated heterocyclic ring containing one-N (R9) -moiety as ring member and additionally containing only carbon atoms as ring members;
each R7 is independently-OH, halogen, -NH 2 -NH (C1-C2 alkyl), -N (C1-C2 alkyl) 2 or-NH (-C (=o) -C1-C2 alkyl);
each R8 is independently-OH, halogen, -NH 2 -NH (C1-C2 alkyl), -N (C1-C2 alkyl) 2 or-NH (-C (=o) -C1-C2 alkyl); and is also provided with
R9 is hydrogen, C1-C4 alkyl or-C (=O) -C1-C2 alkyl.
The compound of paragraph 2C, paragraph 1C, or a pharmaceutically acceptable salt thereof, wherein when A is a group (A1), X is attached to a carbon atom located para to #2, and when A is a group (A2), X is attached to a carbon atom adjacent to the S atom.
The compound of paragraph 1C or paragraph 2C, or a pharmaceutically acceptable salt thereof, wherein a is a group (A1).
The compound of paragraph 1C or paragraph 2C, or a pharmaceutically acceptable salt thereof, wherein A is a group (A2).
Paragraph 5C the compound of any one of paragraphs 1C to 4C or a pharmaceutically acceptable salt thereof, wherein X is-O-, -C (=CH) 2 )-、-CH 2 -or-N (CH) 3 ) -wherein when R2 is halogen, X is a bond.
Paragraph 6C the compound of any one of paragraphs 1C to 5C or a pharmaceutically acceptable salt thereofWherein R1 is hydrogen, C1-C6 alkylene-R3, one of which is not terminal-CH 2 The moiety may be replaced by-O-, or R1 is ring P or ring Q.
The compound of any one of paragraphs 1C to 5C, or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen or C1-C3 alkylene-R3.
The compound of paragraph 8C, paragraph 7C, or a pharmaceutically acceptable salt thereof, wherein R3 is hydrogen, -CN, -OH, -O-C1-C4 alkyl, C2-C4 alkynyl, -C (=O) -OH, -C (=O) -O-C1-C4 alkyl, -C (=O) -NH 2 -C (=o) -NH (C1-C4 alkyl).
A compound of paragraph 9C, paragraph 7C, or a pharmaceutically acceptable salt thereof, wherein R3 is oxazolidin-2-one optionally substituted with one R5.
The compound of any one of paragraphs 1C to 9C, or a pharmaceutically acceptable salt thereof, wherein R3 is hydrogen, -CN, -OH, C2-C4 alkenyl, C2-C4 alkynyl, -O-C1-C4 alkyl, -NH 2 -C (=o) -OH, -C (=o) -O-C1-C4 alkyl, -C (=o) -NH 2 -C (=o) -NH (C1-C4 alkylene-R4), ring P, ring Q, -O-ring P or-O-ring Q.
The compound of any one of paragraphs 1C to 10C, or a pharmaceutically acceptable salt thereof, wherein R2 is halogen, C1-C4 alkyl optionally substituted with one or two R7, or a 6 membered saturated carbocyclic ring optionally substituted with one or two R8, or a 6 membered saturated heterocyclic ring containing one-N (R9) -moiety as a ring member and additionally containing only carbon atoms as ring members.
Paragraph 12C the compound of paragraph 1C or a pharmaceutically acceptable salt thereof, wherein
A is selected from the group consisting of group (A1) and group (A2), and wherein group (A1) is optionally substituted with one or two R10, and group (A2) is optionally substituted with one R10;
each R10 is independently fluorine, chlorine or-NH 2 ；
X is-O-, -C (=CH 2 )-、-CH 2 -, -NH-or-N (C1-C4 alkyl) -, wherein when R2 is halogen or-CN, X is a bond;
r1 is-Y-R3;
y is a bond or a C1-C6 alkylene group, one of which is non-terminal-CH 2 -part may be replaced by-O-;
r3 is hydrogen, -CN, -OH, C2-C4 alkenyl, C2-C4 alkynyl, -O-C1-C4 alkyl, -NH 2 -C (=o) -OH, -C (=o) -O-C1-C4 alkyl, -C (=o) -NH 2 -C (=o) -NH (C1-C4 alkylene-R4), ring P, ring Q, -O-ring P or-O-ring Q;
r4 is hydrogen, -NH 2 or-NH (CH) 3 )；
Ring P is a 6 membered saturated carbocyclic ring optionally substituted with one to two R5, or a 5 membered saturated heterocyclic ring containing one to two heteroatoms selected from N and O optionally substituted with one to two R5;
each R5 is independently-NH 2 -OH, -CN, C1-C2 alkyl, -C1-C2 alkyl-R11, -O-C1-C2 alkyl or oxo;
each R11 is independently halogen, -NH 2 -OH, -CN or-O-C1-C2 alkyl;
ring Q is phenyl optionally substituted with one to three R6, or is 5 membered heteroaryl optionally substituted with one to three R6 containing one to two heteroatoms selected from N, S and O;
Each R6 is independently-NH 2 、-OH、-CN、-CH 3 or-OCH 3 ；
R2 is halogen, C1-C4 alkyl optionally substituted by one or two R7, or is a 6-membered saturated carbocyclic ring optionally substituted by one or two R8, or is a 6-membered saturated heterocyclic ring containing one-N (R9) -moiety as ring member and additionally containing only carbon atoms as ring members;
each R7 is independently halogen or-NH 2 The method comprises the steps of carrying out a first treatment on the surface of the And is also provided with
Each R8 is independently halogen or-NH 2 。
Paragraph 13C the compound of paragraph 1C or a pharmaceutically acceptable salt thereof, wherein
A is a group (A1) optionally substituted with one R10;
r10 is chlorine or-NH 2 ；
X is-O-, -C (=CH 2 )-、-CH 2 -or-N (CH) 3 ) -wherein when R2 is halogen, X is a bond;
r1 is hydrogen or C1-C6 alkylene-R3;
r3 is hydrogen, -CN, -OH, -O-C1-C4 alkyl, C2-C4 alkynyl, -C (=O) -OH, -C (=O) -O-C1-C4 alkyl, -C (=O) -NH 2 -C (=o) -NH (C1-C4 alkyl), or oxazolidin-2-one optionally substituted with one R5;
r5 is C1-C2 alkyl or-C1-C2 alkyl-R11;
r11 is halogen, -NH 2 -OH, -CN or-O-C1-C2 alkyl;
and is also provided with
R2 is fluorine, chlorine, bromine, -CH 3 4-amino-cyclohexyl or 4-amino-3-fluoro-cyclohexyl.
Paragraph 14C the compound of paragraph 1C, or a pharmaceutically acceptable salt thereof, wherein the compound having formula (IA) is a compound having formula (IAa)
R10 is chlorine or-NH 2 ；
X is-O-, -C (=CH 2 )-、-CH 2 -or-N (CH) 3 ) -wherein when R2 is halogen, X is a bond;
r1 is hydrogen or C1-C3 alkylene-R3;
r3 is hydrogen, -CN, -OH, -O-C1-C4 alkyl, C2-C4 alkynyl, -C (=O) -OH, -C (=O) -O-C1-C4 alkyl, -C (=O) -NH 2 -C (=o) -NH (C1-C4 alkyl), or oxazolidin-2-one optionally substituted with one R5;
r5 is C1-C2 alkyl or-C1-C2 alkyl-R11;
r11 is halogen, -NH 2 -OH, -CN or-O-C1-C2 alkyl;
r2 is fluorine, chlorine, bromine, -CH 3 4-amino-cyclohexyl or 4-amino-3-fluoro-cyclohexyl; and is also provided with
n is 0 or 1:
in further embodiments, the present invention provides the following compounds and pharmaceutically acceptable salts thereof:
(6E) -8- (trans-4-aminocyclohexyloxy) -6-methoxyimino-5, 5-dimethyl-benzo [ h ] quinazolin-4-amine;
(6Z) -8- (trans-4-aminocyclohexyloxy) -6-benzyloxyimino-5, 5-dimethyl-benzo [ h ] quinazolin-4-amine;
(6Z) -8- (trans-4-aminocyclohexyloxy) -6-methoxyimino-5, 5-dimethyl-benzo [ h ] quinazolin-4-amine;
(6E) -4-amino-8- (trans-4-aminocyclohexyloxy) -5, 5-dimethyl-benzo [ h ] quinazolin-6-one oxime;
(6Z) -4-amino-8- (trans-4-aminocyclohexyloxy) -5, 5-dimethyl-benzo [ h ] quinazolin-6-one oxime;
3- [ (Z) - [ 4-amino-8- (trans-4-aminocyclohexyloxy) -5, 5-dimethyl-benzo [ h ] quinazolin-6-ylidene ] amino ] oxopropanoic acid methyl ester;
3- [ (Z) - [ 4-amino-8- (trans-4-aminocyclohexyloxy) -5, 5-dimethyl-benzo [ h ] quinazolin-6-ylidene ] amino ] oxypropan-1-ol;
(6Z) -8- (trans-4-aminocyclohexyloxy) -5, 5-dimethyl-6- [2- (1-piperidinyl) ethoxyimino ] benzo [ h ] quinazolin-4-amine;
(6Z) -8- (trans-4-aminocyclohexyloxy) -6- [3- (diethylamino) propoxyimino ] -5, 5-dimethyl-benzo [ h ] quinazolin-4-amine;
(6Z) -8- (trans-4-aminocyclohexyloxy) -6- [2- (diethylamino) ethoxyimino ] -5, 5-dimethyl-benzo [ h ] quinazolin-4-amine;
2- [ (Z) - [ 4-amino-8- (trans-4-aminocyclohexyloxy) -5, 5-dimethyl-benzo [ h ] quinazolin-6-ylidene ] amino ] oxyethanol;
4- [ [ (Z) - [ 4-amino-8- (trans-4-aminocyclohexyloxy) -5, 5-dimethyl-benzo [ h ] quinazolin-6-ylidene ] amino ] oxymethyl ] benzonitrile;
(6Z) -8- (trans-4-aminocyclohexyloxy) -5, 5-dimethyl-6-prop-2-ynyloxy imino-benzo [ h ] quinazolin-4-amine;
[ (Z) - [ 4-amino-8- (trans-4-aminocyclohexyloxy) -5, 5-dimethyl-benzo [ h ] quinazolin-6-ylidene ] amino ] oxyacetonitrile;
3- [ (Z) - [ 4-amino-8- (trans-4-aminocyclohexyloxy) -5, 5-dimethyl-benzo [ h ] quinazolin-6-ylidene ] amino ] oxy-propionic acid ethyl ester;
(6Z) -8- (trans-4-aminocyclohexyloxy) -6-ethoxyimino-5, 5-dimethyl-benzo [ h ] quinazolin-4-amine;
(6Z) -8- (trans-4-aminocyclohexyloxy) -6- [ (3, 5-dimethylisoxazol-4-yl) methoxyimino ] -5, 5-dimethyl-benzo [ h ] quinazolin-4-amine;
(6Z) -8- (trans-4-aminocyclohexyloxy) -6- (3-benzyloxy-propoxyimino) -5, 5-dimethyl-benzo [ h ] quinazolin-4-amine;
4- [ (Z) - [ 4-amino-8- (trans-4-aminocyclohexyloxy) -5, 5-dimethyl-benzo [ h ] quinazolin-6-ylidene ] amino ] oxybutyronitrile;
(6Z) -8- (trans-4-aminocyclohexyloxy) -5, 5-dimethyl-6- (2-pyrrolidin-1-ylethoxyimino) benzo [ h ] quinazolin-4-amine;
(6Z) -8- (trans-4-aminocyclohexyloxy) -6- (2-methoxyethoxyimino) -5, 5-dimethyl-benzo [ h ] quinazolin-4-amine;
(6Z) -8- (trans-4-aminocyclohexyloxy) -6-isobutoxyimino-5, 5-dimethyl-benzo [ h ] quinazolin-4-amine;
2- [ (Z) - [ 4-amino-8- (trans-4-aminocyclohexyloxy) -5, 5-dimethyl-benzo [ h ] quinazolin-6-ylidene ] amino ] oxyacetic acid methyl ester;
2- [ (Z) - [ 4-amino-8- (trans-4-aminocyclohexyloxy) -5, 5-dimethyl-benzo [ h ] quinazolin-6-ylidene ] amino ] oxyacetamide;
2- [ (Z) - [ 4-amino-8- (trans-4-aminocyclohexyloxy) -5, 5-dimethyl-benzo [ h ] quinazolin-6-ylidene ] amino ] oxy-N-methyl-acetamide;
5- [ [ (Z) - [ 4-amino-8- (trans-4-aminocyclohexyloxy) -5, 5-dimethyl-benzo [ h ] quinazolin-6-ylidene ] amino ] oxymethyl ] oxazolidin-2-one;
(6Z) -8- (trans-4-aminocyclohexyloxy) -6- [2- (dimethylamino) ethoxyimino ] -5, 5-dimethyl-benzo [ h ] quinazolin-4-amine;
(6Z) -8- [1- (trans-4-aminocyclohexyl) vinyl ] -6-methoxyimino-5, 5-dimethyl-benzo [ h ] quinazolin-4-amine;
(6E) -8- [1- (trans-4-aminocyclohexyl) vinyl ] -6-methoxyimino-5, 5-dimethyl-benzo [ h ] quinazolin-4-amine;
2- [ (Z) - (4-amino-8-methoxy-5, 5-dimethyl-benzo [ h ] quinazolin-6-ylidene) amino ] oxyacetic acid;
(6Z) -6- [ (trans-4-aminocyclohexyl) methoxyimino ] -8-methoxy-5, 5-dimethyl-benzo [ h ] quinazolin-4-amine;
(6Z) -6- (cis-4-aminocyclohexyloxy) imino-8-methoxy-5, 5-dimethyl-benzo [ h ] quinazolin-4-amine;
(6Z) -6- (trans-4-aminocyclohexyloxy) imino-8-methoxy-5, 5-dimethyl-benzo [ h ] quinazolin-4-amine;
2- [ (Z) - (4-amino-8-methoxy-5, 5-dimethyl-benzo [ h ] quinazolin-6-ylidene) amino ] oxyacetamide;
4- [ (Z) - (4-amino-8-methoxy-5, 5-dimethyl-benzo [ h ] quinazolin-6-ylidene) amino ] oxybutyronitrile;
n- (2-aminoethyl) -2- [ (Z) - (4-amino-8-methoxy-5, 5-dimethyl-benzo [ h ] quinazolin-6-ylidene) amino ] oxy-acetamide;
(5S) -5- [ [ (Z) - [ 4-amino-8- (trans-4-aminocyclohexyloxy) -5, 5-dimethyl-benzo [ h ] quinazolin-6-ylidene ] amino ] oxymethyl ] oxazolidin-2-one;
(5R) -5- [ [ (Z) - (4-amino-8-methoxy-5, 5-dimethyl-benzo [ h ] quinazolin-6-ylidene) amino ] oxymethyl ] oxazolidin-2-one;
(5S) -5- [ [ (Z) - (4-amino-8-methoxy-5, 5-dimethyl-benzo [ h ] quinazolin-6-ylidene) amino ] oxymethyl ] oxazolidin-2-one;
(6Z) -8-methoxy-6-methoxyimino-5, 5-dimethyl-benzo [ h ] quinazolin-4-amine;
(6Z) -8- (trans-4-aminocyclohexyloxy) -10-chloro-6-methoxyimino-5, 5-dimethyl-benzo [ h ] quinazolin-4-amine;
(5R) -5- [ [ (Z) - [ 4-amino-8- (trans-4-aminocyclohexyloxy) -5, 5-dimethyl-benzo [ h ] quinazolin-6-ylidene ] amino ] oxymethyl ] oxazolidin-2-one;
(6Z) -9-chloro-8-methoxy-6-methoxyimino-5, 5-dimethyl-benzo [ h ] quinazolin-4-amine;
(6E) -7-chloro-8-methoxy-6-methoxyimino-5, 5-dimethyl-benzo [ h ] quinazolin-4-amine;
(6E) -8-methoxy-6-methoxyimino-5, 5-dimethyl-benzo [ h ] quinazoline-4, 7-diamine;
(6Z) -8-methoxy-6-methoxyimino-5, 5-dimethyl-benzo [ h ] quinazoline-4, 9-diamine;
(6Z) -7-chloro-8-methoxy-6-methoxyimino-5, 5-dimethyl-benzo [ h ] quinazolin-4-amine;
(6Z) -N8- (trans-4-aminocyclohexyl) -6-methoxyimino-N8-, 5-trimethyl-benzo [ h ] quinazoline-4, 8-diamine;
(6Z) -8- (trans-4-aminocyclohexyloxy) -6-methoxyimino-5, 5-dimethyl-thieno [3,2-h ] quinazolin-4-amine;
(5S) -5- [ [ (Z) - (4-amino-8-methoxy-5, 5-dimethyl-benzo [ h ] quinazolin-6-ylidene) amino ] oxymethyl ] -3-methyl-oxazolidin-2-one;
(5S) -5- [ [ (Z) - (4-amino-8-bromo-5, 5-dimethyl-benzo [ h ] quinazolin-6-ylidene) amino ] oxymethyl ] oxazolidin-2-one;
(5S) -5- [ [ (Z) - (4-amino-8-chloro-5, 5-dimethyl-benzo [ h ] quinazolin-6-ylidene) amino ] oxymethyl ] -3-methyl-oxazolidin-2-one;
(5S) -5- [ [ (Z) - (4-amino-8-bromo-5, 5-dimethyl-benzo [ h ] quinazolin-6-ylidene) amino ] oxymethyl ] -3-methyl-oxazolidin-2-one;
(6Z) -8- (cis-4-aminocyclohexyloxy) -6-methoxyimino-5, 5-dimethyl-benzo [ h ] quinazolin-4-amine;
3- [ (Z) - [ 4-amino-8- (trans-4-aminocyclohexyloxy) -5, 5-dimethyl-benzo [ h ] quinazolin-6-ylidene ] amino ] oxypropionitrile;
(5S) -5- [ [ (Z) - [ 4-amino-8- (trans-4-aminocyclohexyloxy) -5, 5-dimethyl-benzo [ h ] quinazolin-6-ylidene ] amino ] oxymethyl ] -3-methyl-oxazolidin-2-one;
(6Z) -6-methoxyimino-5, 5-dimethyl-8- [ - (1 r,3s,4 r) -4-amino-3-fluoro-cyclohexyloxy ] benzo [ h ] quinazolin-4-amine;
(6Z) -6- (2-aminoethoxyimino) -8-methoxy-5, 5-dimethyl-benzo [ h ] quinazolin-4-amine;
(6Z) -6- (3-aminopropoxyimino) -8-methoxy-5, 5-dimethyl-benzo [ h ] quinazolin-4-amine;
3- [ (E) - [ 4-amino-8- (trans-4-aminocyclohexyloxy) -5, 5-dimethyl-benzo [ h ] quinazolin-6-ylidene ] amino ] oxypropionitrile;
(6Z) -4-amino-6-methoxyimino-5, 5-dimethyl-benzo [ h ] quinazolin-8-ol;
(6Z) -8-methoxy-5, 5-dimethyl-6- [ [ (3R) -pyrrolidin-3-yl ] methoxyimino ] benzo [ h ] quinazolin-4-amine;
(6E) -8-methoxy-5, 5-dimethyl-6- [ [ (3R) -pyrrolidin-3-yl ] methoxyimino ] benzo [ h ] quinazolin-4-amine;
(6Z) -6-allyloxyimino-8- (trans-4-aminocyclohexyloxy) -5, 5-dimethyl-benzo [ h ] quinazolin-4-amine;
(6E) -6-allyloxyimino-8- (trans-4-aminocyclohexyloxy) -5, 5-dimethyl-benzo [ h ] quinazolin-4-amine;
(6Z) -6-methoxyimino-5, 5-dimethyl-8- (4-piperidinyloxy) benzo [ h ] quinazolin-4-amine;
(6Z) -8- (trans-4-aminocyclohexyloxy) -6-isopropoxyimino-5, 5-dimethyl-benzo [ h ] quinazolin-4-amine;
(6E) -8- (trans-4-aminocyclohexyloxy) -6-isopropoxyimino-5, 5-dimethyl-benzo [ h ] quinazolin-4-amine;
(6Z) -6-methoxyimino-N8, 5-trimethyl-N8- (4-piperidinyl) benzo [ h ] quinazoline-4, 8-diamine;
(6Z) -6-methoxyimino-5, 5-dimethyl-8- (4-piperidinylmethyl) benzo [ h ] quinazolin-4-amine;
(6Z) -8-methoxy-5, 5-dimethyl-6- [ [ (3S) -1-methylpyrrolidin-3-yl ] methoxyimino ] benzo [ h ] quinazolin-4-amine;
(4S) -4- [ [ (Z) - (4-amino-8-methoxy-5, 5-dimethyl-benzo [ h ] quinazolin-6-ylidene) amino ] oxymethyl ] pyrrolidin-2-one;
(4R) -4- [ [ (Z) - (4-amino-8-methoxy-5, 5-dimethyl-benzo [ h ] quinazolin-6-ylidene) amino ] oxymethyl ] pyrrolidin-2-one;
(6Z) -8- [ (trans-4-aminocyclohexyl) methyl ] -6-methoxyimino-5, 5-dimethyl-benzo [ h ] quinazolin-4-amine;
(6Z) -8- [ (cis-4-aminocyclohexyl) methyl ] -6-methoxyimino-5, 5-dimethyl-benzo [ h ] quinazolin-4-amine;
(4S) -4- [ [ (Z) - (4-amino-8-methoxy-5, 5-dimethyl-benzo [ h ] quinazolin-6-ylidene) amino ] oxymethyl ] -1-methyl-pyrrolidin-2-one;
(6Z) -10-fluoro-8-methoxy-6-methoxyimino-5, 5-dimethyl-benzo [ h ] quinazolin-4-amine;
(2R) -1- [ (Z) - [ 4-amino-8- (trans-4-aminocyclohexyloxy) -5, 5-dimethyl-benzo [ h ] quinazolin-6-ylidene ] amino ] oxypropan-2-ol;
(2S) -1- [ (Z) - [ 4-amino-8- (trans-4-aminocyclohexyloxy) -5, 5-dimethyl-benzo [ h ] quinazolin-6-ylidene ] amino ] oxypropan-2-ol;
(6Z) -8-bromo-6- (2-methoxyethoxyimino) -5, 5-dimethyl-benzo [ h ] quinazolin-4-amine;
3- [ (Z) - (4-amino-8-bromo-5, 5-dimethyl-benzo [ h ] quinazolin-6-ylidene) amino ] oxypropionitrile;
(6Z) -8- (cis-4-aminocyclohexyloxy) -6- (2-methoxyethoxyimino) -5, 5-dimethyl-benzo [ h ] quinazolin-4-amine;
3- [ (Z) - [ 4-amino-8- (cis-4-aminocyclohexyloxy) -5, 5-dimethyl-benzo [ h ] quinazolin-6-ylidene ] amino ] oxypropionitrile;
(Z) -4-amino-8-bromo-5, 5-dimethyl-benzo [ h ] quinazolin-6-one oxime;
(E) -4-amino-8-bromo-5, 5-dimethyl-benzo [ h ] quinazolin-6-one oxime;
2- [ (Z) - (4-amino-8-bromo-5, 5-dimethyl-benzo [ h ] quinazolin-6-ylidene) amino ] oxyethanol;
2- [ (Z) - [ 4-amino-8- (cis-4-aminocyclohexyloxy) -5, 5-dimethyl-benzo [ h ] quinazolin-6-ylidene ] amino ] oxyethanol;
(5S) -5- [ [ (Z) - [ 4-amino-8- (cis-4-aminocyclohexyloxy) -5, 5-dimethyl-benzo [ h ] quinazolin-6-ylidene ] amino ] oxymethyl ] -3-methyl-oxazolidin-2-one;
(6Z) -8-bromo-6-methoxyimino-5, 5-dimethyl-benzo [ h ] quinazolin-4-amine;
(5S) -5- [ [ (Z) - (4-amino-8-bromo-5, 5-dimethyl-benzo [ h ] quinazolin-6-ylidene) amino ] oxymethyl ] -3- (2-methoxyethyl) oxazolidin-2-one;
(5S) -5- [ [ (Z) - (4-amino-8-bromo-5, 5-dimethyl-benzo [ h ] quinazolin-6-ylidene) amino ] oxymethyl ] -3- (2-hydroxyethyl) oxazolidin-2-one;
(6Z) -4-amino-5, 5-dimethyl-6- [ [ (5S) -2-oxooxazolidin-5-yl ] methoxyimino ] benzo [ h ] quinazoline-8-carbonitrile;
(5S) -5- [ [ (Z) - (4-amino-8-iodo-5, 5-dimethyl-benzo [ h ] quinazolin-6-ylidene) amino ] oxymethyl ] oxazolidin-2-one;
(5S) -5- [ [ (Z) - [ 4-amino-8- (2-hydroxyethoxy) -5, 5-dimethyl-benzo [ h ] quinazolin-6-ylidene ] amino ] oxymethyl ] oxazolidin-2-one;
(6Z) -N8- (trans-4-aminocyclohexyl) -6- (2-methoxyethoxyimino) -5, 5-dimethyl-benzo [ h ] quinazoline-4, 8-diamine;
(6Z) -N8- (cis-4-aminocyclohexyl) -6- (2-methoxyethoxyimino) -5, 5-dimethyl-benzo [ h ] quinazoline-4, 8-diamine;
(5S) -5- [ [ (Z) - (4-amino-8-iodo-5, 5-dimethyl-benzo [ h ] quinazolin-6-ylidene) amino ] oxymethyl ] -3- (2-hydroxyethyl) oxazolidin-2-one;
(5S) -5- [ [ (Z) - (8-acetyl-4-amino-5, 5-dimethyl-benzo [ h ] quinazolin-6-ylidene) amino ] oxymethyl ] oxazolidin-2-one;
(6Z) -8- (trans-4-aminocyclohexyloxy) -6- (2-methoxyethoxyimino) spiro [ benzo [ h ] quinazolin-5, 1' -cyclopentane ] -4-amine;
(6Z) -8- (cis-4-aminocyclohexyloxy) -6- (2-methoxyethoxyimino) spiro [ benzo [ h ] quinazolin-5, 1' -cyclopentane ] -4-amine;
3- [ (Z) - [ 4-amino-8- (cis-4-aminocyclohexyloxy) spiro [ benzo [ h ] quinazolin-5, 1' -cyclopentane ] -6-ylidene ] amino ] oxypropionitrile;
3- [ (Z) - [ 4-amino-8- (trans-4-aminocyclohexyloxy) spiro [ benzo [ h ] quinazolin-5, 1' -cyclopentane ] -6-ylidene ] amino ] oxypropionitrile;
(6Z) -8- (cis-4-amino-4-methyl-cyclohexyloxy) -6- (2-methoxyethoxyimino) -5, 5-dimethyl-benzo [ h ] quinazolin-4-amine;
4-amino-8- (cis-4-aminocyclohexyloxy) spiro [ benzo [ h ] quinazolin-5, 1' -cyclopentane ] -6-one oxime;
(6Z) -8- (cis-4-aminocyclohexyloxy) -5, 5-dimethyl-6- [2- (trifluoromethoxy) ethoxyimino ] benzo [ h ] quinazolin-4-amine;
(6Z) -8- (cis-4-aminocyclohexyloxy) -5, 5-dimethyl-6- (2-phenylethoxyimino) benzo [ h ] quinazolin-4-amine;
(6Z) -8- (cis-4-aminocyclohexyloxy) -5, 5-dimethyl-6- (2-phenoxyethoxyimino) benzo [ h ] quinazolin-4-amine;
(6Z) -8- (cis-4-aminocyclohexyloxy) -5, 5-dimethyl-6- [3- (3-pyridyl) propoxy imino ] benzo [ h ] quinazolin-4-amine;
(6Z) -8- (cis-4-aminocyclohexyloxy) -6- (2-ethoxyethoxyimino) -5, 5-dimethyl-benzo [ h ] quinazolin-4-amine;
(6Z) -8- (cis-4-aminocyclohexyloxy) -5, 5-dimethyl-6- (3-methylsulfonylpropyloxyimino) benzo [ h ] quinazolin-4-amine;
4- [ (Z) - [ 4-amino-8- (cis-4-aminocyclohexyloxy) -5, 5-dimethyl-benzo [ h ] quinazolin-6-ylidene ] amino ] oxy-2, 2-dimethyl-butyronitrile;
(6Z) -8- (cis-4-aminocyclohexyloxy) -5, 5-dimethyl-6- [2- (2, 2-trifluoroethoxy) ethoxyimino ] benzo [ h ] quinazolin-4-amine;
(6Z) -8- (cis-4-aminocyclohexyloxy) -6- (4-fluorobutoxyimino) -5, 5-dimethyl-benzo [ h ] quinazolin-4-amine;
(6Z) -8- (cis-4-aminocyclohexyloxy) -5, 5-dimethyl-6- (4, 4-trifluorobutyloxyimino) benzo [ h ] quinazolin-4-amine;
(6Z) -8- (cis-4-aminocyclohexyloxy) -6- (3, 3-difluorobutyloxyimino) -5, 5-dimethyl-benzo [ h ] quinazolin-4-amine; and
(6Z) -8- (cis-4-aminocyclohexyloxy) -5, 5-dimethyl-6- (3, 3-trifluoropropoxyimino) benzo [ h ] quinazolin-4-amine.
Some intermediates useful in the preparation of compounds of formula (IA) and compounds of formula (IB) are novel and form further aspects of the invention. Thus, in another aspect, the present invention provides a compound having the formula (Int-IA)
And salts thereof, wherein A, X and R2 are as defined for compounds having formula (IA), including as defined in the preferred definitions and embodiments thereof (e.g., as defined in embodiments A1-a, A2-a, B1-a, B2-a, C1-a, C2-a, D1, D2, D3, E1, E2, E3).
In another aspect, the present invention provides a compound having the formula (Int-IB)
And salts thereof, wherein A, ra, rb, X and R2 are as defined for compounds having formula (IB), including as defined in the preferred definitions and embodiments thereof (e.g., as defined in embodiments A1-B, A2-B, B1-B, B2-B, C1-B, C2-B, F1, F2, F3).
In another aspect, the present invention provides a compound having formula (Int-IIA)
And salts thereof, wherein a and R1 are as defined for compounds having formula (IA), including as defined in the preferred definitions and embodiments thereof (e.g., as defined in embodiments A1-a, embodiments A2-a, embodiments B1-a, embodiments B2-a, embodiments C1-a, embodiments C2-a, embodiments D1, embodiments D2, embodiments D3, embodiments E1, embodiments E2, embodiments E3), and E is halogen (e.g., chlorine, bromine or iodine, preferably chlorine or bromine) or-O-L1, and-O-L1 is a leaving group, wherein L1 is selected from perfluoroalkyl sulfonyl such as triflyl (or triflyl) and sulfonyl such as p-tosyl (tosyl) or mesyl (mesyl) or mesyl).
In another aspect, the present invention provides a compound having formula (Int-IIB)
And salts thereof, wherein a, ra, rb and R1 are as defined for compounds having formula (IB), including as defined in the preferred definitions and embodiments thereof (e.g., as defined in embodiments A1-B, embodiments A2-B, embodiments B1-B, embodiments C2-B, embodiments F1, embodiments F2, embodiments F3), and E is halogen (e.g., chlorine, bromine or iodine, preferably chlorine or bromine) or-O-L1, and-O-L1 is a leaving group, wherein L1 is selected from perfluoroalkyl sulfonyl such as triflyl (triflyl or triflosulfonyl) and sulfonyl such as p-toluenesulfonyl (tosyl or p-tosyl) or methanesulfonyl (mesyl or methylsulfonyl).
The invention also relates to pharmaceutical compositions comprising as active ingredient a compound of formula (IA) or a compound of formula (IB) or a pharmaceutically acceptable salt thereof, which are particularly useful for the treatment of neoplastic diseases, in particular cancer, as described herein. The compositions may be formulated for parenteral administration, e.g. nasal, buccal, rectal, pulmonary, vaginal, sublingual, topical, transdermal, ocular, or in particular for oral administration, e.g. in the form of oral solid dosage forms, e.g. granules, pills, powders, tablets, film coated or sugar coated tablets, effervescent tablets, hard and soft capsules or hydroxypropyl methylcellulose (HPMC) capsules (suitably coated), orally disintegrating tablets, oral solutions, lipid emulsions or suspensions, or for parenteral administration, e.g. intravenous, intramuscular or subcutaneous, intrathecal, intradermal or epidural administration to mammals, especially humans, e.g. in the form of solutions, lipid emulsions or suspensions containing microparticles or nanoparticles. The composition may comprise the active ingredient alone, or preferably, in combination with a pharmaceutically acceptable carrier.
The compounds of formula (IA) and the compounds of formula (IB) or pharmaceutically acceptable salts thereof may be processed with pharmaceutically inert inorganic or organic excipients for the production of oral solid dosage forms, such as granules, pills, powders, tablets, film coated or sugar coated tablets, effervescent tablets, hard or HPMC capsules or orally disintegrating tablets. Fillers such as lactose, cellulose, mannitol, sorbitol, calcium phosphate, starch or derivatives thereof, binders such as cellulose, starch, polyvinylpyrrolidone or derivatives thereof, glidants such as talc, stearic acid or salts thereof, flow agents such as fumed silica, can be used as such excipients for the formulation and manufacture of oral solid dosage forms such as granules, pills, powders, tablets, film-coated or sugar-coated tablets, effervescent tablets, hard or HPMC capsules or orally disintegrating tablets. Suitable excipients for soft capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like.
Suitable excipients for the manufacture of oral solutions, lipid emulsions or suspensions are, for example, water, alcohols, polyols, sucrose, invert sugar, glucose, etc.
Suitable excipients for parenteral formulations are, for example, water, alcohols, polyols, glycerol, vegetable oils, lecithins, surfactants and the like.
In addition, the pharmaceutical preparations may contain preservatives, solubilizers (e.g. cyclodextrins), stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. The pharmaceutical preparations may also contain other therapeutically valuable substances.
The dosage can vary within wide limits and, of course, in each particular case meets the individual requirements. Generally, in the case of oral administration, a daily dosage of about 1 to 1000mg of the compound of formula (IA) or the compound of formula (IB) per person should be appropriate, although the lower or upper limit described above may also be exceeded if necessary.
The compounds of formula (IA) and compounds of formula (IB) may also be used in combination with one or more other pharmaceutically active compounds which are also effective against the same disease, preferably using different modes of action, or reducing or preventing the possible unwanted side effects of the compounds of formula (IA) and compounds of formula (IB). The combination partners may be administered simultaneously in such a treatment, e.g. by incorporating them into a single pharmaceutical formulation or sequentially by administration of two or more different dosage forms, each dosage form containing one or more than one combination partner.
The compounds of formula (IA) and the compounds of formula (IB) or pharmaceutically acceptable salts thereof according to the invention as described above are particularly suitable for the treatment of neoplastic diseases, such as cancer, particularly when administered in therapeutically effective amounts. In some embodiments, cancers treated by the compounds of the invention may be treated by inhibiting one or more CLK enzymes. In some embodiments, cancers treated by the compounds of the invention may be treated by inhibiting aberrant splicing. Cancer may be driven by aberrant splicing, for example, the cancer may be a splicing factor mutant cancer. Cancers may rely on oncogenic splice variants.
Examples of proliferative disorders and diseases treated by the compounds of the invention include, but are not limited to, epithelial tumors, squamous cell tumors, basal cell tumors, transitional cell papillomas and carcinomas, adenomas and adenocarcinomas, appendage and skin appendage tumors, myxoepidermoid tumors, cystic tumors, mucinous and serous tumors, ductal, lobular and medullary tumors, acinar cell tumors, complex epithelial tumors, specialized gonadal tumors, paragangliomas and angioglobomas, nevi and melanomas, soft tissue tumors and sarcomas, fibromatous tumors, myxomatous tumors, lipomatous tumors, myomatous tumors, complex mixed stromal tumors, fibroepithelial tumors, synovial-like tumors, mesothelial tumors, germ cell tumors, trophoblastic tumors, mesonephromas, hemangiomas, lymphomas, osteogenic and chondromatous tumors, giant cell tumors, heteroosteogenic tumors, odontogenic tumors, gliomas, neuroepithelial tumors and neuroendocrine tumors, meningiomas, schwannomas, granulomatous and alveolar soft tissue sarcomas, hodgkin's and non-Hodgkin's lymphomas, B-cell lymphomas, T-cell lymphomas, hairy cell lymphomas, burkitt lymphomas (Burkitts lymphoma) and other lymphoreticular tumors, plasmacytomas, mast cell tumors, immunoproliferative diseases, leukemias, heteromyeloproliferative disorders, lymphoproliferative disorders, and myelodysplastic syndromes.
Examples of cancers of affected body organs and regions include, but are not limited to, breast, cervical, ovarian, colon, rectum (including colon and rectum, i.e., colorectal cancer), lung (including small cell lung cancer, non-small cell lung cancer, large cell lung cancer, and mesothelioma), endocrine system, bone, adrenal gland, thymus, liver, stomach (gastric cancer), intestine, pancreas, bone marrow, hematologic malignancy (such as lymphoma, leukemia, myeloma, or lymphoid malignancy), bladder, urinary tract, kidney, skin, thyroid, brain, head, neck, prostate, and testes. Preferably, the cancer is selected from the group consisting of: breast cancer, prostate cancer, cervical cancer, ovarian cancer, gastric cancer, colorectal cancer, pancreatic cancer, liver cancer, brain cancer, neuroendocrine cancer, lung cancer, renal cancer, bladder cancer, mesothelioma, hematological malignancy, melanoma, and sarcoma.
Further examples of proliferative disorders and diseases treated by the compounds of the invention are hematological malignancies, such as acute myelogenous leukemia, myelodysplastic syndrome, chronic myelomonocytic leukemia, chronic lymphocytic leukemia, non-hodgkin's lymphoma; solid tumors, such as mucosal melanoma, uveal melanoma, medulloblastoma, hepatocellular carcinoma, endometrial carcinoma, bladder carcinoma, cutaneous melanoma, lung adenocarcinoma, pancreatic cancer, breast cancer; cancers with mutations in the splicing gene, such as cancers with amplification or fusion of the splicing factor, cancers driven by oncogenic transcription factor signaling, cancers driven by oncogenic splice variants, cancers with partial or complete deletion of the splicing factor and/or genes involved in splice regulation.
The term "treatment" as used herein in the context of treating a disease or disorder generally relates to treatment and therapy of either a human or an animal (e.g., in veterinary applications), wherein some desired therapeutic effect is obtained, e.g., inhibiting the progression of the disease or disorder, and includes reducing the rate of progression, stopping the rate of progression, alleviating symptoms of the disease or disorder, ameliorating the disease or disorder, and curing the disease or disorder. Treatment (i.e., prevention) as a precaution is also included. For example, the term "treating" encompasses use with respect to a patient who has not yet developed, but is at risk of developing, the disease or disorder. For example, treatment includes prevention of cancer, reduction of cancer incidence, alleviation of cancer symptoms, and the like.
The term "therapeutically effective amount" as used herein relates to an amount of a compound, or a material, composition or dosage form comprising a compound, that is effective to produce some desired therapeutic effect when administered according to a desired therapeutic regimen, commensurate with a reasonable benefit/risk ratio.
The term "pharmaceutical composition" is defined herein to mean a solid or liquid formulation containing at least one therapeutic agent to be administered to a subject (e.g., a mammal or a human), optionally with one or more pharmaceutically acceptable excipients, to prevent or treat a particular disease or condition affecting the mammal.
The term "pharmaceutically acceptable" as used herein refers to those articles of manufacture which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of warm-blooded animals (e.g. mammals or humans) without excessive toxicity or other complications commensurate with a reasonable benefit/risk ratio, such as compounds and salts, materials, compositions and/or dosage forms thereof.
The compounds of formula (IA) and the compounds of formula (IB) may be synthesized by the methods given below, by the methods given in the experimental section below or by similar methods. The schemes described herein are not intended to present an exhaustive list of methods for preparing compounds having formula (IA) and compounds having formula (IB); conversely, other techniques known to the skilled chemist may be used for compound synthesis.
Those familiar with organic synthesis will appreciate that the optimum reaction conditions will vary with the particular reactants or solvents used, but such conditions can be determined by routine optimisation procedures. In some cases, the following reaction schemes and/or the order of the reaction steps may be altered to facilitate the reaction or to avoid the formation of unwanted byproducts. Furthermore, the functional groups present at various positions of the molecule must be compatible with the reagents and reactions proposed. Such limitations on substituents compatible with the reaction conditions will be apparent to those skilled in the art and alternative methods must then be used. Furthermore, in some of the reactions mentioned herein, it may be necessary or desirable to protect any sensitive groups in the compound, and it is assumed that such Protecting Groups (PG) are in place when necessary. Conventional protecting groups may be used according to standard practices well known in the art (for illustration, see Greene T.W, wuts P.G.M., protective Groups in Organic Synthesis [ protecting group in organic Synthesis ], 5 th edition, publisher: john Wiley father-son publishing company (John Wiley & Sons), 2014). The protecting group may be removed at any convenient stage in the synthesis using conventional techniques well known in the art, or may be removed in a subsequent reaction step or post-treatment.
In the general reaction sequence outlined below, the abbreviations X and ring a and the general groups Ra, rb, R1 and R2 are as defined for formula (IA) and formula (IB), unless otherwise indicated. Other abbreviations used herein are expressly defined or defined in the experimental section.
The necessary starting materials for the synthetic methods as described herein (if not commercially available) may be prepared by procedures described in the scientific literature or may be prepared from commercially available compounds by modifying the methods reported in the scientific literature. For general guidance on reaction conditions and reagents, the reader is further referred to, for example, march j., smith m., advanced Organic Chemistry [ higher organic chemistry ], 7 th edition, publisher: john wili father-child publishing company (John Wiley & Sons), 2013.
The compounds according to the invention, their pharmaceutically acceptable salts, solvates and hydrates may be prepared according to the general reaction sequence outlined in schemes 1 and 2 below, if desired, followed by:
-manipulating substituents to give new end products. Such manipulations may include, but are not limited to, reduction, oxidation, alkylation, acylation, substitution, coupling (including transition metal catalyzed coupling), and hydrolysis reactions generally known to those skilled in the art;
-removing any protecting groups;
-forming a pharmaceutically acceptable salt; or (b)
-forming a pharmaceutically acceptable solvate or hydrate.
Scheme 1
Scheme 2
The compounds of formulae (IIA), (IIB) and (IV) can be obtained from commercial sources or prepared according to the procedures described in the literature (see, for example, fukuda et al, bioorg. Med. Chem. Lett. [ bioorganic and pharmaceutical chemistry Instructions ]2018,1;28 (20): 3333-3337), or by procedures known to those skilled in the art.
The compounds of formula (Int-IA) and formula (Int-IB) may be prepared from the compounds of formula (IIA) and formula (IIB) by oxidation in water and acetone at a temperature between room temperature and 100 ℃ using, for example, potassium permanganate as an oxidizing agent.
Compounds of formula (Int-IA) and formula (Int-IB) wherein X is-O-and R2 is hydrogen may be prepared from a compound of formula (Int-IA) wherein X is-O-and R2 is CH 3 The compounds of formula (Int-IA) and formula (Int-IB) are prepared by demethylation in a solvent, such as methylene chloride, in the presence of a lewis acid, such as aluminum chloride, boron tribromide or boron trifluoride, at a temperature between 0 ℃ and 100 ℃.
The compounds of formula (IA) and formula (IB) may be represented by compounds of formula (Int-IA) and formula (Int-IB) and E1 is O-NH 2 Is prepared by condensation reaction. The reaction is carried out at a temperature between room temperature and 150 ℃, in a solvent (such as methanol, ethanol or water), with or without an organic base (e.g. sodium acetate, triethylamine, pyridine).
Alternatively, compounds of formula (IA) and formula (IB) wherein X is-O-may be prepared from compounds of formula (IA) and formula (IB) wherein X is-O-and R1 is hydrogen and compounds of formula (IV) wherein E1 is halogen or a leaving group-O-L1 wherein L1 is a methanesulfonyl, p-toluenesulfonyl or trifluoromethanesulfonyl group by substitution reaction. The reaction is generally carried out at a temperature between-20℃and 100℃in a dry aprotic solvent (such as dichloromethane, acetonitrile, N-dimethylformamide, dimethyl sulfoxide or tetrahydrofuran), without or with an inorganic base (such as potassium carbonate or cesium carbonate) or with an organic base (such as triethylamine or N, N-diisopropylethylamine). Formation of the mesylate, tosylate or triflate compound may be achieved by reacting the corresponding alcohol with methanesulfonyl chloride or methanesulfonic anhydride, p-toluenesulfonyl chloride, triflyl chloride or triflic anhydride, respectively, in the presence of a base such as triethylamine or the like in a dry aprotic solvent such as pyridine, acetonitrile, tetrahydrofuran or dichloromethane at a temperature between-30 ℃ and 80 ℃.
Alternatively, compounds of formula (IA) and formula (IB) wherein X is-O-can be prepared from compounds of formula (IA) and formula (IB) wherein X is-O-and R2 is hydrogen and ethanol by photolithographically coupling (Mitsunobu coupling) (as reviewed in o.mitsunobu, synthesis, volume 1, pages 1-28, 1981). The reaction is carried out in the presence of diethyl azodicarboxylate or diisopropyl azodicarboxylate and triphenylphosphine in a wide range of solvents such as N, N-dimethylformamide, tetrahydrofuran, 1, 2-dimethoxyethane or methylene chloride and over a wide temperature range (e.g. between-20 ℃ and 60 ℃). The reaction can also be carried out using polymer supported triphenylphosphine.
Alternatively, compounds of formula (IA) and formula (IB) wherein X is-O-may be prepared from compounds of formula (IA) and formula (IB) wherein X is-O-and R2 is hydrogen and halides or alcohols previously converted to the corresponding mesylate, tosylate or triflate by substitution reactions using the conditions previously described.
Compounds of formula (IA) and formula (IB) wherein X is-NH-or-N (C1-C4 alkyl) -may be prepared from compounds of formula (Int-IIA) and formula (Int-IIB) as previously defined and amines by substitution reactions using the conditions previously described.
Compounds of formula (Int-IIA) and formula (Int-IIB) can be prepared from compounds of formula (IA) and formula (IB) wherein X is-O-and R2 is hydrogen by substitution reactions using the conditions previously described.
Alternatively, compounds of formula (IA) and formula (IB) wherein X is-NH-or-N (C1-C4 alkyl) -may be prepared from compounds of formula (Int-IIA) and formula (Int-IIB) as defined previously and amines by reaction coupling over a transition metal catalyst. Typical catalysts include palladium (II) acetate, tris (dibenzylideneacetone) dipalladium (0), and the like. The reaction is typically carried out at a temperature of from 0 ℃ to 150 ℃, more typically from 80 ℃ to 110 ℃. Typically, the reaction is carried out in the presence of a ligand (e.g., di-tert-butyl- [3, 6-dimethoxy-2- (2, 4, 6-triisopropylphenyl) phenyl ] phosphine, di-tert-butyl- [2,3,4, 5-tetramethyl-6- (2, 4, 6-triisopropylphenyl) phenyl ] phosphine, 2- (dicyclohexylphosphino) biphenyl, 4, 5-bis (diphenylphosphino) -9, 9-dimethylbenzopyran, etc.), and a base (e.g., sodium t-butoxide, cesium carbonate, potassium carbonate, more typically cesium carbonate), in various inert solvents (e.g., toluene, tetrahydrofuran, dioxane, 1, 2-dichloroethane, N-dimethylformamide, dimethyl sulfoxide, water and acetonitrile, or a solvent mixture, more typically in dioxane). Since there are many components in the coupling of transition metal catalysts, such as specific palladium catalysts, ligands, additives, solvents, temperatures, numerous schemes have been identified. Those skilled in the art will be able to identify satisfactory solutions without undue experimentation.
X is-CH 2 -or-C (=ch 2 ) The compounds of formula (IA) and formula (IB) can be prepared from the compounds of formula (Int-IIA) and formula (Int-IIB) as defined previously and boric acid by Suzuki reaction (Suzuki reaction). The suzuki reaction is a palladium-catalyzed cross-coupling reaction between an organoboronic acid and an aryl or vinyl halide or triflate. Typical catalysts include palladium (II) acetate, tetrakis (triphenylphosphine) palladium (0), bis (triphenylphosphine) palladium (II) dichloride, and [1,1' -bis (diphenylphosphino) ferrocene]Palladium (II) dichloride. The reaction may be carried out in a variety of organic solvents including toluene, tetrahydrofuran, dioxane, 1, 2-dichloroethane, N-dimethylformamide, dimethyl sulfoxide and acetonitrile, aqueous solutions and biphasic conditions. The reaction is generally carried out at room temperature to 150 ℃. Additives such as cesium fluoride, potassium hydroxide or sodium ethoxide often accelerate coupling. Instead of boric acid, potassium trifluoroborate and organoboranes or borates may be used. Although there are many components in the suzuki reaction, such as specific palladium catalysts, ligands, additives, solvents, temperatures, numerous schemes have been identified. Those skilled in the art will be able to identify satisfactory solutions without undue experimentation.
Alternatively, X is-CH 2 -or-C (=ch 2 ) Compounds of formula (IA) and formula (IB) can be prepared from compounds of formula (Int-IIA) and formula (Int-IIB) wherein E is boric acid and halogen or triflate by suzuki reaction using the conditions previously described. The compounds of formula (IA) and formula (IB) wherein X is a bond and R2 is halogen can be prepared from compounds of formula (Int-I) wherein X is a bond and R2 is halogen using the methods previously described.
The oximes of the compounds of formula (IA) and formula (IB) exist in the form of 2 isomers and each isomer may be isolated at any convenient stage of the general reaction sequence outlined in schemes 1 and 2.
The skilled chemist will appreciate that it may be necessary to use different protecting groups (e.g. for R1 and R2) during synthesis to provide compounds of formulae (IA) and (IB).
The schemes and methods described herein are not intended to present an exhaustive list of methods for preparing compounds having formulas (IA) and (IB); conversely, other techniques known to the skilled chemist may be used for compound synthesis.
All aspects and embodiments of the invention described herein can be combined in any combination where possible.
Various publications are cited herein to more fully describe and disclose the invention and the state of the art to which the invention pertains. Each of these references is incorporated herein by reference in its entirety into the present disclosure to the same extent as if each individual reference was specifically and individually indicated to be incorporated by reference.
Specific embodiments of the invention are described in the following examples, which serve to illustrate the invention in more detail and are not to be construed as limiting the invention in any way.
Drawings
Fig. 1: FIG. 1 provides a representative Western blot showing that compounds of the invention reduce phosphorylated SRSF6 (P-SRSF 6) in MDA-MB 468 cells. GAPDH was probed by western blot to control equal protein loading and normalization of the samples. The numbers below the blot show the percentage of intensity of P-SRSF6 signal at 100nM compared to DMSO control.
Fig. 2: figure 2 shows tumor growth and weight changes in female NCG mice treated with vehicle or with different doses and schedules in example 29. Will be at 50% Matrigel TM 1×10 of (a) 7 The CAL-51 human triple negative breast cancer cells were inoculated subcutaneously on the flanks of NCG mice (8-12 weeks old). When the tumor reaches 100-150mm 3 Pairing was performed to assign animals to treatment groups (n=8/group) and treatment of each group was started. On days 1, 3, 7, 10, 14, 17 and 2 of the treatment periodTumor volumes were measured twice weekly using calipers (in mm for 1 day 3 Representation). (A) The mean tumor volume (±sem) of each treatment group is shown and at the end of the study (day 21) it is observed that the tumor volume is significant (×p) in the group treated with example 29 three times a week at 60mg/kg and two times a week at 85mg/kg compared to the vehicle-treated group<0.05, one-way ANOVA) was reduced. (B) Average body weight (expressed in g, ±sem) at day 1, day 2, day 3, day 4, day 5, day 7, day 10, day 14, day 17, and day 21 of the treatment period.
Preparation of examples
All reagents and solvents are typically used as received from commercial suppliers;
unless otherwise indicated, the reaction was carried out conventionally in a well dried glass instrument with anhydrous solvents under an argon or nitrogen atmosphere;
evaporation was performed under reduced pressure by rotary evaporation, and after removing residual solids by filtration, a post-treatment procedure was performed;
all temperatures are expressed in degrees celsius (°c) and are approximate temperatures; operation at room temperature (rt), typically in the range of 18 ℃ to 25 ℃, unless otherwise indicated;
Column chromatography (by flash procedure) was used to purify the compounds;
classical flash chromatography is often replaced by an automated system. This does not alter the separation process itself. Those skilled in the art will be able to replace classical flash chromatography by automated flash chromatography and vice versa. Typical automated systems may be used, for example provided by Buchi or Isco (combiflash);
unless otherwise indicated, the reaction mixture may generally be separated by preparative HPLC using, for example, water and acetonitrile as eluent systems. Those skilled in the art will find suitable conditions for each separation; the compounds are isolated after purification as the parent compound or as the corresponding trifluoroacetic acid (TFA) salt or the respective formate salt;
reactions requiring higher temperatures are typically performed using classical heating equipment; but may also be performed at 250W power using a microwave device (CEM Explorer) unless otherwise indicated;
the hydrogenation or hydrogenolysis reaction may be carried out using hydrogen in a balloon or using a system of pascal (Parr) devices or other suitable hydrogenation equipment;
solution concentration and solids drying under reduced pressure, unless otherwise indicated;
Typically, the course of the reaction is followed by TLC, HPLC or LC/MS, and the reaction time is given for illustration purposes only; the yields are given for illustrative purposes only and are not necessarily the maximum obtainable;
the structure and purity of the final product of the present invention is generally confirmed by NMR spectroscopy, HPLC and mass spectrometry techniques.
Proton NMR spectra were recorded on a Bruker 400MHz spectrometer. Chemical shift (delta) relative to Me as an internal standard 4 Ppm of Si or solvent peaks, and NMR coupling constants (J values) are reported in hertz (Hz). Each peak is expressed as broad singlet (br), singlet(s), doublet (d), triplet (t), quartet (q), doublet (dd), triplet (td) or multimodal (m).
HPLC of the final product was generated using a dienex MSQ ESI mode of dienex) Ultimate3000 instrument and the following conditions:
mobile phase a: water containing 0.1% formic acid
Mobile phase B: acetonitrile containing 0.1% formic acid
Column: YMC-Triart C18 μm 100mm 4.6mm
Column temperature: 25 DEG C
And (3) detection: UV 250nm
Injection: 2 μL of 10mM sample DMSO solution
Flow rate: 1.6mL/min
Mass spectra were generated in positive or negative ESI mode using a q-Tof um (Waters AG) or sammer technologies (Thermo Scientific) MSQ Plus) mass spectrometer. The system is provided with a standard Lockspray interface;
Purification of each intermediate to the standard required for the subsequent stage and sufficiently characterized to confirm that the specified structure is correct;
analytical and preparative HPLC on achiral phases using RP-C18 columns;
the following abbreviations (a comprehensive list of standard abbreviations and acronyms, also referred to Journal of Organic Chemistry Guidelines for Authors [ journal of organic chemistry authors ]):
AcOH acetic acid
ACN acetonitrile
Bn benzyl
BOC tert-butoxycarbonyl group
BOC 2 Di-tert-butyl O dicarbonate
BOP (benzotriazol-1-yloxy) tris (dimethylamino) phosphonium hexafluorophosphate
t-Brettphos 2- (di-t-butylphosphino) -2',4',6 '-triisopropyl-3, 6-dimethoxy-1, 1' -biphenyl
t-BuOH
t-Buona sodium t-butoxide
B 2 Pin 2 Bis (pinacolato) diboron
Compounds with CAS registry number for chemical abstracts service
CDCl 3 Deuterated chloroform
DBU 1, 8-diazabicyclo (5.4.0) undec-7-ene
DCE 1, 2-dichloroethane
DCM dichloromethane
DEAD Azodicarboxylic acid diethyl ester
Diox 1, 4-dioxane
DIPEA N, N-diisopropylethylamine
DMA dimethylacetamide
DMAP 4-dimethylaminopyridine
DMF N, N-dimethylformamide
DMSO dimethyl sulfoxide
DMSO-d 6 Deuterated dimethyl sulfoxide
D 2 O-deuterium oxide
EA ethyl acetate
ELSD evaporative light scattering detection
Et 2 O diethyl ether
EtOH ethanol
Ex. Examples
HATU 1- [ bis (dimethylamino) methylene ] -1H-1,2, 3-triazolo [4,5-b ] pyridine cation 3-oxide hexafluorophosphate
HPLC high performance liquid chromatography
KOAc potassium acetate
Lithium aluminium hydride LAH
LC/MS liquid chromatography and mass spectrometry
LDA lithium diisopropylamide
Me4tBuXPhos 2-di-tert-butylphosphino-3, 4,5, 6-tetramethyl-2 ',4',6 '-triisopropyl-1, 1' -biphenyl
MeOH methanol
Me 4 Si tetramethylsilane
MS mass spectrometry
MSA methanesulfonic acid
MW microwave
NaBH 3 CN cyano sodium borohydride
NaBH(OAc) 3 Sodium triacetoxyborohydride
NaHMDS bis (trimethylsilyl) amide sodium
NCS N-chlorosuccinimide
NFSI N-fluorobenzenesulfonimide
NMR nuclear magnetic resonance
Pd/C active carbon palladium-carrying
Pd 2 (dba) 3 Tris (dibenzylideneacetone) dipalladium (0)
Pd 2 (dppf)Cl 2 [1,1' -bis (diphenylphosphino) ferrocene ]Palladium dichloride (II)
Pd(OAc) 2 Palladium acetate (II)
PE Petroleum ether
PhCF 3 Benzotrifluoride (TFA)
PhNTf 2 N-phenyl-bis (trifluoromethanesulfonyl imide)
PhOK potassium phenolate
TBAI tetrabutylammonium iodide
TBS tertiary butyl dimethylsilyl group
TEA triethylamine
TES triethylsilane
TFA trifluoroacetic acid
Tf triflate ester
TfOH triflic acid
THF tetrahydrofuran
Tol toluene
Ts tosyl (4-tosyl)
TsCl 4-tosyl chloride
v/v volume ratio
XPhos dicyclohexyl [2',4',6 '-tris (propan-2-yl) [1,1' -biphenyl ] -2-yl ] phosphane
Zn(CN) 2 Zinc cyanide
The following examples refer to compounds having the formulas (IA) and (IB) as shown in table 1.
The examples listed in the following table can be prepared using the above procedure and detailed synthetic methods are described in detail below. The example numbers used in the leftmost column are used in the text of this application to identify the individual compounds.
TABLE 1
The hyphens in the second column represent the synthesis procedure as follows.
* Based on the acid used in the purification process/the assumption that basic nitrogen atoms are present in the molecule. For examples 112, 113, 114, the elution system used for purification by preparative HPLC was a mixture of acetonitrile and 50mM ammonium carbonate in water and assumed no salt formation.
Preparation of example 1: (6Z) -8- (trans-4-aminocyclohexyloxy) -6-methoxyimino-5, 5-dimethyl-benzo [ h ] quinazolin-4-amine:
step 1:2- [2- (3-methoxyphenyl) -1, 1-dimethyl-ethyl]Preparation of malononitrile:
3-methoxybenzyl magnesium chloride (96.0 mL,24.0mmol,0.25M in THF) was added dropwise to a stirred solution of isopropylidene malononitrile (2.00 g,18.5 mmol) in THF (50 mL) at 0deg.C. The resulting solution was stirred at room temperature for 3 hours. Then 1N aqueous HCl was added at 0deg.C and the resulting mixture was concentrated. The residue was taken up with EA and H 2 And O extraction. The combined organic layers were taken up over Na 2 SO 4 Dried, filtered and concentrated. The residue was purified by column chromatography (silica gel; PE: EA;5:1; v: v) to give 2- [2- (3-methoxyphenyl) -1, 1-dimethyl-ethyl ] as a yellow oil]Malononitrile (1.69 g,38% yield).
1 H NMR(400MHz,CDCl 3 )δppm:7.27(m,1H),6.86(m,1H),6.79(d,J＝7.6Hz,1H),6.74(m,1H),3.82(s,3H),3.44(s,1H),2.81(s,2H),1.29(s,6H)。
MS m/z(+ESI):229.1[M+H] + 。
Step 2: preparation of 1-amino-6-methoxy-3, 3-dimethyl-4H-naphthalene-2-carbonitrile:
trifluoromethanesulfonic acid (1.04 g,6.24 mmol) was added to 2- [2- (3-methoxyphenyl) -1, 1-dimethyl-ethyl ]]Malononitrile (300 mg,1.25 mmol) was in a stirred solution of DCM (6 mL) and the resulting mixture was stirred at 0deg.C for 2 hours. Addition of saturated NaHCO 3 Aqueous solution, and the mixture was extracted with DCM. The combined organic layers were taken up over Na 2 SO 4 Drying, filtration and concentration gave 1-amino-6-methoxy-3, 3-dimethyl-4H-naphthalene-2-carbonitrile (300 mg,95% yield) as a yellow solid, which was used in the next step without further purification.
1 H NMR(400MHz,CDCl 3 )δppm:7.31(d,J＝8.8Hz,1H),6.81(m,1H),6.74(d,J＝2.4Hz,1H),4.51(br,2H),3.85(s,3H),2.69(s,2H),1.17(s,6H)。
MS m/z(+ESI):229.1[M+H] + 。
Step 3: 8-methoxy-5, 5-dimethyl-6H-benzo [ H ]]Preparation of quinazolin-4-amine:
a suspension of 1-amino-6-methoxy-3, 3-dimethyl-4H-naphthalene-2-carbonitrile (1.00 g,3.94 mmol) and formamide (19 mL,473 mmol) was stirred at 180℃for 8 hours. After cooling to room temperature, the reaction mixture was taken up with H 2 O was diluted and extracted with EA. The combined organic layers were taken up over Na 2 SO 4 Dried, filtered and concentrated. The residue was purified by column chromatography (silica gel; PE: EA;1:1; v: v) to give 8-methoxy-5, 5-dimethyl-6H-benzo [ H ] as a pale yellow solid]Quinazolin-4-amine (700 mg,63% yield).
1 H NMR(400MHz,DMSO-d 6 )δppm:8.24(s,1H),7.99(d,J＝8.8Hz,1H),6.86(m,1H),6.79(d,J＝2.8Hz,1H),6.37(br,2H),3.79(s,3H),2.75(s,2H),1.28(s,6H)。
MS m/z(+ESI):256.1[M+H] + 。
Step 4: 4-amino-5, 5-dimethyl-6H-benzo [ H ]]Preparation of quinazolin-8-ol:
BBr is subjected to a temperature of-40 DEG C 3 (4.8 mL,4.80mmol,1M in DCM) to 8-methoxy-5, 5-dimethyl-6H-benzo [ H ]]A stirred solution of quinazolin-4-amine (450 mg,1.58 mmol) in DCM (30 mL). The resulting solution was stirred at room temperature for 18 hours. Addition of saturated NaHCO 3 The aqueous solution was collected by filtration and the resulting green solid was purified by filtration with H 2 O is washed and dried under reduced pressure at 60 ℃ to obtain 4-amino-5, 5-dimethyl-6H-benzo [ H ]]Quinazolin-8-ol (350 mg,82% yield).
1 H NMR(400MHz,DMSO-d 6 )δppm:8.21(s,1H),7.88(d,J＝8.4Hz,1H),6.67(m,1H),6.59(s,1H),6.29(br,2H),2.67(s,2H),1.26(s,6H)。
MS m/z(+ESI):242.2[M+H] + 。
Step 5: n- [ trans-4- [ (4-amino-5, 5-dimethyl-6H-benzo [ H ]]Quinazolin-8-yl) oxy]Cyclohexane (Cyclohexane)
Base group]Preparation of tert-butyl carbamate:
PPh at 0 DEG C 3 (600 mg,2.24 mmol) was added to 4-amino-5, 5-dimethyl-6H-benzo [ H ]]To a stirred solution of quinazolin-8-ol (300 mg,1.12 mmol) and tert-butyl N- (cis-4-hydroxycyclohexyl) carbamate (380 mg,1.68 mmol) in THF (10 mL) was then added DEAD (360 mg,2.01 mmol). The suspension was stirred at 45℃for 16 hours. The reaction was concentrated and purified by combined flash chromatography (comb flash) to give N- [ trans-4- [ (4-amino-5, 5-dimethyl-6H-benzo [ H ] as a white solid]Quinazolin-8-yl) oxy]Cyclohexyl group]Tert-butyl carbamate (200 mg,28% yield).
MS m/z(+ESI):439.3[M+H] + 。
Step 6: n- [ trans-4- (4-amino-5, 5-dimethyl-6-oxo-benzo [ h ]]Quinazolin-8-yl) oxy-rings
Hexyl group]Preparation of tert-butyl carbamate:
KMnO at 0 °c 4 (362 mg,2.28 mmol) was added to N- [4- [ (4-amino-5, 5-dimethyl-6H-benzo [ H ] ]Quinazoline-8-yl) oxy]Cyclohexyl group]Tert-butyl carbamate (250 mg,0.45 mmol) in acetone (10 mL) and H 2 To the stirred solution in O (2 mL) was then added MgSO 4 (137 mg,1.14 mmol). The resulting suspension was stirred at 45℃for 24 hours. The reaction mixture was taken up with EA and saturated Na 2 S 2 O 3 Extracting with aqueous solution. The combined organic layers were taken up over Na 2 SO 4 Drying, filtering and concentrating to obtain N- [ trans-4- (4-amino-5, 5-dimethyl-6-oxo-benzo [ h ] as a white solid]Quinazolin-8-yl) oxy-cyclohexyl]Tert-butyl carbamate (270 mg,59% yield), which was used in the next step without further purification.
MS m/z(+ESI):453.4[M+H] + 。
Step 7: n- [ trans-4- (4-amino-6-hydroxyimino-5, 5-dimethyl-benzo [ h ]]Quinazolin-8-yl) oxy
Cyclohexyl radical]Preparation of tert-butyl carbamate:
hydroxylamine hydrochloride (352 mg,4.97 mmol) was added to a stirred solution of tert-butyl N- [4- (4-amino-5, 5-dimethyl-6-oxo-benzo [ h ] quinazolin-8-yl) oxy cyclohexyl ] carbamate (250 mg,0.49 mmol) in pyridine (3 mL). The resulting mixture was stirred at 115℃for 4 hours. The solvent was removed and the residue was purified by combined flash chromatography (combiflash) to give tert-butyl N- [ trans-4- (4-amino-6-hydroxyimino-5, 5-dimethyl-benzo [ h ] quinazolin-8-yl) oxy cyclohexyl ] carbamate (190 mg,51% yield) as an off-white solid.
MS m/z(+ESI):468.3[M+H] + 。
Step 8: (6Z) -N- [ trans-4- (4-amino-6-methoxyimino-5, 5-dimethyl-benzo [ h ]]Quinazoline-
8-yl) oxy cyclohexyl]Preparation of tert-butyl carbamate:
methyl iodide (50 mg,0.35 mmol) was added to N- [4- (4-amino-6-hydroxyimino-5, 5-dimethyl-benzo [ h ]]Quinazolin-8-yl) oxy-cyclohexyl]A stirred solution of tert-butyl carbamate (90 mg,0.17 mmol) in DMF (2 mL) was then added Cs 2 CO 3 (115 mg,0.35 mmol) and mixing the resulting mixtureThe mixture was stirred for 1 hour. The solvent was removed and the residue was taken up with DCM and H 2 And O extraction. The combined organic layers were taken up over Na 2 SO 4 Dried, filtered and concentrated, and the residue is purified by preparative HPLC to give (6Z) -N- [ trans-4- (4-amino-6-methoxyimino-5, 5-dimethyl-benzo [ h ] as a white solid]Quinazolin-8-yl) oxy-cyclohexyl]Tert-butyl carbamate (40 mg,46% yield).
MS m/z(+ESI):482.3[M+H] + 。
Step 9: (6Z) -8- (trans-4-aminocyclohexyloxy) -6-methoxyimino-5, 5-dimethyl-benzo [ h ]]
Preparation of quinazolin-4-amine:
TFA (0.5 mL) was added to a stirred solution of tert-butyl (6Z) -N- [ trans-4- (4-amino-6-methoxyimino-5, 5-dimethyl-benzo [ h ] quinazolin-8-yl) oxy cyclohexyl ] carbamate (40 mg,0.08 mmol) in DCM (2 mL). After 3 hours, the solvent was removed and the crude product was purified by preparative HPLC to give (6Z) -8- (trans-4-aminocyclohexyloxy) -6-methoxyimino-5, 5-dimethyl-benzo [ h ] quinazolin-4-amine (28 mg,93% yield) as a white solid.
1 H NMR(400MHz,DMSO-d 6 +D 2 O)δppm:8.51(s,1H),7.98(d,J＝9.2Hz,1H),7.55(d,J＝2.8Hz,1H),7.29(dd,J＝9.2Hz,2.8Hz,1H),4.43(m,1H),3.86(s,3H),3.08(m,1H),2.14(m,2H),1.98(m,2H),1.50(m,10H)。
MS m/z(+ESI):382.3[M+H] + 。
Preparation of example 4: (6Z) -8- [1- (trans-4-aminocyclohexyl) vinyl ] -6-methoxyimino-5, 5-dimethyl-benzo [ h ] quinazolin-4-amine:
step 1: 4-amino-8-methoxy-5, 5-dimethyl-benzo [ h ]]Preparation of quinazolin-6-one:
KMnO at 0 °c 4 (22.4 g,141 mmol) added to 8-methylOxy-5, 5-dimethyl-6H-benzo [ H ]]Quinazolin-4-amine (4 g,14.10 mmol) in acetone (150 mL) and H 2 To the stirred solution in O (30 mL) was then added MgSO 4 (4.28 g,35.3 mmol). After stirring at 45℃for 5h, the reaction mixture was taken up with EA and saturated Na 2 S 2 O 3 Extracting with aqueous solution. The combined organic layers were taken up over Na 2 SO 4 Dried, filtered and concentrated. The residue was purified by column chromatography (silica gel; PE: EA;1:1, v: v) to give 4-amino-8-methoxy-5, 5-dimethyl-benzo [ h ] as a white solid]Quinazolin-6-one (2.2 g,57% yield).
1 H NMR(400MHz,DMSO-d 6 +D 2 O)δppm:8.54(d,J＝8.8Hz,1H),8.37(s,1H),7.48(d,J＝2.8Hz,1H),7.42(dd,J＝8.8Hz,2.8Hz,1H),3.88(s,3H),1.50(s,6H)。
MS m/z(+ESI):270.2[M+H] + 。
Step 2: 4-amino-8-hydroxy-5, 5-dimethyl-benzo [ h ]]Preparation of quinazolin-6-one:
BBr at 0 ℃ 3 (6.84 mL,6.84mmol,1M in DCM) to 4-amino-8-methoxy-5, 5-dimethyl-benzo [ h ]]A stirred solution of quinazolin-6-one (1.00 g,3.34 mmol) in DCM (5 mL). The resulting mixture was stirred at room temperature for 16 hours and at 60 ℃ for a further 8 hours. The reaction mixture was poured into ice-cold water and saturated NaHCO was added 3 The aqueous solution was adjusted to pH 7.5 and then extracted with EA. The combined organic layers were taken up over Na 2 SO 4 Drying, filtering and concentrating to obtain 4-amino-8-hydroxy-5, 5-dimethyl-benzo [ h ] as pale yellow solid]Quinazolin-6-one (823mg, 87% yield) was used in the next step without further purification.
MS m/z(+ESI):256.1[M+H] + 。
Step 3: 4-amino-6-methoxyimino-5, 5-dimethyl-benzo [ h ]]Preparation of quinazolin-8-ol:
methoxy amine hydrochloride (CAS 593-56-6,1.82g,21.2 mmol) was added to 4-amino-8-hydroxy-5, 5-dimethyl-benzo [ h ]]Quinazolin-6-one (300 mg,1.06 mmol) on-PIPIn a stirred solution in pyridine (2 mL). The reaction suspension was stirred at 150 ℃ for 22 hours. The reaction mixture was treated with EA and H 2 And O extraction. The combined organic layers were taken up over Na 2 SO 4 Drying, filtering and concentrating to obtain 4-amino-6-methoxyimino-5, 5-dimethyl-benzo [ h ] as pale yellow solid]Quinazolin-8-ol (300 mg,90% yield) was used in the next step without further purification.
MS m/z(+ESI):285.2[M+H] + 。
Step 4: trifluoro methanesulfonic acid (4-amino-6-methoxyimino-5, 5-dimethyl-benzo [ h ]]Quinazolin-8-yl
Preparation of esters:
n-phenyl-bis (trifluoromethanesulfonyl imide) (350 mg,0.95 mmol) was added to 4-amino-6-methoxyimino-5, 5-dimethyl-benzo [ h ] ]Quinazolin-8-ol (300 mg,0.95 mmol) in THF (5 mL) was stirred and K was then added 2 CO 3 (400 mg,2.85 mmol). After 1 hour at 45℃the reaction mixture was treated with EA and H 2 And O extraction. The combined organic layers were taken up over Na 2 SO 4 Dried, filtered and concentrated, and the crude product is purified by column chromatography (silica gel; PE: EA;1:1; v: v) to give trifluoromethanesulfonic acid (4-amino-6-methoxyimino-5, 5-dimethyl-benzo [ h ] as a yellow solid]Quinazolin-8-yl) ester (300 mg,65% yield).
MS m/z(+ESI):417.1[M+H] + 。
Step 5: n- [ trans-4- [ methoxy (methyl) carbamoyl]Cyclohexyl group]Preparation of tert-butyl carbamate:
n, O-dimethylhydroxylamine hydrochloride (268 mg,6.44 mmol) was added to a stirred solution of BOC-trans-aminocyclohexanecarboxylic acid (CAS 53292-89-0,1.60g,6.44 mmol) in DMF (20 mL), followed by HATU (2.97 g,7.73 mmol) and DIPEA (3.36 mL,19.33 mmol). After stirring for 18 hours, the reaction mixture was taken up with EA and H 2 And O extraction. The combined organic layers were taken up over Na 2 SO 4 Dried, filtered and concentrated. The residue was purified by column chromatography (silica; PE: EA;1:1; v: v) to give N-well as a white solid[ trans-4- [ methoxy (methyl) carbamoyl)]Cyclohexyl group]Tert-butyl carbamate (1.53 g,79% yield).
1 H NMR(400MHz,CDCl 3 )δppm:4.38(br,1H),3.69(s,3H),3.43(br,1H),3.17(s,3H),2.61(m,1H),2.10(m,2H),1.83(m,2H),1.62(m,2H),1.44(s,9H),1.14(m,2H)。
MS m/z(+ESI):287.2[M+H] + 。
Step 6: preparation of tert-butyl N- (trans-4-acetylcyclohexyl) carbamate:
methyl magnesium bromide (3.30 mL,9.90mmol,3M in Et) was added at-10deg.C 2 O) is added dropwise to the N- [ trans-4- [ methoxy (methyl) carbamoyl group]Cyclohexyl group]A stirred solution of tert-butyl carbamate (1.00 g,3.30 mmol) in THF (20 mL). After stirring at 0deg.C for 4 hours, saturated NH was added 4 Aqueous Cl and the resulting mixture was extracted with EA. The combined organic layers were taken up over Na 2 SO 4 Dried, filtered and concentrated. The residue was purified by column chromatography (silica; PE: EA;3:1; v: v) to give tert-butyl N- (trans-4-acetylcyclohexyl) carbamate (650 mg,73% yield) as a white solid.
1 H NMR(400MHz,CDCl 3 )δppm:4.38(br,1H),3.39(br,1H),2.28(m,1H),2.24(s,3H),2.11(m,2H),1.96(m,2H),1.49-1.38(m,11H),1.18-1.08(m,2H)。
Step 7: 1- [ trans-4- (tert-butoxycarbonylamino) cyclohexyl triflate]Preparation of vinyl esters:
NaHMDS (0.41 mL,0.41mmol,1M in THF) was added to a stirred solution of tert-butyl N- (trans-4-acetylcyclohexyl) carbamate (100 mg,0.37 mmol) in THF (5 mL) at-78deg.C. After stirring at-78℃for 1 hour, N-phenyl-bis (trifluoromethanesulfonyl imide) (149 mg,0.41 mmol) was added at 0℃and the resulting mixture was stirred at 0℃for 3 hours. Adding saturated NH 4 Aqueous Cl and the mixture was extracted with EA. The combined organic layers were taken up over Na 2 SO 4 Dried, filtered and concentrated. The residue was purified by column chromatography (silica; PE: EA;5:1; v: v)To obtain 1- [ trans-4- (tert-butoxycarbonylamino) cyclohexyl triflate as white solid]Vinyl ester (120 mg,78% yield).
1 H NMR(400MHz,CDCl 3 )δppm:5.10(d,J＝3.6Hz,1H),4.92(m,1H),4.40(br,1H),3.42(br,1H),2.18-2.02(m,5H),1.45(s,9H),1.38-1.27(m,2H),1.18-1.11(m,2H)。
Step 8: n- [ trans-4- [1- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) vinyl]
Cyclohexyl group]Preparation of tert-butyl carbamate:
will B 2 Pin 2 (284 mg,1.08 mmol) added to 1- [ trans-4- (tert-butoxycarbonylamino) cyclohexyl triflate]A stirred solution of vinyl ester (300 mg,0.72 mmol) in toluene (10 mL) was followed by the addition of PPh 3 (39mg，0.14mmol)、PdCl 2 (PPh 3 ) 2 (52 mg,0.07 mmol) and PhOK (199mg, 1.45 mmol). After 5 hours at 50℃the reaction mixture was cooled to room temperature and then quenched with EA and H 2 And O extraction. The combined organic layers were taken up over Na 2 SO 4 Dried, filtered and concentrated. The residue was purified by column chromatography (silica; PE: EA;5:1; v: v) to give N- [ trans-4- [1- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) vinyl as a white solid]Cyclohexyl group]Tert-butyl carbamate (180 mg,64% yield).
1 H NMR(400MHz,CDCl 3 )δppm:5.73(d,J＝2.8Hz,1H),5.58(d,J＝2.4Hz,1H),4.38(br,1H),3.40(br,1H),2.04(m,3H),1.75(m,2H),1.46(s,9H),1.38(m,2H),1.27(s,12H),1.15(m,2H)。
MS m/z(+ESI):352.3[M+H] + 。
Step 9:2- [ trans-4- [1- (4-amino-6-methoxyimino-5, 5-dimethyl-benzo [ h ] ]Quinazoline-8-
Radical) vinyl group]Cyclohexyl group]Preparation of tert-butyl acetate:
n- [ trans-4- [1- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) vinyl group]Cyclohexyl group]Tert-butyl carbamate (150 mg,0.39 mmol) was added to triflic acid [. Times.4-amino-6-methoxyimino-5, 5-dimethyl-benzo [ h ]]Quinazolin-8-yl ester (190 mg,0.39 mmol) in 1, 4-dioxane (2 mL) followed by Pd (dppf) 2 Cl 2 (57 mg,0.08 mmol) and K 3 PO 4 (250 mg,1.15 mmol). After stirring at 100℃for 3 hours, the reaction mixture was cooled to room temperature and then taken up with EA and H 2 And O extraction. The combined organic layers were taken up over Na 2 SO 4 Drying, filtering and concentrating to obtain 2- [ trans-4- [1- (4-amino-6-methoxyimino-5, 5-dimethyl-benzo [ h ] as yellow solid]Quinazolin-8-yl) vinyl]Cyclohexyl group]Tert-butyl acetate (150 mg,64% yield), which was used in the next step without further purification.
MS m/z(+ESI):492.3[M+H] + 。
Step 10: (6Z) -8- [1- (trans-4-aminocyclohexyl) vinyl group]-6-methoxyimino-5, 5-dimethyl
Radical-benzo [ h ]]Preparation of quinazolin-4-amine:
a solution of tert-butyl 2- [ trans-4- [1- (4-amino-6-methoxyimino-5, 5-dimethyl-benzo [ h ] quinazolin-8-yl) vinyl ] cyclohexyl ] acetate (145 mg,0.23 mmol) in TFA (2 mL) was sonicated for 5 min. The reaction mixture was concentrated and the crude product was purified by preparative HPLC to give (6Z) -8- [1- (trans-4-aminocyclohexyl) vinyl ] -6-methoxyimino-5, 5-dimethyl-benzo [ h ] quinazolin-4-amine (24 mg,25% yield) as a white solid.
1 H NMR(400MHz,DMSO-d 6 +D 2 O) δppm 8.42 (s, 1H), 8.11 (d, j=8.4 hz, 1H), 8.02 (d, j=1.6 hz, 1H), 7.65 (dd, j=8.4 hz,1.6hz, 1H), 5.38 (s, 1H), 5.16 (s, 1H), 3.85 (s, 3H), 3.01 (m, 1H), 2.50 (m, 1H) overlapping DMSO signals, 1.98 (m, 2H), 1.87 (m, 2H), 1.50 (s, 6H), 1.37 (m, 2H), 1.30 (m, 2H).
MS m/z(+ESI):392.4[M+H] + 。
Preparation of example 5: 2- [ (Z) - (4-amino-8-methoxy-5, 5-dimethyl-benzo [ h ] quinazolin-6-ylidene) amino ] oxyacetic acid:
step 1: 4-amino-8-methoxy-5, 5-dimethyl-benzo [ h ]]Preparation of quinazolin-6-one oxime:
the title compound (3.7 g,88% yield) was prepared as a yellow solid according to scheme 1 and in analogy to example 1 (step 7) using 4-amino-8-methoxy-5, 5-dimethyl-benzo [ h ] quinazolin-6-one (4.00 g,13.7 mmol) and hydroxylamine hydrochloride (9.43 g,134 mmol) as starting materials.
MS m/z(+ESI):285.2[M+H] + 。
Step 2:2- [ (4-amino-8-methoxy-5, 5-dimethyl-benzo [ h ]]Quinazolin-6-ylidene) amino group]Oxyethyl
Preparation of tert-butyl acid:
bromoacetic acid tert-butyl ester (141. Mu.L, 0.95 mmol) was added to 4-amino-8-methoxy-5, 5-dimethyl-benzo [ h ]]A stirred solution of quinazolin-6-one oxime (100 mg,0.32 mmol) in DMF (1 mL) was then added Cs 2 CO 3 (316 mg,0.95 mmol) and NaI (48 mg,0.32 mmol). After stirring for 16 hours, the solvent was removed and the residue was taken up with EA and H 2 And O extraction. The combined organic layers were taken up over Na 2 SO 4 Drying, filtering and concentrating to obtain 2- [ (4-amino-8-methoxy-5, 5-dimethyl-benzo [ h ] as brown oil]Quinazolin-6-ylidene) amino group]Tert-butyl oxyacetate (130 mg,93% yield), which was used in the next step without further purification.
MS m/z(+ESI):399.3[M+H] + 。
Step 3:2- [ (Z) - (4-amino-8-methoxy-5, 5-dimethyl-benzo [ h ]]Quinazolin-6-ylidene) amino group]Oxygen gas
Preparation of the base acetic acid:
a suspension of tert-butyl 2- [ (4-amino-8-methoxy-5, 5-dimethyl-benzo [ h ] quinazolin-6-ylidene) amino ] oxyacetate (130 mg,0.29 mmol) in 4N aqueous HCl (3 mL) was stirred for 3 hours. The reaction mixture was concentrated and the crude product was purified by preparative HPLC to give 2- [ (Z) - (4-amino-8-methoxy-5, 5-dimethyl-benzo [ h ] quinazolin-6-ylidene) amino ] oxyacetic acid (38 mg,36% yield) as a white solid.
1 H NMR(400MHz,DMSO-d 6 +D 2 O)δppm:8.48(s,1H),7.99(d,J＝8.8Hz,1H),7.85(d,J＝2.8Hz,1H),7.27(dd,J＝8.8Hz,2.8Hz,1H),4.67(s,2H),3.85(s,3H),1.47(s,6H)。
MS m/z(+ESI):343.3[M+H] + 。
Preparation of example 7: 2- [ (Z) - (4-amino-8-methoxy-5, 5-dimethyl-benzo [ h ] quinazolin-6-ylidene) amino ] oxyacetamide
NH is added to 4 (HCO 3 ) (64 mg,0.79 mmol) was added to 2- [ (Z) - (4-amino-8-methoxy-5, 5-dimethyl-benzo [ h ]]Quinazolin-6-ylidene) amino group]To a stirred solution of oxyacetic acid (100 mg,0.26 mmol) in DMF (2 mL) was then added HATU (206 mg,0.52 mmol) and NaHCO 3 (68 mg,0.79 mmol). After stirring for 16 hours, the reaction mixture was concentrated and the crude product was purified by prep. HPLC to give 2- [ (Z) - (4-amino-8-methoxy-5, 5-dimethyl-benzo [ h ] as a white solid]Quinazolin-6-ylidene) amino group]Oxyacetamides (33 mg,35% yield).
1 H NMR(400MHz,DMSO-d 6 +D 2 O)δppm:8.52(s,1H),8.00(d,J＝8.8Hz,1H),7.92(d,J＝2.8Hz,1H),7.28(dd,J＝8.8Hz,2.8Hz,1H),4.47(s,2H),3.87(s,3H),1.48(s,6H)。
MS m/z(+ESI):342.3[M+H] + 。
Preparation of example 8: n- (2-aminoethyl) -2- [ (Z) - (4-amino-8-methoxy-5, 5-dimethyl-benzo [ h ] quinazolin-6-ylidene) amino ] oxy-acetamide:
step 1: carbonic acid 2- [ [2- [ (Z) - (4-amino-8-methoxy-5, 5-dimethyl-benzo [ h ]]Quinazoline (quinazoline)-6-subunit
Radical) amino group]Oxyacetyl groups]Amino group]Preparation of ethyl ester tert-butyl ester:
N-BOC-ethylenediamine (105. Mu.L, 0.63 mmol) was added to 2- [ (Z) - (4-amino-8-methoxy-5, 5-dimethyl-benzo [ h ]]Quinazolin-6-ylidene) amino group]To a stirred solution of oxyacetic acid (120 mg,0.31 mmol) in DMF (2 mL) was then added HATU (247 mg,0.63 mmol) and DIPEA (160. Mu.L, 0.95 mmol). After stirring for 24 hours, the reaction mixture was concentrated and taken up with EA and H 2 And O extraction. The combined organic layers were taken up over Na 2 SO 4 Drying, filtering and concentrating to obtain 2- [ [2- [ (Z) - (4-amino-8-methoxy-5, 5-dimethyl-benzo [ h ] carbonate as dark brown oil]Quinazolin-6-ylidene) amino group ]Oxyacetyl groups]Amino group]Tert-butyl ethyl ester (150 mg,88% yield), which was used in the next step without further purification.
MS m/z(+ESI):485.3[M+H] + 。
Step 2: n- (2-aminoethyl) -2- [ (Z) - (4-amino-8-methoxy-5, 5-dimethyl-benzo [ h ]]Quinazolines
Lin-6-subunit) amino group]Preparation of oxy-acetamides:
the title compound (58 mg,53% yield) was prepared as a light brown solid according to scheme 1 and in analogy to example 1 (step 9) using 2- [ [2- [ (Z) - (4-amino-8-methoxy-5, 5-dimethyl-benzo [ h ] quinazolin-6-ylidene) amino ] oxyacetyl ] amino ] ethyl carbonate tert-butyl ester (150 mg,0.28 mmol) as starting material.
1 H NMR(400MHz,DMSO-d 6 +D 2 O)δppm:8.44(s,1H),8.06(d,J＝8.8Hz,1H),7.86(d,J＝2.8Hz,1H),7.25(dd,J＝8.8Hz,2.8Hz,1H),4.53(s,2H),3.86(s,3H),3.34(t,J＝6.4Hz,2H),2.85(t,J＝6.4Hz,2H),1.48(s,6H)。
MS m/z(+ESI):385.3[M+H] + 。
Preparation of example 9: (6Z) -6- (cis-4-aminocyclohexyloxy) imino-8-methoxy-5, 5-dimethyl-benzo [ h ] quinazolin-4-amine:
[ 4-Methylbenzenesulfonic acid trans-4- (tert-butoxycarbonylamino) cyclohexyl group]Preparation of esters:
TsCl (8.50 g,44.1 mmol) was added to a stirred solution of BOC-trans-4-amino hexanol (5.00 g,22.0 mmol) in DCM (20 mL), followed by TEA (9.32 mL,66.2 mmol) and DMAP (275 mg,2.21 mmol). After stirring for 24 hours, the solid was filtered off, the solution was concentrated and the residue was purified by column chromatography (silica gel; PE: EA;1:1; v: v) to give 4-methylbenzenesulfonic acid [ trans-4- (tert-butoxycarbonylamino) cyclohexyl ] ester (7.5 g,83% yield) as a pale yellow solid.
1 H NMR(400MHz,DMSO-d 6 )δppm:7.79(d,J＝8.0Hz,2H),7.46(d,J＝8.0Hz,2H),6.71(d,J＝7.2Hz,1H),4.34(m,1H),3.20(m,1H),2.41(s,3H),1.73(m,4H),1.46(m,2H),1.35(s,9H),1.18(m,2H)。
Preparation of example 9: (6Z) -6- (cis-4-aminocyclohexyloxy) imino-8-methoxy-5, 5-dimethyl-
Benzo [ h ]]Quinazolin-4-amine:
the title compound (6Z) -6- (cis-4-aminocyclohexyloxy) imino-8-methoxy-5, 5-dimethyl-benzo [ h ] quinazolin-4-amine was prepared as a white solid using 4-methylbenzenesulfonic acid [ trans-4- (tert-butoxycarbonylamino) cyclohexyl ] ester and 4-amino-8-methoxy-5, 5-dimethyl-benzo [ h ] quinazolin-6-one oxime as starting materials according to scheme 1 and in analogy to example 1 (steps 8 and 9).
1 H NMR(400MHz,DMSO-d 6 +D 2 O)δppm:8.45(s,1H),8.07(d,J＝8.8Hz,1H),7.77(d,J＝2.8Hz,1H),7.23(dd,J＝8.8Hz,2.4Hz,1H),4.25(m,1H),3.86(s,3H),3.06(m,1H),2.05(m,2H),1.67(m,4H),1.50(s,6H),1.44(m,2H)。
MS m/z(+ESI):382.3[M+H] + 。
Preparation of example 12: (5R) -5- [ [ (Z) - (4-amino-8-methoxy-5, 5-dimethyl-benzo [ h ] quinazolin-6-ylidene) amino ] oxymethyl ] oxazolidin-2-one:
(5R) -5- (chloromethyl) oxazolidin-2-one (CAS 169048-79-7, 284 mg,1.90 mmol) was added to 4-amino-8-methoxy-5, 5-dimethyl-benzo [ h ]]A stirred solution of quinazolin-6-one oxime (100 mg,0.32 mmol) in DMF (2 mL) was then added Cs 2 CO 3 (316 mg,0.95 mmol) and TBAI (316 mg,0.95 mmol). After stirring at 70℃for 2 hours, the reaction mixture was concentrated and the crude product was purified by prep HPLC to give (5R) -5- [ [ (Z) - (4-amino-8-methoxy-5, 5-dimethyl-benzo [ h ] as a white solid ]Quinazolin-6-ylidene) amino group]Oxymethyl group]Oxazolidin-2-one (11 mg,9% yield).
1 H NMR(400MHz,DMSO-d 6 +D 2 O) delta ppm 8.40 (s, 1H), 8.06 (d, j=8.8 hz, 1H), 7.61 (d, j=2.8 hz, 1H), 7.21 (dd, j=8.8 hz,2.8hz, 1H), 4.85 (m, 1H), 4.25 (m, 2H), 3.84 (s, 3H), 3.57 (d, j=8.8 hz, 1H), 3.27 (dd, j=8.8 hz,2.8hz, 1H), 1.50 and 1.48 (2 s, 6H).
MS m/z(+ESI):384.3[M+H] + 。
Preparation of example 36: (6Z) -8- (trans-4-aminocyclohexyloxy) -6-methoxyimino-5, 5-dimethyl-thieno [3,2-h ] quinazolin-4-amine:
step 1: preparation of 5, 5-dimethyl-6, 7-dihydrobenzothiophen-4-one:
methyl iodide (5.98 mL,95.6 mmol) was added to 6, 7-dihydro-5H-benzo [ b ] at 0deg.C]To a stirred solution of thiophen-4-one (5.00 g,31.9 mmol) in THF (50 mL) was then added tBuONa (9.28 g,95.6 mmol). After stirring at 0deg.C for 1 hour, the reaction mixture was concentrated and taken up with EA and saturated NH 4 And (5) extracting with an aqueous Cl solution. The combined organic layers were taken up over Na 2 SO 4 Drying, filtration and concentration gave 5, 5-dimethyl-6, 7-dihydrobenzothiophen-4-one (6.00 g,94% yield) as a brown oil)。
1 H NMR(400MHz,DMSO-d 6 )δppm:7.38(d,J＝5.2Hz,1H),7.24(d,J＝5.2Hz,1H),3.04(t,J＝6.4Hz,2H),1.98(t,J＝6.4Hz,2H),1.09(s,6H)。
MS m/z(+ESI):181.1[M+H] + 。
Step 2: preparation of 5, 5-dimethyl-6, 7-dihydro-4H-benzothiophene:
LAH (390 mg,9.99 mmol) was taken under Et at 0deg.C and under argon 2 Suspension in O (20 mL) was added to AlCl 3 (2.69 g,20.0 mmol) in Et 2 O (30 mL) and the resulting suspension was stirred at 0deg.C for 10 min. 5, 5-dimethyl-6, 7-dihydrobenzothien-4-one (1 g,4.99 mmol) was taken up in Et at 0deg.C 2 The solution in O (10 mL) was added drop wise to the suspension. After stirring at 0℃for 30 minutes, H was used 2 O deactivates the reaction mixture. The organic layer was washed with brine, dried over Na 2 SO 4 Drying, filtration and concentration gave 5, 5-dimethyl-6, 7-dihydro-4H-benzothiophene (850 mg,92% yield) as a yellow oil, which was used in the next step without further purification.
1 H NMR(400MHz,CDCl 3 )δppm:7.07(d,J＝5.2Hz,1H),6.72(d,J＝5.2Hz,1H),2.79(t,J＝6.4Hz,2H),2.42(s,2H),1.62(t,J＝6.4Hz,2H),1.01(s,6H)。
Step 3: preparation of 5, 5-dimethyl-4, 6-dihydrobenzothiophen-7-one:
at 0deg.C, cerium (IV) ammonium nitrate (180 g,325 mmol) was added to H 2 A solution in O (160 mL) was added dropwise to 5, 5-dimethyl-6, 7-dihydro-4H-benzothiophene (15 g,81.19 mmol) in AcOH (160 mL) and H 2 O (40 mL) in a stirred solution. After stirring at 0deg.C for 3 hours, the reaction mixture was taken up with EA and H 2 And O extraction. The combined organic layers were taken up over Na 2 SO 4 Dried, filtered and concentrated. The residue was purified by column chromatography (silica gel; PE: EA;100:1 to 50:1; v: v) to give 5, 5-dimethyl-4, 6-dihydrobenzothiophen-7-one (11 g,68% yield) as a dark brown oil.
MS m/z(+ESI):181.0[M+H] + 。
Step 4: preparation of methyl 5, 5-dimethyl-7-oxo-4, 6-dihydrobenzothiophene-6-carboxylate:
NaH (6.59 g,165 mmol) was added in portions to a stirred solution of 5, 5-dimethyl-4, 6-dihydrobenzothiophen-7-one (11.0 g,54.9 mmol) in dimethyl carbonate (60 mL). After stirring at 90℃for 1 hour, the reaction mixture was taken up with EA and H 2 And O extraction. The combined organic layers were taken up over Na 2 SO 4 Dried, filtered and concentrated. The residue was purified by column chromatography (silica gel; PE: EA;20:1; v: v) to give methyl 5, 5-dimethyl-7-oxo-4, 6-dihydrobenzothiophene-6-carboxylate (13 g,89% yield) as a yellow oil.
MS m/z(+ESI):239.0[M+H] + 。
Step 5:5, 5-dimethyl-3, 6-dihydrothieno [3,2-h]Preparation of quinazolin-4-one:
a mixture of methyl 5, 5-dimethyl-7-oxo-4, 6-dihydrobenzothiophene-6-carboxylate (5.00 g,18.9 mmol) in formamidine acetate (13.0 g,119 mmol) was stirred at 180℃for 2 hours. The reaction mixture was then cooled to room temperature and taken up with H 2 O dilution. The resulting suspension was filtered and the filter cake was purified by H 2 O is washed and dried to obtain 5, 5-dimethyl-3, 6-dihydrothieno [3,2-h ] as brown solid]Quinazolin-4-one (3.1 g,64% yield) was used in the next step without further purification.
1 H NMR(400MHz,CDCl 3 )δppm:12.22(s,1H),8.03(s,1H),7.67(d,J＝5.2Hz,1H),7.02(d,J＝5.2Hz,1H),2.74(s,2H),1.32(s,6H)。
MS m/z(+ESI):233.1[M+H] + 。
Step 6:5, 5-dimethyl-6H-thieno [3,2-H]Preparation of quinazolin-4-amine:
BOP (2.27 g,5.04 mmol) was added to 5, 5-dimethyl-3, 6-dihydrothieno [3,2-h]To a stirred solution of quinazolin-4-one (1.00 g,3.87 mmol) in ACN (10 mL) was then added DBU (895. Mu.L, 5.81 mmol). After stirring for 30 minutes, NH was added 4 OH solution (25 mL) and the resulting solution was stirred at 80℃for 16 h. The solvent was removed and the crude product was purified by combined flash chromatography (combiflash) to give 5, 5-dimethyl-6H-thieno [3,2-H ] as a yellow solid]Quinazolin-4-amine (650 mg,65% yield).
1 H NMR(400MHz,DMSO-d 6 +D 2 O)δppm:8.36(s,1H),7.81(d,J＝4.8Hz,1H),7.09(d,J＝4.8Hz,1H),2.86(s,2H),1.32(s,6H)。
MS m/z(+ESI):232.1[M+H] + 。
Step 7: (4-amino-5, 5-dimethyl-6H-thieno [3, 2-H)]Quinazolin-8-yl) boronic acid preparation:
LDA (0.35 mL,0.69mmol,2M in hexane/THF) was added dropwise to 5, 5-dimethyl-6H-thieno [3,2-H ] at-70 ℃]A stirred solution of quinazolin-4-amine (200 mg,0.69 mmol) in THF (12 mL) was stirred at-70℃for 1 hour. The pinacol ester of isopropoxycoric acid (CAS 61676-62-8, 291. Mu.L, 1.38 mmol) was added dropwise at-70 ℃. After stirring for 1 hour at-70℃with saturated NH 4 The reaction was deactivated with aqueous Cl solution and concentrated to give (4-amino-5, 5-dimethyl-6H-thieno [3, 2-H) as a yellow solid ]Quinazolin-8-yl) boronic acid (160 mg,59% yield), which was used in the next step without further purification.
MS m/z(+ESI):276.1[M+H] + 。
Step 8: 4-amino-5, 5-dimethyl-6H-thieno [3,2-H]Preparation of quinazolin-8-ol:
NaBO is processed 3 x4H 2 O (182 mg,1.14 mmol) was added to (4-amino-5, 5-dimethyl-6H-thieno [3, 2-H)]Quinazolin-8-yl) boronic acid (150 mg,0.38 mmol) in MeOH (10 mL) under stirring. After 1 hour, the solvent was removed and the crude product was purified by column chromatography (silica gel; meOH: DCM;1:10; v: v) to give 4-amino-5, 5-dimethyl-6H-thieno [3,2-H ] as a yellow solid]Quinazolin-8-ol (70 mg,59% yield).
MS m/z(+ESI):248.2[M+H] + 。
Preparation of example 36: (6Z) -8- (trans-4-aminocyclohexyloxy) -6-methoxyimino-5, 5-dimethyl-thieno [3,2-h ] quinazolin-4-amine:
the title compound (6Z) -8- (trans-4-aminocyclohexyloxy) -6-methoxyimino-5, 5-dimethyl-thieno [3,2-H ] quinazolin-4-amine was prepared as a yellow solid using 4-methylbenzenesulfonic acid [ trans-4- (tert-butoxycarbonylamino) cyclohexyl ] ester, 4-amino-5, 5-dimethyl-6H-thieno [3,2-H ] quinazolin-8-ol, hydroxylamine hydrochloride and iodomethane as starting materials according to scheme 1 and in analogy to example 1 (steps 5-9).
1 H NMR(400MHz,DMSO-d 6 +D 2 O)δppm:8.18(s,1H),7.15(s,1H),4.25(m,1H),3.91(s,3H)。3.07(m,1H),2.16(m,2H),1.98(m,2H),1.56(s,6H),1.50(m,4H)。
MS m/z(+ESI):388.3[M+H] + 。
Preparation of example 37: (5R) -5- [ [ (Z) - [ 4-amino-8- (trans-4-aminocyclohexyloxy) -5, 5-dimethyl-benzo [ h ] quinazolin-6-ylidene ] amino ] oxymethyl ] oxazolidin-2-one:
step 1: n- [ trans-4- [ (6Z) -4-amino-5, 5-dimethyl-6- [ [ (5R) -2-oxo-oxazolidin-5-yl]
Methoxyimino group]Benzo [ h ]]Quinazolin-8-yl]Oxy cyclohexyl]Preparation of tert-butyl carbamate:
(5R) -5- (chloromethyl) -2-oxazolidinone (CAS 169048-79-7, 73mg,0.49 mmol) was added to N- [ trans-4- [ (6Z) -4-amino-6-hydroxyimino-5, 5-dimethyl-benzo [ h)]Quinazolin-8-yl]Oxy cyclohexyl]A stirred solution of tert-butyl carbamate (80 mg,0.16 mmol) in DMF (2 mL) was then added Cs 2 CO 3 (162 mg,0.49 mmol) and TBAI (6 mg,0.016 mmol). After stirring for 36 hours, the reaction mixture was concentrated and taken up with EA and H 2 And O extraction. The combined organic layers were taken up over Na 2 SO 4 Drying, filtering and concentrating to obtain N- [ trans-4- [ (6Z) ] as pale yellow oil4-amino-5, 5-dimethyl-6- [ [ (5R) -2-oxo-oxazolidin-5-yl]Methoxyimino group]Benzo [ h ]]Quinazolin-8-yl]Oxy cyclohexyl]Tert-butyl carbamate (100 mg,54% yield), which was used in the next step without further purification.
MS m/z(+ESI):567.3[M+H] + 。
Step 2: (5R) -5- [ [ (Z) - [ 4-amino-8- (trans-4-aminocyclohexyloxy) -5, 5-dimethyl-benzo [ h ]]
Quinazolin-6-subunit]Amino group]Oxymethyl group]Preparation of oxazolidin-2-ones:
the title compound (12 mg,23% yield) was prepared as a white solid according to scheme 1 and in analogy to example 4 (step 10) using N- [ trans-4- [ (6Z) -4-amino-5, 5-dimethyl-6- [ [ (5R) -2-oxooxazolidin-5-yl ] methoxyimino ] benzo [ h ] quinazolin-8-yl ] oxycyclohexyl ] carbamic acid tert-butyl ester (100 mg,0.09 mmol) as starting material.
1 H NMR(400MHz,DMSO-d 6 +D 2 O)δppm:8.25(s,1H),8.12(d,J＝8.8Hz,1H),7.54(d,J＝2.8Hz,1H),7.13(dd,J＝8.8Hz,2.8Hz,1H),4.83(m,1H),4.35(m,1H),4.22(m,2H),3.60(m,1H),3.25(m,1H),3.00(m,1H),2.14(m,2H),1.94(m,2H),1.50(m,10H)。
MS m/z(+ESI):467.4[M+H] + 。
Preparation of example 39: (6Z) -8- (trans-4-aminocyclohexyloxy) -10-chloro-6-methoxyimino-5, 5-dimethyl-benzo [ h ] quinazolin-4-amine:
step 1: n- [ trans-4- [ (6Z) -4-amino-10-chloro-6-methoxyimino-5, 5-dimethyl-benzo [ h ]]
Quinazolin-8-yl]Oxy cyclohexyl]Preparation of tert-butyl carbamate:
NCS (5 mg,0.035 mmol) was added to (6Z) -N- [ trans-4- (4-amino-6-methoxyimino-5, 5-dimethyl-benzo [ h ]]Quinazolin-8-yl) oxy-cyclohexyl]Tert-butyl carbamate (20 mg,0.029 m)mol) in AcOH (0.2 mL) and then Pd (OAc) was added 2 (0.5 mg, 0.002mmol). After stirring at 80℃for 3 hours, the reaction mixture was taken up with EA and H 2 And O extraction. The combined organic layers were taken up over Na 2 SO 4 Drying, filtering and concentrating to obtain N- [ trans-4- [ (6Z) -4-amino-10-chloro-6-methoxyimino-5, 5-dimethyl-benzo [ h ] as a yellow solid]Quinazolin-8-yl]Oxy cyclohexyl]Tert-butyl carbamate (18 mg,96% yield), which was used in the next step without further purification.
1 H NMR(400MHz,DMSO-d 6 ) Delta ppm 8.26 (s, 1H), 7.26 (d, j=2.4 hz, 1H), 7.19 (d, j=2.4 hz, 1H), 6.64 (s, 2H), 4.39 (m, 1H), 3.30 (m, 1H), 3.82 (s, 3H), 2.06 (m, 2H), 1.82 (m, 2H), 1.43 (m, 4H), 1.38 (s, 9H), 1.23 (s, 6H).
MS m/z(+ESI):516.3,518.2[M+H] + 。
Step 2: (6Z) -8- (trans-4-aminocyclohexyloxy) -10-chloro-6-methoxyimino-5, 5-dimethyl-benzene
And [ h ]]Preparation of quinazolin-4-amine:
the title compound (10 mg,52% yield) was prepared as a white solid following scheme 1 and in analogy to example 1 (step 9) using N- [ trans-4- [ (6Z) -4-amino-10-chloro-6-methoxyimino-5, 5-dimethyl-benzo [ h ] quinazolin-8-yl ] oxycyclohexyl ] carbamic acid tert-butyl ester (26 mg,0.04 mmol) as starting material.
1 H NMR(400MHz,DMSO-d 6 +D 2 O)δppm:8.36(s,1H),7.31(d,J＝2.4Hz,1H),7.29(d,J＝2.4Hz,1H),4.45(m,1H),3.84(s,3H),3.07(m,1H),2.12(m,2H),1.97(m,2H),1.49(m,4H),1.43(s,6H)。
MS m/z(+ESI):416.2,418.2[M+H] + 。
Preparation of example 41: (6Z) -9-chloro-8-methoxy-6-methoxyimino-5, 5-dimethyl-benzo [ h ] quinazolin-4-amine:
NCS (3 mg,0.22 mmol) was added to (6Z) -8-methoxy-6-methoxyimino-5, 5-dimethyl-benzo [ h ] ]To a stirred solution of quinazolin-4-amine (60 mg,0.18 mmol) in AcOH (0.9 mL) was then added TFA (0.60 mL). After stirring for 16 hours, the reaction mixture was taken up with DCM and H 2 And O extraction. The combined organic layers were taken up over Na 2 SO 4 Dried, filtered and concentrated, and the crude product is purified by preparative HPLC to give (6Z) -9-chloro-8-methoxy-6-methoxyimino-5, 5-dimethyl-benzo [ h ] as a white solid]Quinazolin-4-amine (8 mg,13% yield).
1 H NMR(400MHz,DMSO-d 6 +D 2 O)δppm:8.44(s,1H),8.16(s,1H),7.76(s,1H),3.95(s,3H),3.93(s,3H),1.51(s,6H)。
MS m/z(+ESI):333.2,335.2[M+H] + 。
Preparation of example 42: (6Z) -8-methoxy-6-methoxyimino-5, 5-dimethyl-benzo [ h ] quinazoline-4, 9-diamine:
step 1: (6Z) -8-methoxy-6-methoxyimino-5, 5-dimethyl-9-nitro-benzo [ h ]]Quinazoline-4-
Preparation of amine:
HNO is added at-15 DEG C 3 (0.5 mL,11.2 mmol) to (6Z) -8-methoxy-6-methoxyimino-5, 5-dimethyl-benzo [ h ]]Quinazolin-4-amine (130 mg,0.39 mmol) at H 2 SO 4 (0.5 mL) in a stirred solution. After stirring at-15℃for 30 minutes, saturated K was slowly added at-15 ℃ 2 CO 3 The aqueous solution reached pH 7 and the resulting mixture was extracted with DCM. The combined organic layers were taken up over Na 2 SO 4 Dried, filtered and concentrated, and the crude product is purified by preparative HPLC to give (6Z) -8-methoxy-6-methoxyimino-5, 5-dimethyl-9-nitro-benzo [ h ] as a yellow solid ]Quinazolin-4-amine (30 mg,20% yield).
MS m/z(+ESI):344.2[M+H] + 。
Step 2: (6Z) -8-methoxy-6-methoxyimino-5, 5-dimethyl-benzo [ h ]]Quinazoline-4, 9-diamines
Is prepared from the following steps:
na is mixed with 2 S 2 O 4 (104 mg,0.52 mmol) was added to (6Z) -8-methoxy-6-methoxyimino-5, 5-dimethyl-9-nitro-benzo [ h ]]Quinazolin-4-amine (25 mg,0.06 mmol) in MeOH (0.3 mL) and H 2 To the stirred solution in O (0.1 mL) was then added K 2 CO 3 (27 mg,0.20 mmol). After stirring for 2 hours, the reaction mixture was taken up with DCM and H 2 And O extraction. The combined organic layers were taken up with Na 2 SO 4 Dried, filtered and concentrated, and the crude product is purified by preparative HPLC to give (6Z) -8-methoxy-6-methoxyimino-5, 5-dimethyl-benzo [ h ] as a yellow solid]Quinazoline-4, 9-diamine (6 mg,24% yield).
1 H NMR(400MHz,DMSO-d 6 +D 2 O)δppm:8.22(s,1H),7.57(s,1H),7.54(s,1H),3.82(s,3H),3.79(s,3H),1.49(s,6H)。
MS m/z(+ESI):314.2[M+H] + 。
Preparation of example 44: (6Z) -N8- (trans-4-aminocyclohexyl) -6-methoxyimino-N8, 5-trimethyl-benzo [ h ] quinazoline-4, 8-diamine:
step 1: (6Z) -N8- (trans-4-aminocyclohexyl) -6-methoxyimino-5, 5-dimethyl-benzo [ h ]]Quinuclidine and its preparation
Preparation of oxazoline-4, 8-diamine:
trifluoro methanesulfonic acid (4-amino-6Z-methoxyimino-5, 5-dimethyl-benzo [ h ]]A mixture of quinazolin-8-yl ester (150 mg,0.31 mmol) and trans-1, 4-diaminocyclohexane (1.92 mL,15.3 mmol) was stirred at 200℃for 30 min under microwave radiation. The reaction mixture was taken up with DCM and H 2 And O extraction. The combined organic layers were taken up over Na 2 SO 4 Drying, filtering and concentrating to obtain the product(6Z) -N8- (trans-4-aminocyclohexyl) -6-methoxyimino-5, 5-dimethyl-benzo [ h ] as a yellow semisolid]Quinazoline-4, 8-diamine (120 mg,87% yield) was used in the next step without further purification.
MS m/z(+ESI):381.3[M+H] + 。
Step 2: n- [ trans-4- [ [ (6Z) -4-amino-6-methoxyimino-5, 5-dimethyl-benzo [ h ]]Quinazolines
Lin-8-yl]Amino group]Cyclohexyl group]Preparation of tert-butyl carbamate:
BOC (boil off gas) 2 O (119 mg,0.54 mmol) was added to (6Z) -N8- (trans-4-aminocyclohexyl) -6-methoxyimino-5, 5-dimethyl-benzo [ h ]]To a stirred solution of quinazoline-4, 8-diamine (120 mg,0.27 mmol) in 1, 4-dioxane (1 mL) was then added saturated NaHCO 3 Aqueous solution (0.25 mL). After stirring for 2 hours, the reaction mixture was taken up with DCM and H 2 And O extraction. The combined organic layers were taken up over Na 2 SO 4 Dried, filtered and concentrated. The residue was purified by combined flash chromatography (combiflash) to give N- [ trans-4- [ [ (6Z) -4-amino-6-methoxyimino-5, 5-dimethyl-benzo [ h ] as a pale yellow solid]Quinazolin-8-yl]Amino group]Cyclohexyl group]Tert-butyl carbamate (85 mg,43% yield).
MS m/z(+ESI):481.3[M+H] + 。
Step 3: n- [ trans-4- [ [ (6Z) -4-amino-6-methoxyimino-5, 5-dimethyl-benzo [ h ] ]Quinazolines
Lin-8-yl]-methyl-amino group]Cyclohexyl group]Preparation of tert-butyl carbamate:
paraformaldehyde (36 mg,0.44 mmol) is added to N- [ trans-4- [ [ (6Z) -4-amino-6-methoxyimino-5, 5-dimethyl-benzo [ h ]]Quinazolin-8-yl]Amino group]Cyclohexyl group]To a stirred solution of tert-butyl carbamate (65 mg,0.09 mmol) in MeOH (5 mL) was then added AcOH (26. Mu.L, 0.44 mmol) and NaBH 3 CN (29 mg,0.44 mmol). After stirring for 1 hour, the reaction mixture was taken up with EA and H 2 And O extraction. The combined organic layers were taken up over Na 2 SO 4 Drying, filtering and concentrating to obtain N- [ trans-4- [ [ (6Z) -4-amino-6-methoxyylidene as a yellow oilAmino-5, 5-dimethyl-benzo [ h ]]Quinazolin-8-yl]-methyl-amino group]Cyclohexyl group]Tert-butyl carbamate (65 mg,75% yield), which was used in the next step without further purification.
MS m/z(+ESI):495.3[M+H] + 。
Step 4: (6Z) -N8- (trans-4-aminocyclohexyl) -6-methoxyimino-N8, 5-trimethyl-benzo
[h]Preparation of quinazoline-4, 8-diamine:
the title compound (6 mg,17% yield) was prepared as a yellow solid according to scheme 1 and in analogy to example 1 (step 9) using N- [ trans-4- [ [ (6Z) -4-amino-6-methoxyimino-5, 5-dimethyl-benzo [ h ] quinazolin-8-yl ] -methyl-amino ] cyclohexyl ] carbamic acid tert-butyl ester (85 mg,0.08 mmol) as starting material.
1 H NMR(400MHz,DMSO-d 6 +D 2 O)δppm:8.44(s,1H),7.86(d,J＝8.8Hz,1H),7.37(d,J＝2.4Hz,1H),7.03(dd,J＝8.8Hz,2.4Hz,1H),3.85(s,3H),3.71(m,1H),3.04(m,1H),2.83(s,3H),2.01(m,2H),1.71(m,4H),1.52(m,2H),1.48(s,6H)。
MS m/z(+ESI):395.3[M+H] + 。
Preparation of example 51: (5S) -5- [ [ (Z) - (4-amino-8-bromo-5, 5-dimethyl-benzo [ h ] quinazolin-6-ylidene) amino ] oxymethyl ] oxazolidin-2-one:
step 1: (4-amino-5, 5-dimethyl-6-oxo-benzo [ h ]]Preparation of quinazolin-8-yl) triflate
The preparation method comprises the following steps:
the title compound (1.7 g,62% yield) was prepared as a yellow solid according to scheme 1 and in analogy to example 4 (step 4) using 4-amino-8-hydroxy-5, 5-dimethyl-benzo [ h ] quinazolin-6-one (1.7 g,6.33 mmol) as starting material.
MS m/z(+ESI):388.0[M+H] + 。
Step 2: 4-amino-8-bromo-5, 5-dimethyl-benzo [ h ]]Preparation of quinazolin-6-one:
t-Brettphos (0.17 g,0.36 mmol) was added to trifluoromethanesulfonic acid (4-amino-5, 5-dimethyl-6-oxo-benzo [ h ]]Quinazolin-8-yl) ester (0.75 g,1.75 mmol) in Diox (6 mL) followed by Pd addition 2 (dba) 3 (0.16 g,0.17 mmol), KBr (2.09 g,17.4 mmol) and KF (51 mg,0.87 mmol). After 16 hours at 120℃the reaction mixture was cooled to room temperature, concentrated and the residue was purified by column chromatography (silica gel; PE: EA;1:1; v: v) to give 4-amino-8-bromo-5, 5-dimethyl-benzo [ h ] as a yellow solid]Quinazolin-6-one (0.25 g,23% yield).
MS m/z(+ESI):318.1,320.1[M+H] + 。
(5S) -5- [ [ (Z) - (4-amino-8-bromo-5, 5-dimethyl-benzo [ h ] ]Quinazolin-6-ylidene) amino group]Oxyformazan
Base group]Preparation of oxazolidin-2-ones:
the title compound was prepared as a yellow solid according to scheme 1 and in analogy to example 1 (step 7) and example 12 using 4-amino-8-bromo-5, 5-dimethyl-benzo [ h ] quinazolin-6-one, hydroxylamine hydrochloride and (5S) -5- (chloromethyl) oxazolidin-2-one (CAS 169048-83-3) as starting materials.
1 H NMR(400MHz,DMSO-d 6 +D 2 O)δppm:8.50(s,1H),8.23(d,J＝2.0Hz,1H),8.03(d,J＝8.4Hz,1H),7.88(dd,J＝8.4Hz,2.0Hz,1H),4.84(m,1H),4.27(m,2H),3.57(m,1H),3.25(m,1H),1.51(s,3H),1.50(s,3H)
MS m/z(+ESI):432.1,434.1[M+H] + 。
Preparation of example 52: (5S) -5- [ [ (Z) - (4-amino-8-chloro-5, 5-dimethyl-benzo [ h ] quinazolin-6-ylidene) amino ] oxymethyl ] -3-methyl-oxazolidin-2-one:
step 1:5, 5-dimethyl-8- (4, 5-tetramethyl-1, 3, 2-dioxolane)Borane-2-yl) -6H-benzo
[h]Preparation of quinazolin-4-amine:
will B 2 Pin 2 (197mg, 0.58 mmol) added to triflic acid (4-amino-5, 5-dimethyl-6H-benzo [ H ]]Quinazolin-8-yl) ester (240 mg,0.58 mmol) in Diox (18 mL) followed by Pd addition 2 (dppf)Cl 2 (44 mg,0.058 mmol) and KOAc (172 mg,1.74 mmol). After 5 hours at 90℃the reaction mixture was cooled to room temperature and then quenched with EA and H 2 And O extraction. The combined organic layers were taken up over Na 2 SO 4 Dried, filtered and concentrated. The residue was purified by column chromatography (silica gel; PE: EA;3:2; v: v) to give 5, 5-dimethyl-8- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -6H-benzo [ H ] as a dark green solid ]Quinazolin-4-amine (210 mg,93% yield).
1 H NMR(400MHz,CDCl 3 )δppm:8.51(s,1H),8.21(d,J＝8.0Hz,1H),7.80(d,J＝8.0Hz,1H),7.63(s,1H),5.24(br,2H),2.87(s,2H),1.37(s,12H),1.25(s,6H)。
MS m/z(+ESI):352.2[M+H] + 。
Step 2: 8-chloro-5, 5-dimethyl-6H-benzo [ H ]]Preparation of quinazolin-4-amine:
CuCl is added 2 (52 mg,0.38 mmol) to 5, 5-dimethyl-8- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -6H-benzo [ H ]]A solution of quinazolin-4-amine (0.15 g,0.38 mmol) in t-BuOH (1 mL) and MeOH (4 mL). After 2 hours at 90 ℃, the solids were removed by filtration and the filtrate was concentrated. The crude product was purified by preparative HPLC (note 2) to give 8 chloro-5, 5-dimethyl-6H-benzo [ H ] as a white solid]Quinazolin-4-amine. (140 mg,99% yield).
1 H NMR(400MHz,DMSO-d 6 +D 2 O)δppm:8.61(s,1H),7.87(d,J＝8.4Hz,1H),7.55(dd,J＝8.4Hz,2.0Hz,1H),7.51(d,J＝2.0Hz,1H),2.89(s,2H),1.29(s,6H)。
MS m/z(+ESI):260.1,262.1[M+H] + 。
(5S) -5- [ [ (Z) - (4-amino-8-chloro-5, 5-di- ]Methyl-benzo [ h ]]Quinazolin-6-ylidene) amino group]Oxyformazan
Base group]-preparation of 3-methyl-oxazolidin-2-one:
the title compound was prepared as a yellow solid according to scheme 1 and in analogy to example 1 (steps 6 and 7) and example 12 using 8 chloro-5, 5-dimethyl-6H-benzo [ H ] quinazolin-4-amine, hydroxylamine hydrochloride and (5S) -5- (chloromethyl) -3-methyl-oxazolidin-2-one (CAS 140478-99-5) as starting materials.
1 H NMR(400MHz,DMSO-d 6 +D 2 O)δppm:8.44(s,1H),8.13(d,J＝8.4Hz,1H),8.01(d,J＝2.0Hz,1H),7.72(dd,J＝8.4Hz,2.0Hz,1H),4.75(m,1H),4.34(m,1H),4.24(m,1H),3.62(m,1H),3.28(m,1H),2.65(s,3H),1.50(s,6H)。
MS m/z(+ESI):402.2,404.1[M+H] + 。
Preparation of example 69: (6Z) -6-methoxyimino-N8, 5-trimethyl-N8- (4-piperidinyl) benzo [ h ] quinazoline-4, 8-diamine:
Step 1: n- [ (6Z) -4-amino-6-methoxyimino-5, 5-dimethyl-benzo [ h ]]Quinazolin-8-yl]Second step
Preparation of amide:
acetamide (781 mg,12.96 mmol) was added to trifluoromethanesulfonic acid [ (6Z) -4-amino-6-methoxyimino-5, 5-dimethyl-benzo [ h ]]Quinazolin-8-yl]To a stirred solution of the ester (300 mg,0.65 mmol) in tBuOH (20 mL) was then added K 3 PO 4 (699mg，3.24mmol)、Pd 2 (dba) 3 (121 mg,0.13 mmol) and Me4tBuXPhos (127 mg,0.26 mmol). After stirring at 110℃for 2 hours, the reaction mixture was taken up with DCM and H 2 And O extraction. The combined organic layers were taken up over Na 2 SO 4 Dried, filtered and concentrated. The residue was purified by column chromatography (silica gel; DCM: meOH;10:1; v: v) to give N- [ (6Z) -4-amino-6-methoxyimino-5, 5-dimethyl-benzo [ h ] as a brown foam]Quinazolin-8-yl]Acetamide (200 mg,85% yield))。
MS m/z(+ESI):326.2[M+H] + 。
Step 2: (6Z) -6-Methoxyimino-5, 5-dimethyl-benzo [ h ]]Preparation of quinazoline-4, 8-diamine:
NaOH (805 mg,19.92 mmol) was added to N- [ (6Z) -4-amino-6-methoxyimino-5, 5-dimethyl-benzo [ h ]]Quinazolin-8-yl]Acetamide (180 mg,0.50 mmol) in MeOH (3 mL) and H 2 O (3 mL) in a stirred solution. After stirring at 50 ℃ for 16 hours, the reaction mixture was extracted with EA and brine. The combined organic layers were taken up over Na 2 SO 4 Drying, filtering and concentrating to obtain (6Z) -6-methoxyimino-5, 5-dimethyl-benzo [ h ] as yellow semi-solid]Quinazoline-4, 8-diamine (170 mg,72% yield) was used in the next step without further purification.
MS m/z(+ESI):284.1[M+H] + 。
Step 3:4- [ [ (6Z) -4-amino-6-methoxyimino-5, 5-dimethyl-benzo [ h ]]Quinazolin-8-yl]Ammonia
Base group]Preparation of piperidine-1-carboxylic acid tert-butyl ester:
n- (tert-Butoxycarbonyl) -4-piperidone (80 mg,0.39 mmol) was added to (6Z) -6-methoxyimino-5, 5-dimethyl-benzo [ h ]]Quinazoline-4, 8-diamine (170 mg,0.36 mmol) in DCE (5 mL) and then NaBH (OAc) was added 3 (236 mg,1.08 mmol). After stirring for 16 hours, saturated NH was used 4 The reaction mixture was deactivated with aqueous Cl and extracted with EA. The combined organic layers were taken up over Na 2 SO 4 Dried, filtered and concentrated. The residue was purified by column chromatography (silica gel; DCM: meOH;10:1; v: v) to give 4- [ [ (6Z) -4-amino-6-methoxyimino-5, 5-dimethyl-benzo [ h ] as a yellow solid]Quinazolin-8-yl]Amino group]Piperidine-1-carboxylic acid tert-butyl ester (168 mg,81% yield).
MS m/z(+ESI):467.2[M+H] + 。
Preparation of example 69: (6Z) -6-Methoxyimino-N8, 5-trimethyl-N8- (4-piperidinyl) benzo [ h ]
Quinazoline-4, 8-diamine:
the title compound (18 mg,34% yield) was prepared as a yellow solid following scheme 1 and in analogy to example 1 (step 9) and example 44 (step 3) using 4- [ [ (6Z) -4-amino-6-methoxyimino-5, 5-dimethyl-benzo [ h ] quinazolin-8-yl ] amino ] piperidine-1-carboxylic acid tert-butyl ester and paraformaldehyde as starting materials.
1 H NMR(400MHz,DMSO-d 6 +D 2 O)δppm:8.43(s,1H),7.87(d,J＝9.2Hz,1H),7.40(d,J＝2.4Hz,1H),7.11(dd,J＝9.2Hz,2.4Hz,1H),4.13(m,1H),3.84(s,3H),3.38(m,2H),3.08(m,2H),2.83(s,3H),1.90(m,2H),1.83(m,2H),1.48(s,6H)。
MS m/z(+ESI):381.2[M+H] + 。
Preparation of example 70: (6Z) -6-methoxyimino-5, 5-dimethyl-8- (4-piperidinylmethyl) benzo [ h ] quinazolin-4-amine:
step 1: 6-Methoxyimino-5, 5-dimethyl-8- (4, 5-tetramethyl-1, 3, 2-dioxaborolan)
Alkan-2-yl) benzo [ h]Preparation of quinazolin-4-amine:
the title compound (220 mg,93% yield) was prepared as a brown semi-solid following scheme 1 and in analogy to example 52 (step 1) using trifluoromethanesulfonic acid (4-amino-6-methoxyimino-5, 5-dimethyl-benzo [ h ] quinazolin-8-yl) ester (250 mg,0.54 mmol) as starting material.
MS m/z(+ESI):395.3[M+H] + 。
Step 2:4- [ (4-amino-6-methoxyimino-5, 5-dimethyl-benzo [ h ]]Quinazolin-8-yl) methylene]
Preparation of piperidine-1-carboxylic acid tert-butyl ester:
tert-butyl 4- (bromomethylene) piperidine-1-carboxylate (190 mg,0.67 mmol) was added to 6-methoxyimino-5, 5-dimethyl-8- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzo [ h ] ]Quinazolin-4-amine (260 mg,0.51 mmol)(ii) in Diox (3 mL) and H 2 To the stirred solution in O (0.4 mL) was then added Pd (dppf) Cl 2 (38 mg,0.05 mmol) and K 3 PO 4 (0.33 g,1.54 mmol). After stirring at 120℃for 1 hour, the reaction mixture was concentrated and the residue was purified by combined flash chromatography (ACN: H containing 0.1% HCOOH) 2 O) purification to give 4- [ (4-amino-6-methoxyimino-5, 5-dimethyl-benzo [ h ] as a dark brown solid]Quinazolin-8-yl) methylene]Tert-butyl piperidine-1-carboxylate (250 mg,84% yield).
MS m/z(+ESI):464.3[M+H] + 。
Step 3:4- [ (4-amino-6-methoxyimino-5, 5-dimethyl-benzo [ h ]]Quinazolin-8-yl) methyl]Piperazine sheet
Preparation of tert-butyl pyridine-1-carboxylate:
10% Palladium on active carbon (37 mg,0.03 mmol) was added to a stirred solution of 4- [ (4-amino-6-methoxyimino-5, 5-dimethyl-benzo [ h ] quinazolin-8-yl) methylene ] piperidine-1-carboxylic acid tert-butyl ester (200 mg,0.34 mmol) in EtOH (5 mL). After stirring for 16 hours under a stream of hydrogen, the catalyst was removed by filtration and the solution was concentrated to give tert-butyl 4- [ (4-amino-6-methoxyimino-5, 5-dimethyl-benzo [ h ] quinazolin-8-yl) methyl ] piperidine-1-carboxylate (20 mg,62% yield) as a pale yellow semi-solid, which was used in the next step without further purification.
MS m/z(+ESI):466.3[M+H] + 。
Step 4: (6Z) -6-Methoxyimino-5, 5-dimethyl-8- (4-piperidylmethyl) benzo [ h]Quinazoline-4-
Preparation of amine:
the title compound (15 mg,19% yield) was prepared as a white solid following scheme 1 and in analogy to example 1 (step 9) using 4- [ (4-amino-6-methoxyimino-5, 5-dimethyl l-benzo [ h ] quinazolin-8-yl) methyl ] piperidine-1-carboxylic acid tert-butyl ester (190 mg,0.20 mmol) as starting material.
1 H NMR(400MHz,DMSO-d 6 +D 2 O)δppm:8.43(s,1H),8.03(d,J＝8.0Hz,1H),7.83(d,J＝1.2Hz,1H),7.44(dd,J＝8.0Hz,1.2Hz,1H),3.84(s,3H),3.24(m,2H),2.81(m,2H),2.63(m,2H),1.83(m,1H),1.74(m,2H),1.49(s,6H),1.32(m,2H)。
MS m/z(+ESI):366.2[M+H] + 。
Preparation of example 76: (4S) -4- [ [ (Z) - (4-amino-8-methoxy-5, 5-dimethyl-benzo [ h ] quinazolin-6-ylidene) amino ] oxymethyl ] -1-methyl-pyrrolidin-2-one:
step 1: 4-Methylbenzenesulfonic acid [ (3S) -5-oxopyrrolidin-3-yl]Preparation of methyl ester:
the title compound (140 mg,12% yield) was prepared as a pale yellow liquid according to scheme 1 and in analogy to example 9 (step 1) using (4S) -4- (hydroxymethyl) pyrrolidin-2-one (900 mg,3.91 mmol) as starting material.
MS m/z(+ESI):270.2[M+H] + 。
Step 2: 4-Methylbenzenesulfonic acid [ (3S) -1-methyl-5-oxo-pyrrolidin-3-yl]Preparation of methyl ester:
NaH (35 mg,0.87 mmol) was added to 4-methylbenzenesulfonic acid [ (3S) -5-oxopyrrolidin-3-yl ] at 0deg.C]Methyl ester (130 mg,0.43 mmol) was added to a stirred solution of THF (5 mL) followed by methyl iodide (33. Mu.L, 0.74 mmol). After stirring at room temperature for 30 min, the reaction mixture was taken up with DCM and H 2 And O extraction. The combined organic layers were taken up over Na 2 SO 4 Drying, filtering and concentrating to obtain the off-white semisolid 4-methylbenzenesulfonic acid [ (3S) -1-methyl-5-oxo-pyrrolidin-3-yl)]Methyl ester (120 mg,88% yield), which was used in the next step without further purification.
MS m/z(+ESI):284.1[M+H] + 。
Step 3: (4S) -4- [ [ (Z) - (4-amino-8-methoxy-5, 5-dimethyl-benzo [ h ]]Quinazoline-6-subunit
Amino group]Oxymethyl group]-preparation of 1-methyl-pyrrolidin-2-one:
4-Methylbenzenesulfonic acid [ (3S) -1-methyl-5-oxo-pyrrolidin-3-yl]Methyl ester (120 mg,0.57 mmol) was added to 4-amino-8-methoxy-5, 5-dimethyl-benzo [ h ]]A stirred solution of quinazolin-6-one oxime (180 mg,0.57 mmol) in DMF (5 mL) was then added Cs 2 CO 3 (380 mg,1.14 mmol) and NaI (58 mg,0.38 mmol). After stirring at 100 ℃ for 20 min, the reaction mixture was concentrated and the residue was purified by preparative HPLC to give (4S) -4- [ [ (Z) - (4-amino-8-methoxy-5, 5-dimethyl-benzo [ h ] as a white solid]Quinazolin-6-ylidene) amino group]Oxymethyl group]-1-methyl-pyrrolidin-2-one (22 mg,14% yield).
1 H NMR(400MHz,DMSO-d 6 +D 2 O)δppm:8.55(s,1H),7.97(d,J＝8.8Hz,1H),7.58(d,J＝2.4Hz,1H),7.28(dd,J 1 ＝8.8Hz,J 2 ＝2.4Hz,1H),4.11(d,J＝6.4Hz,2H),3.87(s,3H),3.43(m,1H),3.12(m,1H),2.68(m,1H),2.63(s,3H),2.37(m,1H),2.08(m,1H),1.50(s,6H)。
MS m/z(+ESI):396.3[M+H] + 。
Preparation of example 77: (6Z) -10-fluoro-8-methoxy-6-methoxyimino-5, 5-dimethyl-benzo [ h ] quinazolin-4-amine:
(6Z) -8-methoxy-6-methoxyimino-5, 5-dimethyl-benzo [ h ]]Quinazolin-4-amine (20 mg,0.06 mmol), NFSI (59 mg,0.18 mmol) and Pd 2 (dba) 3 (10 mg,0.02 mmol) in PhCF 3 The mixture in (1.2 mL) was stirred at 110℃for 1 hour under microwave radiation. The reaction mixture was taken up with DCM and H 2 And O extraction. The combined organic layers were taken up over Na 2 SO 4 Dried, filtered and concentrated. The residue was purified by preparative HPLC to give (6Z) -10-fluoro-8-methoxy-6-methoxyimino-5, 5-dimethyl-benzo [ h ] as a white solid]Quinazolin-4-amine (7 mg,5% yield).
1 H NMR(400MHz,DMSO-d 6 +D 2 O)δppm:8.45(s,1H),7.33(d,J＝2.4Hz,1H),7.19(dd,J＝14.0Hz,2.4Hz,1H),3.87(s,3H),3.86(s,3H),1.46(s,6H)。
MS m/z(+ESI):317.3[M+H] + 。
Preparation of example 78: (2R) -1- [ (Z) - [ 4-amino-8- (trans-4-aminocyclohexyloxy) -5, 5-dimethyl-benzo [ h ] quinazolin-6-ylidene ] amino ] oxypropan-2-ol:
step 1: n- [4- [ (6Z) -4-amino-6- [ (2R) -2-hydroxypropoxy group]Imino-5, 5-dimethyl-benzo
[h]Quinazolin-8-yl]Oxy cyclohexyl]Preparation of tert-butyl carbamate:
KOH (6 mg,0.11 mmol) was added to N- [4- [ (6Z) -4-amino-6-hydroxyimino-5, 5-dimethyl-benzo [ h ]]Quinazolin-8-yl]Oxy cyclohexyl]Tert-butyl carbamate (50 mg,0.09 mmol) and (R) - (+) -1, 2-propylene oxide (9 mg,0.14 mmol) in H 2 O (0.3 mL) and DMSO (0.9 mL). After stirring for 48 hours, the mixture was treated with EA and H 2 And O extraction. The combined organic layers were taken up over Na 2 SO 4 Dried, filtered and concentrated to give N- [4- [ (6Z) -4-amino-6- [ (2R) -2-hydroxypropoxy ] as a pale yellow solid]Imino-5, 5-dimethyl-benzo [ h ]]Quinazolin-8-yl]Oxy cyclohexyl]Tert-butyl carbamate (55 mg,92% yield), which was used in the next step without further purification.
MS m/z(+ESI):526.4[M+H] + 。
Step 2: (2R) -1- [ (Z) - [ 4-amino-8- (trans-4-aminocyclohexyloxy) -5, 5-dimethyl-benzo [ h ]]
Quinazolin-6-subunit]Amino group]Preparation of oxypropan-2-ol:
MSA (174 mg,1.78 mmol) was added to N- [4- [ (6Z) -4-amino-6- [ (2R) -2-hydroxypropoxy]Imino-5, 5-dimethyl-benzo [ h ]]Quinazolin-8-yl]Oxy cyclohexyl]Tert-butyl carbamate (110 mg,0.18 mmol) in ACN (1.2 mL). After stirring for 18 hours, the reaction mixture was taken up with H 2 Diluting with NaHCO 3 The aqueous solution was brought to pH 7 and then extracted with DCM/MeOH (20:1, v/v). The combined organic layers were taken up over Na 2 SO 4 Dried, filtered and concentrated. The residue was purified by preparative HPLC to give (2R) -1- [ (Z) - [ 4-amino-8- (trans-4-aminocyclohexyloxy) -5, 5-dimethyl-benzo [ h ] as a white solid]Quinazolin-6-subunit]Amino group]Oxypropan-2-ol (23 mg,28% yield).
1 H NMR(400MHz,DMSO-d 6 +D 2 O)δppm:8.42(s,1H),8.01(d,J＝8.8Hz,1H),7.72(d,J＝2.8Hz,1H),7.19(dd,J＝8.8Hz,2.8Hz,1H),4.40(m,1H),3.91(m,3H),3.07(m,1H),2.15(m,2H),1.97(m,2H),1.48(m,10H),1.06(d,J＝6.0Hz,3H)。
LC-MS m/z(+ESI):426.3[M+H] + 。
Preparation of example 90: (5S) -5- [ [ (Z) - (4-amino-8-bromo-5, 5-dimethyl-benzo [ h ] quinazolin-6-ylidene) amino ] oxymethyl ] -3- (2-methoxyethyl) oxazolidin-2-one:
step 1: preparation of (5S) -5- (chloromethyl) -3- (2-methoxyethyl) oxazolidin-2-one:
1-bromo-2-methoxyethane (596 mg,4.20 mmol) was added to a stirred solution of (5S) -5- (chloromethyl) oxazolidin-2-one (500 mg,3.50 mmol) in DMF (4 mL), followed by Cs addition 2 CO 3 (2.33 g,7.01 mmol) and NaI (804 mg,5.25 mmol). After stirring at 60℃for 18 hours, saturated NH was used 4 The reaction mixture was deactivated with aqueous Cl and extracted with EA. The combined organic layers were taken up over Na 2 SO 4 Drying, filtration and concentration gave (5S) -5- (chloromethyl) -3- (2-methoxyethyl) oxazolidin-2-one (370 mg,38% yield) as a yellow oil, which was used in the next step without further purification.
Step 2: (5S) -5- [ [ (Z) - (4-amino-8-bromo-5, 5-dimethyl-benzo [ h ]]Quinazolin-6-ylidene) amino group]
Oxymethyl group]-3- (2-methoxy)Preparation of aminoethyl) oxazolidin-2-one:
NaI (98 mg,0.65 mmol) was added to a stirred solution of 4-amino-8-bromo-5, 5-dimethyl-benzo [ h ] quinazolin-6-one oxime (120 mg,0.32 mmol) and (5S) -5- (chloromethyl) -3- (2-methoxyethyl) oxazolidin-2-one (358 mg,1.29 mmol) in DMSO (3 mL), followed by KOH (64 mg,0.97 mmol). After stirring for 8 hours, the reaction mixture was purified by preparative HPLC to give (5S) -5- [ [ (Z) - (4-amino-8-bromo-5, 5-dimethyl-benzo [ h ] quinazolin-6-ylidene) amino ] oxymethyl ] -3- (2-methoxyethyl) oxazolidin-2-one (33 mg,18% yield) as a yellow solid.
1 H NMR(400MHz,DMSO-d 6 +D 2 O)δppm:8.30(s,1H),8.13(m,2H),7.77(dd,J＝8.4Hz,2.0Hz,1H),4.76(m,1H),4.24(m,2H),3.67(t,J＝8.8Hz,2H),3.36(m,2H),3.25(m,2H),3.17(s,3H),1.49(s,3H),1.48(s,3H)。
MS m/z(+ESI):490.3,492.3[M+H] + 。
Preparation of example 92: (6Z) -4-amino-5, 5-dimethyl-6- [ [ (5S) -2-oxooxazolidin-5-yl ] methoxyimino ] benzo [ h ] quinazoline-8-carbonitrile:
zn (CN) 2 (75 mg,0.62 mmol) was added to (5S) -5- [ [ (Z) - (4-amino-8-bromo-5, 5-dimethyl-benzo [ h ]]Quinazolin-6-ylidene) amino group]Oxymethyl group]Oxazolidin-2-one (100 mg,0.21 mmol) in a stirred suspension of DMA (5 mL) followed by Pd addition 2 (dba) 3 (19 mg,0.02 mmol) and XPhos (10 mg,0.02 mmol). The resulting suspension was stirred at 120℃for 30 minutes under microwave radiation. The reaction mixture was treated with EA and H 2 And O extraction. The combined organic layers were taken up over Na 2 SO 4 Dried, filtered and concentrated. The residue was purified by preparative HPLC to give (6Z) -4-amino-5, 5-dimethyl-6- [ [ (5S) -2-oxooxazolidin-5-yl as a white solid]Methoxyimino group]Benzo [ h ]]Quinazoline-8-carbonitrile (56 mg,62% yield).
1 H NMR(400MHz,DMSO-d 6 +D 2 O)δppm:8.48(s,1H),8.40(d,J＝1.6Hz,1H),8.31(d,J＝8.4Hz,1H),8.09(dd,J＝8.4Hz,1.6Hz,1H),4.85(m,1H),4.31(m,2H),3.59(m,1H),3.27(m,1H),1.51(s,6H)。
LC-MS m/z(+ESI):379.3[M+H] + 。
Preparation of example 93: (5S) -5- [ [ (Z) - (4-amino-8-iodo-5, 5-dimethyl-benzo [ h ] quinazolin-6-ylidene) amino ] oxymethyl ] oxazolidin-2-one:
NaI (95 mg,0.62 mmol) was added to a stirred suspension of (5S) -5- [ [ (Z) - (4-amino-8-bromo-5, 5-dimethyl-benzo [ h ] quinazolin-6-ylidene) amino ] oxymethyl ] oxazolidin-2-one (150 mg,0.31 mmol) in 1, 4-dioxane (1 mL), followed by (1 r,2 r) -N1, N2-dimethylcyclohexane-1, 2-diamine (13 mg,0.09 mmol) and CuI (12 g,0.06 mmol). The resulting suspension was stirred at 120 ℃ under microwave radiation for 1 hour, then filtered, washed with DCM and purified by preparative HPLC to give (5S) -5- [ [ (Z) - (4-amino-8-iodo-5, 5-dimethyl-benzo [ h ] quinazolin-6-ylidene) amino ] oxymethyl ] oxazolidin-2-one as a white solid (62 mg,40% yield).
1 H NMR(400MHz,DMSO-d 6 +D 2 O)δppm:8.52(s,1H),8.42(d,J＝1.6Hz,1H),8.07(dd,J＝8.4Hz,1.6Hz,1H),7.86(d,J＝8.4Hz,1H),4.85(m,1H),4.30(m,2H),3.60(m,1H),3.27(m,1H),1.50(s,3H),1.49(s,3H)。
LC-MS m/z(+ESI):480.2[M+H] + 。
Preparation of example 94: (5S) -5- [ [ (Z) - [ 4-amino-8- (2-hydroxyethoxy) -5, 5-dimethyl-benzo [ h ] quinazolin-6-ylidene ] amino ] oxymethyl ] oxazolidin-2-one:
step 1: 4-amino-8-benzyloxy1-methyl-5, 5-dimethyl-benzo [ h ]]Preparation of quinazolin-6-one:
benzyl bromide (2.7 g,15.67 mmol) was added to 4-amino-8-hydroxy-5, 5-dimethyl-benzo [ h ]]A stirred solution of quinazolin-6-one (5 g,9.79 mmol) in DMF (50 mL) was then added Cs 2 CO 3 (9.77 g,29.38 mmol). After stirring for 1 hour, the reaction mixture was taken up with EA and H 2 And O extraction. The combined organic layers were taken up over Na 2 SO 4 Dried, filtered and concentrated. The residue was purified by column chromatography (silica gel; PE: EA;2:1, v: v) to give 4-amino-8-benzyloxy-5, 5-dimethyl-benzo [ h ] as a yellow solid]Quinazolin-6-one (2.3 g,61% yield).
1 H NMR(400MHz,DMSO-d 6 )δppm:8.56(d,J＝8.8Hz,1H),8.38(s,1H),7.56(d,J＝2.8Hz,1H),7.49(m,3H),7.39(m,2H),7.35(m,1H),6.87(s,2H),5.26(s,2H),1.50(s,6H)。
LC-MS m/z(+ESI):346.3[M+H] + 。
Step 2: 4-amino-8-benzyloxy-5, 5-dimethyl-benzo [ h ]]Preparation of quinazolin-6-one oxime:
the title compound (450 mg,82% yield) was prepared as a yellow solid following scheme 1 and in analogy to example 1 (step 7) using 4-amino-8-benzyloxy-5, 5-dimethyl-benzo [ h ] quinazolin-6-one (500 mg,1.37 mmol) and hydroxylamine hydrochloride (970 mg,13.7 mmol) as starting materials.
LC-MS m/z(+ESI):361.2[M+H] + 。
Step 3: (5S) -5- [ [ (Z) - [ 4-amino-5, 5-dimethyl-8- (2-phenylethyl) benzo [ h ]]Quinazoline-6-
Subunit]Amino group]Oxymethyl group]Preparation of oxazolidin-2-ones:
(5S) -5- (chloromethyl) oxazolidin-2-one (CAS 169048-83-3,1.07g,7.49 mmol) was added to 4-amino-8-benzyloxy-5, 5-dimethyl-benzo [ h ]]To a stirred suspension of quinazolin-6-one oxime (1 g,2.50 mmol) in DMSO (20 mL) was then added KOH (428 mg,7.49 mmol) and NaI (756 mg,4.99 mmol). After stirring for 16 hours, the mixture was treated with EA and H 2 And O extraction. The combined organic layersThrough Na 2 SO 4 Dried, filtered and concentrated. The residue was purified by combined flash chromatography (combiflash) to give (5S) -5- [ [ (Z) - [ 4-amino-5, 5-dimethyl-8- (2-phenylethyl) benzo [ h ] as a pale yellow solid]Quinazolin-6-subunit]Amino group]Oxymethyl group]Oxazolidin-2-one (350 mg,27% yield).
LC-MS m/z(+ESI):460.2[M+H] + 。
Step 4: (5S) -5- [ [ (Z) - (4-amino-8-hydroxy-5, 5-dimethyl-benzo [ h ]]Quinazolin-6-ylidene) ammonia
Base group]Oxymethyl group]Preparation of oxazolidin-2-ones:
10% palladium on charcoal (365 mg,0.34 mmol) was added to a stirred solution of (5S) -5- [ [ (Z) - [ 4-amino-5, 5-dimethyl-8- (2-phenylethyl) benzo [ h ] quinazolin-6-ylidene ] amino ] oxymethyl ] oxazolidin-2-one (350 mg,0.69 mmol) in MeOH (15 mL). After stirring for 16 hours under a stream of hydrogen, the catalyst was removed by filtration and the solution was concentrated to give (5S) -5- [ [ (Z) - (4-amino-8-hydroxy-5, 5-dimethyl-benzo [ h ] quinazolin-6-ylidene) amino ] oxymethyl ] oxazolidin-2-one as a pale yellow viscous oil (280 mg,99% yield) which was used in the next step without further purification.
LC-MS m/z(+ESI):370.2[M+H] + 。
Step 5: (5S) -5- [ [ (Z) - [ 4-amino-8- [2- [ tert-butyl (dimethyl) silyl ]]Oxyethoxy radical]-5,5-
Dimethyl-benzo [ h ]]Quinazolin-6-subunit]Amino group]Oxymethyl group]Preparation of oxazolidin-2-ones:
(2-Bromoethoxy) (tert-butyl) dimethylsilane (CAS 86864-60-0, 589mg,2.39 mmol) was added to (5S) -5- [ [ (Z) - (4-amino-8-hydroxy-5, 5-dimethyl-benzo [ h)]Quinazolin-6-ylidene) amino group]Oxymethyl group]Oxazolidin-2-one (280 mg,0.68 mmol) in DMF (5 mL) was stirred solution followed by K 2 CO 3 (476 mg,3.41 mmol). After stirring at 85℃for 3 hours, the reaction mixture was taken up with EA and H 2 And O extraction. The combined organic layers were taken up over Na 2 SO 4 Dried, filtered and concentrated. The residue was purified by combined flash chromatography (combiflash),to obtain (5S) -5- [ [ (Z) - [ 4-amino-8- [2- [ tert-butyl (dimethyl) silicon base ] as colorless liquid]Oxyethoxy radical]-5, 5-dimethyl-benzo [ h ]]Quinazolin-6-subunit]Amino group]Oxymethyl group]Oxazolidin-2-one (200 mg,53% yield).
LC-MS m/z(+ESI):528.4[M+H] + 。
Step 6: (5S) -5- [ [ (Z) - [ 4-amino-8- (2-hydroxyethoxy) -5, 5-dimethyl-benzo [ h ]]Quinazoline-
6-subunit]Amino group]Oxymethyl group]Preparation of oxazolidin-2-ones:
to a stirred solution of (5S) -5- [ [ (Z) - [ 4-amino-8- [2- [ tert-butyl (dimethyl) silyl ] oxyethoxy ] -5, 5-dimethyl-benzo [ h ] quinazolin-6-ylidene ] amino ] oxymethyl ] oxazolidin-2-one (195 mg,0.35 mmol) in THF (10 mL) was added hydrogen fluoride (497 mg,3.51 mmol), and the resulting solution was sonicated for 10 min. The reaction mixture was concentrated and the residue was purified by preparative HPLC to give (5S) -5- [ [ (Z) - [ 4-amino-8- (2-hydroxyethoxy) -5, 5-dimethyl-benzo [ h ] quinazolin-6-ylidene ] amino ] oxymethyl ] oxazolidin-2-one (58 mg,36% yield) as a white solid.
1 H NMR(400MHz,DMSO-d 6 +D 2 O)δppm:8.13(d,J＝8.8Hz,1H),7.55(d,J＝2.4Hz,1H),7.51(s,1H),7.13(dd,J＝8.8Hz,2.4Hz,1H),4.86(m,1H),4.23(m,2H),4.50(m,2H),3.73(m,2H),3.57(m,1H),3.26(m,1H),1.50(s,3H),1.48(s,3H)。
LC-MS m/z(+ESI):414.3[M+H] + 。
Preparation of example 98: (5S) -5- [ [ (Z) - (8-acetyl-4-amino-5, 5-dimethyl-benzo [ h ] quinazolin-6-ylidene) amino ] oxymethyl ] oxazolidin-2-one:
tributyl (1-ethoxyvinyl) tin (CAS 97674-02-7, 310mg,0.83 mmol) was added to (5S) -5- [ [ (Z) - (4-amino-8-bromo-5, 5-dimethyl-benzo [ h)]Quinazolin-6-ylidene) amino group]Oxymethyl group]Oxazolidin-2-one (200 mg,0.42 mmol) in DMF5 mL) and then LiCl (18 mg,0.42 mmol) and Pd (dppf) Cl were added 2 (31 mg,0.04 mmol). The resulting suspension was stirred at 80℃for 16 hours. The solvent was removed and the residue was taken up with EA and H 2 And O extraction. The combined organic layers were taken up over Na 2 SO 4 Dried, filtered and concentrated. The crude product was dissolved in THF (2 mL) and 1N aqueous HCl (1 mL) was added. After stirring for 1 hour, the solvent was removed and the residue was purified by preparative HPLC to give (5S) -5- [ [ (Z) - (8-acetyl-4-amino-5, 5-dimethyl-benzo [ h ] as a white solid]Quinazolin-6-ylidene) amino group]Oxymethyl group]Oxazolidin-2-one (106 mg,25% yield).
1 H NMR(400MHz,DMSO-d 6 +D 2 O)δppm:8.61(d,J＝1.6Hz,1H),8.43(s,1H),8.29(d,J＝8.4Hz,1H),8.14(dd,J＝8.4Hz,1.6Hz,1H),4.85(m,1H),4.32(m,2H),3.59(m,1H),3.30(m,1H),2.62(s,3H),1.52(s,3H),1.51(s,3H)。
LC-MS m/z(+ESI):396.3[M+H] + 。
Biological examples
CLK3 kinase assay
UsingThe Ultra technology (PerkinElmer) basically measures CLK3 kinase activity as recommended by the supplier. Briefly, 2.5 μl of test samples were dispensed into white, low volume, round bottom, 384 well plates (Corning) catalog number 4512 in 4% DMSO at 4 times the desired final concentration. Then 5. Mu.L of recombinant human CLK3 (Semer Fielder technology Co., catalog number PV 3826) and labeled protein substrate ULTight prepared in 1.33 Xkinase buffer (Semer Fielder technology Co., ltd. (Thermo Fisher Scientific), catalog number PV 3189) were added TM Mixtures of CREBtide (Perkin Elmer, catalog number TRF 0107). Finally, the reaction was initiated by adding 2.5. Mu.L of 4x ATP solution in kinase buffer. The plates were sealed with an adhesive foil and incubated in the dark at 30℃for 3 hours. CLK3, ulight TM The final CREBtide and ATP concentrations were 0.5nM, 50nM and 300. Mu.M, respectively. Then addmu.L of 40mM EDTA to terminate the reaction. Then add and dilute in->Eu-anti-phosphorylation-CREB antibody (Perkin Elmer, cat# TRF 0200) in detection buffer (Perkin Elmer, cat# CR 97) to a final concentration of 2nM, and incubating the reaction at room temperature in the dark for 1 hour. The signals were measured using a Synergy 4 reader (berteng) with 320/80nm filters for excitation and 620/10nm and 665/8nm filters for donor and acceptor emission, respectively. The relative inhibition values were calculated by normalizing the raw data using solvent control wells (0% inhibition) and wells that did not receive ATP (100% inhibition). Calculation of IC by fitting concentration response data to sigmoid 4-parameter logarithmic logic model 50 Values. The results are shown in table 2 below.
MDA-MB-231 proliferation assay
MDA-MB-231 cells were cultured in DMEM high glucose (4, 5 g/L) containing L-glutamine (BAIKANGTE Co., ltd., bioConcept, catalog No. 1-26F 03-I) supplemented with 1% sodium pyruvate (Sigma, catalog No. S8636), 1% penicillin streptomycin (BAIKATE Co., catalog No. 4-01F 00H), and 10% FBS (Sigma Co., catalog No. F9665) using standard techniques. Cells were seeded in a black, clear bottomed 384 well plate (Greiner Bio-one, cat. No. 781091) for tissue culture in 20 μl of medium at a density of 750 cells/well and the plate was subjected to 5% CO at 37 ℃ before treatment 2 Incubate overnight under the conditions. The test compounds were serially diluted in DMSO to the final concentration required for 200 x. The solution was then diluted 1:40 with medium and 5. Mu.L aliquots were mixed into wells containing cells. The final concentration of DMSO was 0.5%. Plates were incubated for 72 hours, then YO-PRO was used TM -1 iodide (zemoer feishi technologies, catalog number Y3603) the cell number was measured essentially as recommended by the manufacturer. Briefly, 12.5. Mu.M of YO-PRO in 5 XYO-PRO buffer (100 mM sodium citrate, 130mM NaCl, pH 4) was used TM -1 iodide solution with an equal volume of lysis buffer (0.6% NP-40, 30mMEDTA, 30mM EGTA, 0.33xYO-PRO buffer) and 12.5. Mu.L of the mixture was dispensed into each well. Plates were incubated for 30 minutes at room temperature in the dark. Fluorescence intensity signals were then measured on a Synergy 4 reader (BioTek) using a 485/20nm filter for excitation and a 530/25nm filter for emission, respectively. The relative proliferation values were calculated by normalizing the raw data using DMSO-treated cells (100% proliferation) and the signals obtained in the cells assessed at the time of compound addition (0% proliferation). Concentration response data were fitted to an sigmoid 4-parameter logarithmic logic model with a maximum of 100%. GI was calculated from the curve when the compound concentration was reduced to proliferate to 50% 50 Values. The results are shown in table 2 below:
table 2: CLK3 biochemical results and growth inhibition of MDA-MB-231 cells
nt = untested
Assessment of inhibition of phosphorylated SRSF6 levels in MDA-MB-468 cells
MDA-MB-468 cells (ATCC, HTB-132) were cultured in DMEM (Baikett, catalog No. 1-26F 03) supplemented with 10% FBS (Sigma, catalog No. F9665), 1% sodium pyruvate (Sigma, catalog No. S8636), 1% penicillin streptomycin (Baikett, catalog No. 4-01F 00-H). When cells reached 70% density in 6-well plates (TPP, catalog No. 92006), they were testedCompound vehicle DMSO or test compound at a final concentration of 100nM for 2 hours. Thereafter, the medium is removed and the cells are passed through a medium containing protease and phosphatase inhibitors (half TM Protease and phosphatase inhibitor cocktail 100x, siemens technologies (thermo scientific), catalog number 1861281) and 1mM PMSF (Fluka, catalog number 93482) were scraped in lysis buffers (20mM Tris HCl pH 7.5, 150mM NaCl, 1mM EGTA, 1mM EDTA, 1% Triton, and 1% NP-40) and pooled. The clarified lysate was stored in Eppendorf tubes at-80℃until use and the protein concentration in the lysate was determined using Pierce 660nm protein assay reagent (Semerfeishi technologies Co., catalog No. 22660). Mu.g of protein was diluted in 4 XLaemmli buffer (Berle Corp. (Biorad) catalog No. 161-0747) containing 10% beta-mercaptoethanol, separated by SDS-PAGE using 10% gel, and then by Turbo TM The system semi-dry blotting method (bure) was transferred to PVDF membranes (Trans Blot Turbo Transfer Pack bure, catalog No. 1704156). Primary antibody was incubated overnight at 4℃in TBS-0.1% Tween-20 buffer containing 3% BSA bovine albumin Fr.V (Millipore, catalog No. 81-053-3). The following primary antibodies were used: mouse anti-phosphorylated SR protein clone 1H4 (Milbot, cat# MABE 50) diluted 1:5000, and rabbit anti-GAPDH clone 14C10 (Cell Signaling), cat# 2118S diluted 1:2000 to control equal protein loading. HRP conjugated secondary antibody was diluted 1:5000 in TBS-0.1% tween-20 buffer containing 5% defatted dry cow milk (sigma, cat# M7409) at room temperature and incubated for one hour. The following secondary antibodies were used: goat anti-mouse HRP (Jackson, cat# 115-035-146) and goat anti-rabbit HRP (Jackson, cat# 111-035-144). The membranes were incubated with ECL major western blot detection reagent (Amersham, catalog No. RPN 2236) and specific signals were detected using Fusion SOLO S device (Vilber Lourmat). The pixel intensity (MW 55kDa, for the marker) of phosphorylated SRSF6 and GAPDH (MW 37 kDa) signals in Western blots were determined using Evolution-Capt image analysis software (v 17.01, vilber Lourmat). DMSO controls were used to set the phosphorylated SRSF6 signal at baseline, the phosphorylated SRSF6 signal of each sample was normalized by the corresponding GAPDH signal, and the intensity percentage of P-SRSF6 signal was calculated at 100nM compound compared to DMSO controls (see fig. 1).
Several examples of the present invention were tested for inhibition of phosphorylated SRSF6 levels in MDA-MB-468 cells and showed inhibition levels of over 50% compared to DMSO controls when tested at a concentration of 100 nM. The results are shown in table 3 below.
Table 3: phosphorylation-SRSF 6 levels in MDA-MB-468 cells
Mouse xenograft model
The efficacy of example 29 was evaluated in a mouse xenograft model. For this purpose, a CAL-51 triple negative breast cancer xenograft model was used, in which tumor cells were subcutaneously injected into the flank of immunodeficient NCG mice (lack of functional/mature T, B and NK cells, and reduced macrophage and dendritic cell function). CAL-51 cells (DSMZ, # ACC302) were cultured in Du's modified eagle's medium (Dulbecco's Modified Eagle Medium) supplemented with 10% heat-inactivated fetal bovine serum at 37 ℃. CAL-51 cells were harvested as they grew exponentially.
Studies were performed using female NCG mice (Cha Lisi river laboratories (Charles River Laboratories)) of 8-12 weeks of age. Will be at 50% Matrigel TM 1×10 of (a) 7 The CAL-51 cells were inoculated subcutaneously in the flank region of the mice at a final injection volume of 0.1 mL/mouse. Once the tumor reaches 100-150mm 3 Pairing was performed to assign mice to different treatment groups. Mice in the control group were orally administered vehicle daily (5% ethanol; 8) at an administration volume of 10mL/kg5.5% citrate buffer 50mM pH 3;9.5% tween 80). In the vehicle described above, the formate of example 29 was freshly prepared on the day of dosing. The solution of example 29 was administered orally at an administration volume of 10mL/kg, at 25mg/kg daily or at 60mg/kg three times a week or at 85mg/kg twice a week (dose represents free base equivalent).
Tumor volumes (in mm) were measured in two dimensions using calipers on days 1, 3, 7, 10, 14, 17 and 21 during treatment 3 Representation). Figure 2 depicts tumor growth and weight changes during treatment. Results represent mean ± SEM. Tumor volumes at the end of the study were analyzed by one-way ANOVA analysis to compare treatment and vehicle groups. Significance level is set to P <0.05. Using GraphPad TM Prism version 9 was used for calculations. At the end of the study (day 21), the tumor volume of mice treated with example 29 at 60mg/kg three times a week or at 85mg/kg twice a week was significantly smaller compared to the tumor volume of animals treated with vehicle. On day 21 of the treatment period and compared to the vehicle-treated group, the tumor volumes of the 25mg/kg, 60mg/kg and 85mg/kg groups of example 29 were 41.8%, 42.7% and 46.8%, respectively (FIG. 2A). The treatment with example 29 was well tolerated as demonstrated by weight assessments performed on days 1, 2, 3, 4, 5, 7, 10, 14, 17 and 21 of the treatment period (fig. 2B).
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