BENZO[h]QUINAZOLINE-4-AMINE DERIVATIVES FOR CANCER TREATMENT

Abstract

FIELD: pharmaceutical compositions.SUBSTANCE: invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein Ra and Rb are both -CH3; A is -CH2-; T is -N(R11)-; R11 is hydrogen, C1-C4 alkylene-R11a or C3-C6 cycloalkyl; R11a is hydrogen; R1 is -YR3; Y is C1-C6 alkylene, wherein the alkylene moiety may include a 3-5-membered saturated carbocyclic ring as part of the moiety; R3 is -CN or a P ring; the P ring is a 3-6-membered saturated heterocyclic ring containing one N and one O and substituted with oxo; X is -O- or X is a bond when R2 is halogen; R2 is halogen, C1-C4 alkyl substituted with one R7, or is a 4-7-membered saturated carbocyclic ring substituted with one R8; R7 is -N(R7a)R7b; each R7a and R7b is independently hydrogen or C1-C4 alkylene-R7c; each R7c is independently hydrogen; R8 is -N(R8a)R8b; R8a and R8b, if they do not form together a ring, are independently hydrogen or C1-C4 alkylene-R8c or R8a and R8b may form together a 4-7-membered saturated heterocyclic ring containing one O; and R8c is hydrogen.EFFECT: new compounds targeting the CDC2-like kinase (CLK) family have been obtained and can be used in the treatment of neoplastic diseases such as cancer.6 cl, 5 dwg, 3 tbl

Description

[0001] The present invention relates to compounds targeting the CDC2-like kinase (CLK) family and their use in the treatment of non-plastic diseases such as cancer.

[0002] Recurrent mutations in components of the splicing machinery have been reported in diseases such as cancer. CLKs belong to the CMGC family of kinases and include four family members: CLK1, -2, -3, and -4. CLKs are known to play a key role in the regulation of alternative splicing (AS) through phosphorylation of splicing factors of the se ρ ine-arginine-rich (SR) protein family. Alternative splicing of transcripts is an important regulatory mechanism in eukaryotes that allows a single gene to generate multiple protein isoforms with different functions. CLK-mediated phosphorylation of SR proteins is involved in their redistribution from speckles to a diffuse nucleoplasmic distribution pattern [Colwill et al., EMBO J. 1996, 15 (2):2 65-75). SR protein phosphorylation must be tightly regulated for nuclear import, spliceosome assembly, and ultimately for proper splicing, particularly to promote exon inclusion.Small molecule CLK inhibitors have been reported to be effective in preclinical animal models of cancer (Yoshida T et al., Cancer Res. 2015, 75(7):1516–26; Ivan K et al., EMBO Mol Hied. 2018 10(6):e8289; Zhu D et al., Mol Cancer Ther. 2018, 17(8): 1727–1738). Thus, targeting CLKs offers potential for anticancer therapy, such as in splicing factor-mutant cancers where there is a compelling rationale for exploiting aberrant splicing as a vulnerability and therapeutic opportunity.

[0003] In one aspect, the present invention provides compounds of formula (I)

[0004]

[0005] and their pharmaceutically acceptable salts; where

[0006] Ra and Rb are both -CH3 or Ra and Rb together form a bridging moiety -CH2-CH2-CH2- or -CH2-CH2-CH2-CH2-;

[0007] A represents -CH2- or -C(=O)-;

[0008] T represents -N(R11)-, -N(R11)-C(=O)-, -N(R11)-S(O2)-, -O-, -C(R12)(R13)-, -C=C(R12)2, -S-, -S(O)-, -S(O2)-, -S(O2)-N(R14)- or -C(=O)-N(R14)-;

[0009] R11, if it does not form a ring with R1 or R2, is hydrogen, C1-C4alkylene-R11a, C1-C4haloalkylene-R11a, or C3-C6cycloalkyl, wherein the cycloalkyl is optionally substituted with one or two R11b;

[0010] each R12, if it does not form a ring with R2, is independently hydrogen, C1-C4alkylene-R12a, C1-C4haloalkylene-R12a, or C3-C6cycloalkyl, wherein the cycloalkyl is optionally substituted with one or two R12b;

[0011] R14, if it does not form a ring with R1 or R2, is hydrogen, C1-C4alkylene-R14a, C1-C4haloalkylene-R14a, or C3-C6cycloalkyl, wherein the cycloalkyl is optionally substituted with one or two R14b;

[0012] each R11a, R12a and R14a independently represent hydrogen, halogen, -OH, -CN, -NH2, -O-C1-C2alkyl, -O-C1-C2haloalkyl, -NH(C1-C2alkyl) or -N(C1-C2alkyl)2;

[0013] each R11b, R12b and R14b independently represents halogen, -OH, -CN, -NH2, -O-C1-C2alkyl, -O-C1-C2haloalkyl, NH(C1-C2alkyl) or -N(C1-C2alkyl)2;

[0014] R13 represents hydrogen, C1-C4 alkyl or C1-C4 haloalkyl;

[0015] R2 and R11, R2 and R12, or R2 and R14 may together form a partially unsaturated 6- to 7-membered heterocyclic ring containing no further heteroatoms as ring members, wherein the heterocyclic ring is optionally substituted with one or two R2a;

[0016] each R2a independently represents halogen, -OH, -CN, -NH2, -O-C1-C2alkyl, -O-C1-C2haloalkyl, -NH(C1-C2alkyl) or -N(C1-C2alkyl)2;

[0017] R1 and R11 or R1 and R14 may together form a saturated or partially unsaturated 4- to 7-membered heterocyclic ring optionally containing one or two additional heteroatoms as ring members selected from N, O and S, wherein the heterocyclic ring is optionally substituted with one to three R1a, or R1 and R11 or R1 and R14 may together form a 5- to 6-membered heteroaryl ring optionally containing one to three additional heteroatoms as ring members selected from N and O, wherein the heteroaryl ring is optionally substituted with one to three R1b;

[0018] each R1a independently represents halogen, -OH, -CN, -NH2, C1-C4 alkylene-R1b, C1-C4 haloalkylene-R1b, -O-C1-C4 alkyl, -O-C1-C4 haloalkyl, -NH (C1-C4 alkyl), -N (C1-C4 alkyl)2, -C(=O)NH2, -C(=O)NH(C1-C4 alkyl), -C (=O) N (C1-C4 alkyl)2 or oxo;

[0019] each R1b independently represents halogen, -OH, -CN, -NH2, C1-C4 alkylene-R1c, C1-C4 haloalkylene-R1c, -O-C1-C4 alkyl, -O-C1-C4 haloalkyl, -NH(C1-C4 alkyl) or -N(C1-C4 alkyl)2, C(=O)NH2, -C(=O)NH(C1-C4 alkyl) or -C(=O)N(C1-C4 alkyl)2;

[0020] each R1c independently represents hydrogen, halogen, -OH, -CN, -NH2, -O-C1-C2alkyl, -O-C1-C2haloalkyl, -NH(C1-C2alkyl) or -N(C1-C2alkyl)2;

[0021] R1, if it does not form a ring with R11 or R14, is hydrogen or -Y-R3;

[0022] Y represents a bond or C1-C6 alkylene, wherein one non-terminal -CH2- moiety may be replaced by -O- and wherein the alkylene moiety may be substituted with one or two moieties independently selected from -OH, -O-C1-C4 alkyl and -O-C1-C4 haloalkyl, and wherein the alkylene moiety may include a 3-5-membered saturated or partially unsaturated carbocyclic ring as part of the moiety;

[0023] R3 is hydrogen, -CN, -OH, C1-C4haloalkyl, C2-C4alkenylene-R4, C2-C4alkynylene-R4, -O-C1-C4alkylene-R4, -O-C1-C4haloalkyl, -NH2, -NH(C1-C4alkylene-R4), -N(C1-C4alkylene-R4)2, -C(=O)-0H, -C (=O)-O-C1-C4alkylene-R4, -C(=O)-NH2, -C(=O)-NH (C1-C4alkylene-R4), -C (=O)-N (C1-C4alkylene-R4)2, -NH-C (=O)-C1-C4alkylene-R4, -N (C1-C4alkyl) -C (=O) -C1-C4alkylene-R4, Ring P, Ring Q, -O-Ring P, -O-Ring Q, -NH-S(O2)-C1-C4alkylene-R4, -N(C1-C4alkyl)-S(O2)-C1-C4alkylene-R4, -S-C1-C4alkylene-R4 or -S(O2)-C1-C4alkyl-R4, provided that the atom in R3 bonded to Y is not a heteroatom when (i) Y is a bond and (ii) T is not -N(R11)-, -C(R12)(R13)- or C=C(R12)2;

[0024] R4 represents hydrogen, halogen, -NH2, -NH(C1-C2alkyl) or -N(C1-C2alkyl)2;

[0025] Ring P is a 3- to 6-membered saturated or partially unsaturated carbocyclic ring optionally substituted with one to three R5, or is a 3- to 6-membered saturated or partially unsaturated heterocyclic ring containing one or two heteroatoms selected from N and O, optionally substituted with one to three R5;

[0026] each R5 independently represents halogen, -NH2, -OH, -CN, C1-C4alkylene-R5a, -O-C1-C4alkylene-R5a, or oxo;

[0027] each R5a independently represents hydrogen, halogen, -NH2, -OH, -CN, or -O-C1-C2alkyl;

[0028] Ring Q is phenyl optionally substituted with one to three R6, or is a 5-6 membered

[0029] a heteroaryl ring containing one or two heteroatoms selected from N, S and O, optionally substituted with one to three R6;

[0030] each R6 independently represents halogen, -NH2, -OH, -CN, C1-C4alkylene-R6a, or -O-C1-C4alkylene-R6a;

[0031] each R6a independently represents hydrogen, halogen, -NH2, -OH, -CN, or -O-C1-C2alkyl;

[0032] X is -O-, -C(=O)-, -C(=CH2)-, -N(R10a)- or -CH(R10b)-, wherein X is a bond when R2 is halogen or -CN, and wherein when X is -C(=O)-, then R2 is not hydrogen, or where X-R2 is hydrogen;

[0033] R10a, if it does not form a ring with R2, is hydrogen or C1-C4 alkyl;

[0034] R10b represents hydrogen or C1-C4 alkyl;

[0035] R2 and R10a may together form a 4- to 7-membered saturated or partially unsaturated heterocyclic ring, optionally containing an -N(R9)- moiety as a ring member in addition to the nitrogen atom X and, otherwise, containing only carbon atoms as ring members, optionally substituted with one or two R8;

[0036] R2 and R10b together may form a 4- to 7-membered saturated or partially unsaturated carbocyclic ring or a 4- to 7-membered saturated or partially unsaturated heterocyclic ring containing the moiety -N(R9)- as a ring member and, otherwise, containing only carbon atoms as ring members, optionally substituted with one or two R8;

[0037] R2, if it does not form a ring with R10a, R10b, R11, R12 or R14, is hydrogen, halogen, -CN, C1-C4 alkyl optionally substituted with one or two R7, or is a 4- to 7-membered saturated or partially unsaturated carbocyclic ring optionally substituted with one or two R8, or is a 4- to 7-membered saturated or partially unsaturated heterocyclic ring containing one -N(R9)- moiety as a ring member or containing only carbon atoms as ring members;

[0038] each R7 independently represents -CN, -OH, halogen, -N(R7a)R7b or -NH(-C(=O)-C1-C4alkyl);

[0039] each R7a and R7b, if they do not together form a ring, independently represents hydrogen, C1-C4 alkylene-R7c, or 01-04 haloalkylene-R7c;

[0040] each R7c independently represents hydrogen, halogen, -O-C1-C2alkyl or -O-C1-C2haloalkyl;

[0041] R7a and R7b together may form a 4-7-membered saturated or partially unsaturated heterocyclic ring, optionally containing one or two additional heteroatoms as ring members selected from N, O and S, and wherein the heterocyclic ring is optionally substituted with one or two R7d;

[0042] each R7d independently represents halogen, -OH, -CN, -NH2, C1-C2alkyl, C1-C2haloalkyl, -O-C1-C2alkyl, -O-C1-C2haloalkyl, -NH(C1-C2alkyl) or -N(C1-C2alkyl)2;

[0043] each R8 independently represents -CN, -OH, halogen, -N(R8a)R8b, -NH(-C(=O)-01-04alkyl), C1-C4alkyl or 01-04haloalkyl;

[0044] each R8a and R8b, if they do not together form a ring, independently represents hydrogen, 01-04alkylene-R8c, or 01-04haloalkylene-R8c;

[0045] R8c represents hydrogen, halogen, -O-C1-C2alkyl or -O-C1-02haloalkyl;

[0046] R8a and R8b together may form a 4- to 7-membered saturated or partially unsaturated heterocyclic ring, optionally containing one or two additional heteroatoms as ring members selected from N, O and S, and wherein the heterocyclic ring is optionally substituted with one or two R8d;

[0047] each R8d independently represents halogen, -OH, -CN, -NH2, C1-C2alkyl, C1-C2haloalkyl, -O-C1-C2alkyl, -O-C1-C2haloalkyl, -NH(C1-C2alkyl) or -N(C1-C2alkyl)2;

[0048] R9 is hydrogen, C1-C4alkylene-R9a, C1-C4haloalkylene-R9a, or -C(=O)-C1-C4alkyl; and

[0049] R9a represents hydrogen, halogen, -O-C1-C2alkyl or -O-C1-C2haloalkyl.

[0050] In another aspect, the present invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof for use in the treatment of neoplastic diseases in a subject selected from a mammal, in particular a human.

[0051] In another aspect, the present invention provides the use of compounds of formula (I) and pharmaceutically acceptable salts thereof in the manufacture of a medicament for the treatment of neoplastic diseases in a subject selected from a mammal, in particular a human.

[0052] In a further aspect, the present invention provides methods for treating neoplastic diseases in a subject selected from a mammal, in particular a human, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, for example in a therapeutically effective amount for said subject.

[0053] In a further aspect, the present invention provides pharmaceutical compositions comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable excipients.

[0054] Each alkyl moiety, either by itself or as part of a larger group such as alkoxy, is a straight or branched chain. Examples include methyl, ethyl, n-propyl, prop-2-yl, n-butyl, but-2-yl, 2-methylprop-1-yl, or 2-methylprop-2-yl.

[0055] Each alkylene moiety, either by itself or as part of a larger group, is a straight or branched chain and is, for example, -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(CH3)-CH2-, -CH(CH2CH3)-, or -CH2CH(CH3)CH2-.

[0056] Each alkenyl moiety, either by itself or as part of a larger group such as alkenyloxy, is a straight or branched chain. Each moiety can have either the (E)- or (Z)-configuration. Examples include vinyl and allyl.

[0057] Each alkenylene moiety, either by itself or as part of a larger group such as alkenyloxy, is straight or branched chain and represents, for example, -CH2-CH=CH-. Each moiety may have either the (E)-z or (Z)-configuration.

[0058] Each alkynyl moiety, either by itself or as part of a larger group such as alkynyloxy, is straight or branched chain and is, for example, ethynyl or propargyl.

[0059] Each alkynylene moiety, either by itself or as part of a larger group, is a straight or branched chain and is, for example, -CH2-C≡C-.

[0060] Each haloalkyl moiety, either by itself or as part of a larger group such as haloalkoxy, is an alkyl group substituted by one or more identical or different halogen atoms. Examples include difluoromethyl, trifluoromethyl, chlorodifluoromethyl, and 2,2,2-trifluoroethyl. Haloalkyl moieties include, for example, from 1 to 5 halogen substituents or from 1 to 3 halogen substituents.

[0061] Each cycloalkyl moiety (also referred to as a carbocyclic ring moiety) may be saturated or partially unsaturated (unless otherwise specified) and may be in mono- or bicyclic form, preferably in monocyclic form. Preferred cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. An example of a bicyclic cycloalkyl group is bicyclo[2.2.1]heptan-2-yl.

[0062] Halogen is fluorine, chlorine, bromine or iodine.

[0063] The term "heteroaryl ring" refers to an aromatic ring system containing the specified 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 an atom outside the ring connecting the ring to the rest of the molecule.

[0064] The term "heterocyclic ring" refers to a saturated or partially unsaturated carbocyclic ring (unless otherwise specified) further containing the stated number of heteroatoms selected from nitrogen, oxygen, and sulfur as ring members. The nitrogen ring member is present as an -NH- moiety unless otherwise substituted. Such rings do not contain adjacent oxygen atoms, adjacent sulfur atoms, or adjacent oxygen and sulfur atoms within the ring or together with an atom outside the ring connecting the ring to the rest of the molecule.

[0065] Oxo represents the =O group. When a moiety is said to be "substituted with oxo," this is considered to be substitution with one substituent, for example, when a P ring can be substituted with one to three R5 and R5 can be oxo, then the P ring can be substituted with oxo and two more R5 groups. Typically, a ring cannot be substituted with more than one oxo group.

[0066] When a group is said to be optionally substituted, it may be unsubstituted or substituted by the stated number of substituents.

[0067] When ring nomenclature is given for a specific moiety, it applies provided there are no (other) substituents on the ring. For example, piperidin-1-yl places the nitrogen atom at the point of attachment, regardless of the identity of any substituents that may be present on the piperidine moiety. Cyclohex-4-ylamine places the amino substituent at position 4 on cyclohexyl relative to the point of attachment, regardless of the identity of any additional substituents that may be present on the cyclohexyl moiety.

[0068] Where isomers of (E) and (Z) are possible, for example when R3 is alkenylene, the compounds of the invention include all isomers of (E) and (Z), as well as mixtures thereof in any ratio. Similarly, when cis and trans isomers are possible, for example when R2 is cyclohex-4-ylamine, both cis and trans isomers are within the scope of formula (I). Whenever the compounds of formula (I) contain one or two or more centers of chirality, for example when Y is a branched alkylene, such compounds may be present as pure enantiomers or pure diastereoisomers, as well as mixtures thereof in any ratio, and all such isomers are included within the scope of the compounds of formula (I). The compounds of the invention also include all tautomeric forms of the compounds of formula (I), where such possibilities exist, for example when a saturated ring is substituted with oxo.Isotopically labeled compounds including deuterium substitutions as well as carbon-13 and / or carbon-14 labels are also included within the scope of compounds of formula (I).

[0069] The compounds of formula (I) can also be solvated, especially hydrated, which are also included within the scope of the compounds of formula (I). Solvation and hydration can take place during the preparation process. Reference to the compounds of the invention includes pharmaceutically acceptable salts of said compounds. Such salts can also exist in the form of hydrates and solvates. Examples of pharmacologically acceptable salts of the compounds of formula (I) are salts of physiologically acceptable mineral 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.Further examples of pharmacologically acceptable salts of the compounds of formula (I) 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.

[0070] The following examples of definitions of substituents and embodiments may be combined in any combination where possible.

[0071] Ra and Rb are both -CH3 or Ra and Rb together form a bridging moiety -CH2-CH2-CH2- or -CH2-CH2-CH2-CH2-.

[0072] Preferably, Ra and Rb are both -CH3 or together form a bridging moiety -CH2-CH2-CH2-CH2-, such as shown in Example 37.

[0073] A is -CH2- or -C(=O)-. Preferably, A is -CH2-.

[0074] T represents -N(R11)-, -N(R11)-C(=O)-, -N(R11)-S(O2)-, -O-, -C(R12)(R13)-, -C=C(R12)2, -S-, -S(O)-, -S(O2)-, -S (O2)-N(R14)- or -C(=O)-N(R14)-.

[0075] Preferably, T is -N(R11)-, -N(R11)-S(O2)-, -O-, -C(R12)(R13)-, -C=C(R12)2, -S-, -S(O2)-, -S(O2)-N(R14)-, or -C(=O)-N(R14)-.

[0076] More preferably, T is -N(R11)-, -N(R11)-S(O2)-, -O-, -C(R12)(R13)-, -C=C(R12)2, -S-, or -C(=O)-N(Rl4)-.

[0077] Even more preferably, T is -N(R11)- or -N(R11)-S(O2)-.

[0078] In the -C=C(R12)2 fragment, R1 is bonded to the first carbon atom, as shown here:

[0079]

[0080] Specific examples of T (when R1 does not form a ring with R11 or R14 and R2 does not form a ring with R11, R12 or R14) include -CH2-, -CH(CH3)-, -C(CH3)=CH-, -N(CH3)-C(=O)-, -N(CH3)-S(O2)-, -N-(cyclopropyl)-, -N (CH2CH2CN)-, -N(CH2CH2CH3)-, -N(CH2CH2OH)-, N(CH2CH3)-, -N(CH3)-, -NH-, -NH-C(=O)-, -NH-S(O2)-, -O-, -S-, -S(O2) -N(CH3)-S(O2)-NH-, -S(O2)- and -C(=O)-NH-

[0081] R11 is hydrogen, C1-C4alkylene-R11a, C1-C4haloalkylene-R11a, or C3-C6cycloalkyl, wherein the cycloalkyl is optionally substituted with one or two R11b (when R11 does not form a ring with R1 or R2).

[0082] Preferably, R11 (when R11 does not form a ring with R1 or R2) is hydrogen, C1-C4alkylene-R11a, C1-C4haloalkylene-R11a, or C3-C6cycloalkyl.

[0083] More preferably, R11 (when R11 does not form a ring with R1 or R2) is hydrogen, C1-C4 alkylene-R11a, C1-C4 haloalkylene-R11a, or C3-C4 cycloalkyl.

[0084] Specific examples of R11 (when R11 does not form a ring with R1 or R2) include -CH3, cyclopropyl, -CH2CH2CH3, -CH2CH2CH, CH2CH2OH, -CH2CH3, and hydrogen.

[0085] R11a represents hydrogen, halogen, -OH, -CN, -NH2, -O-C1-C2alkyl, -O-C1-C2haloalkyl, -NH(C1-C2alkyl) or -N(C1-C2alkyl)2-

[0086] Preferably, R11a is hydrogen, halogen, -CH or -OH.

[0087] Specific examples of R11a include hydrogen, -CN, and -OH.

[0088] Each R11b independently represents halogen, -OH, CN, -NH2, -O-C1-C2alkyl, -O-C1-C2halogenoalkyl, -NH(C1-C2alkyl), or -N(C1-C2alkyl)2.

[0089] Each R12 is independently hydrogen, C1-C4alkylene-R12a, C1-C4haloalkylene-R12a, or C3-C6cycloalkyl, wherein the cycloalkyl is optionally substituted with one or two R12b (when R12 does not form a ring with R2).

[0090] Preferably, each R12 (when R12 does not form a ring with R2) is independently hydrogen or C1-C4 alkylene-R12a,

[0091] Specific examples of R12 include hydrogen, -CH3, and -CH2OH.

[0092] Each R12a independently represents hydrogen, halogen,

[0093] -OH, -CN, -NH2, -O-C1-C2alkyl, -O-C1-C2haloalkyl, -NH(C1-C2alkyl) or -N(C1-C2alkyl)2.

[0094] Preferably, each R12a independently represents hydrogen, halogen, -CN, or -OH.

[0095] Specific examples of R12a include hydrogen and -OH.

[0096] Each R12b independently represents halogen, -OH, CN, -NH2, -O-C1-C2alkyl, -O-C1-C2haloalkyl, -NH(C1-C2alkyl) or -N(C1-C2alkyl)2.

[0097] R13 represents hydrogen, C1-C4 alkyl or C1-C4 haloalkyl.

[0098] Specific examples of R13 include hydrogen.

[0099] R14 is hydrogen, C1-C4alkylene-R14a, C1-C4haloalkylene-R14a, or C3-C6cycloalkyl, wherein the cycloalkyl is optionally substituted with one or two R14b (when R14 does not form a ring with R1 or R2).

[0100] Preferably, R14 (when R14 does not form a ring with R1 or R2) is hydrogen or C1-C4 alkyl.

[0101] Specific examples of R14 include hydrogen and -CH3.

[0102] R14a represents hydrogen, halogen, -OH, -CN, -NH2, -O-C1-C2alkyl, -O-C1-C2haloalkyl, -NH(C1-C2alkyl) or -N(C1-C2alkyl)2.

[0103] Each R14b independently represents halogen, -OH, CN, -NH2, -O-C1-C2alkyl, -O-C1-C2haloalkyl, -NH(C1-C2alkyl) or -N(C1-C2alkyl)2.

[0104] R2 and R11 may together form a partially unsaturated 6- to 7-membered heterocyclic ring containing no further heteroatoms as ring members, wherein the heterocyclic ring is optionally substituted with one or two R2a.

[0105] Preferably, R2 and R11 can together form a partially unsaturated 6-membered heterocyclic ring containing no further heteroatoms when T is -N(R11)- and X is -O-, and otherwise do not form a heterocyclic ring.

[0106] Specific examples of the bridging moiety formed by R2 and R11 include CH2CH2- when T is -N(R11)- and X is -O-, namely -N(R1)CH2CH2O-, for example, N(H)CH2CH2O-, -N(CH2CH2CN)CH2CH2O- and -N(CH3)CH2CH2O-, including substituents T and X (T on the left side, X on the right side of the bridging moiety, as shown).

[0107] R2 and R12 together may form a partially unsaturated 6- to 7-membered heterocyclic ring containing no further heteroatoms as ring members, wherein the heterocyclic ring is optionally substituted with one or two R2a.

[0108] R2 and R14 together may form a partially unsaturated 6- to 7-membered heterocyclic ring containing no further heteroatoms as ring members, wherein the heterocyclic ring is optionally substituted with one or two R2a.

[0109] Each R2a independently represents halogen, -OH, -CN, -NH2, -O-C1-C2alkyl, -O-C1-C2haloalkyl, -NH(C1-C2alkyl), or -N(C1-C2alkyl)2.

[0110] R1 and R11 may together form a saturated or partially unsaturated 4-7-membered heterocyclic ring, optionally containing one or two additional heteroatoms as ring members selected from N, O and S, wherein the heterocyclic ring is optionally substituted with one to three R1a, or R1 and R11 may together form a 5-6-membered heteroaryl ring, optionally containing one to three additional heteroatoms as ring members selected from N and O, wherein the heteroaryl ring is optionally substituted with one to three R1b.

[0111] Preferably, R1 and R11 may together form a 4- to 6-membered saturated or partially unsaturated heterocyclic ring, optionally containing one additional heteroatom as a ring member selected from N and O, for example, a ring selected from piperidinyl, morpholinyl, pyrrolidinyl, azetidinyl, 2,5-dihydropyrrolyl and 1,1-dioxide-1,2-thiazolidin-2-yl, wherein the heterocyclic ring is optionally substituted with one or two R1a, or R1 and R11 together may form a 5-membered heteroaryl ring, optionally containing one additional heteroatom as a ring member selected from N, for example selected from pyrrolyl, and wherein the heteroaryl ring is optionally substituted with one or two R1b.

[0112] More preferably, R1 and R11 may together form a 5-6-membered saturated heterocyclic ring containing no further heteroatoms as ring members, for example, a ring selected from piperidinyl, pyrrolidinyl and 1,1-dioxide-1,2-thiazolidin-2-yl, wherein the heterocyclic ring is optionally substituted with one R1a, or R1 and R11 may together form a 5-membered heteroaryl ring containing no further heteroatoms as ring members, for example, selected from pyrrolyl, and wherein the heteroaryl ring is optionally substituted with one R1b.

[0113] Specific examples of the heterocyclic rings formed by R1 and R11 when T is -N(R11)- include piperidinyl (including, for example, 4-hydroxypiperidinyl), morpholinyl, pyrrolidinyl (including, for example, 3-hydroxypyrrolidinyl, 3-methoxypyrrolidinyl, 3-cyanopyrrolidinyl, 3-carboxamidepyrrolidinyl), azetidinyl (including, for example, 3-hydroxyazetidinyl, 3-hydroxymethylazetidinyl), 2,5-dihydropyrrolyl (including, for example, 2H-pyrrolyl-5-one) and 1,1-dioxide-1,2-thiazolidinyl.

[0114] Specific examples of the heteroaryl ring formed by R1 and R11 when T is -N(R11)- include pyrrolyl (including, for example, 3,4-dimethoxypyrrolyl and 3-methoxypyrrolyl).

[0115] R1 and R14 together may form a saturated or partially unsaturated 4-7-membered heterocyclic ring, optionally containing one or two additional heteroatoms as ring members selected from N, O and S, wherein the heterocyclic ring is optionally substituted with one to three R1a, or R1 and R14 together may form a 5-6-membered heteroaryl ring, optionally containing one to three additional heteroatoms as ring members selected from N and O, wherein the heteroaryl ring is optionally substituted with one to three R1b.

[0116] Each R1a independently represents halogen, -OH, -CN, -NH2, C1-C4 alkylene-R1c, C1-C4 haloalkylene-R1c, -O-C1-C4 alkyl, -O-C1-C4 haloalkyl, -NH(C1-C4 alkyl), -N(C1-C4 alkyl)2, -C(=O)NH2, -C(=O)NH(C1-C4 alkyl), -C (=O) N(C1-C4 alkyl)2, or oxo.

[0117] Preferably, each R1a is independently halogen, -OH, -CN, C1-C4alkylene-R1c, -O-C1-C4haloalkyl, C(=O)NH2, or oxo.

[0118] More preferably, each R1a independently represents halogen, -OH, -CN, or -C(=O)NH2.

[0119] Specific examples of R1a include -OH, -CN, -OCH3, -CH2OH, C(=O)NH2, and oxo.

[0120] Each R1b independently represents halogen, -OH, -CN, -NH2, C1-C4 alkylene-R1c, C1-C4 haloalkylene-R1c, -O-C1-C4 alkyl, -O-C1-C4 haloalkyl, -NH(C1-C4 alkyl) or -N(C1-C4 alkyl)2, C(=O)NH2, -C(=O)NH(C1-C4 alkyl) or -C(=O)N(C1-C4 alkyl)2.

[0121] Preferably, each R1b is independently halogen, -OH, -CN, C1-C4alkylene-R1c, or -O-C1-C4haloalkyl.

[0122] More preferably, each R1b is halogen, -OH, or -CN.

[0123] Specific examples of R1b include -OH, -CN, -OCH3, and -CH2OH.

[0124] Each R1c independently represents hydrogen, halogen, -OH, -CN, -NH2, -O-C1-C2alkyl, -O-C1-C2haloalkyl, -NH(C1-C2alkyl), or -N(C1-C2alkyl)2.

[0125] Preferably, each R1c independently represents hydrogen or -OH.

[0126] Specific examples of R1c include hydrogen and -OH.

[0127] R1 is hydrogen or -Y-R3 (when R1 does not form a ring with R11 or R14).

[0128] Preferably, R1 (when R1 does not form a ring with R11 or R14) is hydrogen, C1-C6 alkylene-R3, wherein the alkylene moiety may be substituted with one -OH, wherein the alkylene moiety may include a 3-membered saturated carbocyclic ring as part of the moiety, and wherein there are no more than three intermediate carbon atoms between the compound with T and the compound with R3, or wherein R1 is a P ring or a Q ring.

[0129] More preferably, R1 (when R1 does not form a ring with R11 or R14) is hydrogen, C1-C3 alkylene-R3, P ring, or Q ring.

[0130] Specific examples of R1 when it does not form a ring with R11 or R14 include hydrogen, -CH2-tetrahydropyran-4-yl, -CH2C(-CH2CH2-)-CN, -CH2C(CH3)2-CN, -CH2C(CH3)2-OH, -CH2-C(=O)NHCH3, CH2CH(OH)CH2-OH, -CH2CH2-CF3, -CH2CH2CH2-CN, -CH2CH2-CN, -CH2CH2-NHC(=O)CH3, -CH2CH2-NHS(O2)CH3, -CH2CH2-OCF3, -CH2CH2-OCH3, -CH2CH2-OH, -CH2CH2-oxazolidin-5-yl-2-one, -CH2CH2-S(O2)CH3, -CH2CH2-SCH3, -CH2CH3, -CH2-CN, -CH2-OH, -CH2-oxazolidin-5-yl-2-one, -CH3, CH2CH2-OCH2CH3, -CH2CH2CH3, 4-fluorophenyl1, -CH(CH3)2, -CH2-2-(1-fluoroeth-1yl)-1,3, 4-oxadiazol-4-yl, -CH2-C (=O) OCH2CH3, -CH2C (=O) OH, -CH2CH(CH3)2, -CH2CH2C(CH3)2OH, -CH2CH2C (=O) OH, -CH2CH2CH(CH3)2, -CH2CH2CH2CH3, -CH2CH2NH2, -CH2-imidazolyl (e.g., -CH2-imidazol-4-yl), -CH2-oxazolyl (e.g., -CH2-oxazol-4-yl), -CH2-pyridin-3-yl (e.g., -CH2-pyridin-3-yl and -CH2-pyridin-4-yl), cyclopropyl, -CH2CH2C(=O)NH2, -CH2C(CH3)2C(=O)NH2, and CH2C(CH3)2CH2OH.

[0131] Y represents a bond or a C1-C6 alkylene moiety, wherein one non-terminal -CH2- moiety may be replaced with -O- and wherein the alkylene moiety may be substituted with one or two moieties independently selected from -OH, -O-C1-C4 alkyl and -O-C1-C4 haloalkyl, and wherein the alkylene moiety may include a 3- to 5-membered saturated or partially unsaturated carbocyclic ring as part of this moiety. Reference to a "non-terminal -CH2- moiety" refers to a -CH2- moiety that is not at either end of the alkylene moiety (i.e., not a terminal -CH2- moiety that is proximal to the connection with T, and not a terminal -CH2- moiety that is distal to the connection with T).

[0132] Preferably, Y is a bond or C1-C6 alkylene, wherein the alkylene group may be substituted with one -OH, wherein the alkylene group may include a 3-membered saturated carbocyclic ring as part of the moiety and wherein there are no more than three intermediate carbon atoms between the compound with T and the compound with R3.

[0133] More preferably, Y is C1-C6 alkylene in which there are not more than three intermediate carbon atoms between the compound with T and the compound with R3 and wherein one CH2 moiety is replaced by C (-CH2CH2-).

[0134] In some embodiments, Y is C1-C3 alkylene.

[0135] Specific examples of Y include the bond, -CH2-, -CH2C(-CH2CH2-)-, -CH2C(CH3)2-, -CH2CH(OH)CH2-, -CH2CH2-, -CH2CH2CH2-, -C(CH3)2-, -CH2CH2C(CH3)2-, -CH2CH2CH2CH2-, -CH2C(CH3)2- and -CH2C(CH3)2CH2-.

[0136] Link -C(-CH2CH2-)- corresponds to the fragment:

[0137]

[0138] R3 is hydrogen, -CN, -OH, C1-C4haloalkyl, C2-C4alkenylene-R4, C2-C4alkynylene-R4, -O-C1-C4alkylene-R4, -O-C1-C4haloalkyl, -NH2, -NH(C1-C4alkylene-R4), -N(C1-C4alkylene-R4)2, -C(=O)-OH, -C(=O)-O-C1-C4alkylene-R4, -C(=O)-NH2, -C(=O)-NH(C1-C4alkylene-R4), -C(=O)-N(C1-C4alkylene-R4)2, -NH-C(=O)-C1-C4alkylene-R4, -N(C1-C4alkyl) -C(=O)-C1-C4alkylene-R4, P Ring, Q Ring, -O-P Ring, -O-Q Ring, -NH-S(O2)-C1-C4alkylene-R4, -N(C1-C4alkyl)-S(O2)-C1-C4alkylene-R4, -S-C1-C4alkylene-R4 or -S(O2)-C1-C4alkyl-R4, provided that the atom in R3 attached to Y is not a heteroatom when (i) Y is a bond and (ii) T is not -N(R11)-, -C(R12)(R13)- or -C=C(R12)2.

[0139] Preferably, R3 is hydrogen, -CN, -OH, C1-C4haloalkyl, -O-C1-C4alkylene-R4, -O-C1-C4haloalkyl, NH2, -NH(C1-C4alkylene-R4), -N(C1-C4alkylene-R4)2, -C(=O)-OH, C(=O)-O-C1-C4alkylene-R4, -C(=O)-NH2, -C(=O)-NH(C1-C4alkylene-R4), -C(=O)-N(C1-C4alkylene-R4)2, -NH-C(=O)-C1-C4alkylene-R4, -N(C1-C4alkyl)-C(=O)-C1-C4alkylene-R4, Ring P, Ring Q, -NH-S(O2)-C1-C4alkylene-R4, -N(C1-C4alkyl)-S(O2)-C1-C4alkylene-R4, -S-C1-C4alkylene-R4 or -S(O2)-C1-C4alkyl-R4.

[0140] More preferably, R3 is hydrogen, -CN, -OH, C1-C4haloalkyl, -O-C1-C4alkylene-R4, -O-C1-C4haloalkyl, -NH2, -NH(C1-C4alkylene-R4), -N(C1-04alkylene-R4)2, -C(=O)-OH, C(=O)-NH2, P ring or Q ring.

[0141] Specific examples of R3 include hydrogen, tetrahydropyran-4-yl, -CN, -OH, -C(=O)NHCH3, -CF3, -NHC(=O)CH3, -NHS(O2)CH3, -OCF3, -OCH3, -oxazolidin-5-yl-2-one, -S(O2)CH3, -SCH3, -OCH2CH3, 4-fluorophenyl, 1, 3, 4-oxadiazol-4-yl (e.g., 2-(1-fluoroeth-1yl)-1, 3, 4-oxadiazol-4-yl), -C(=O)OCH2CH3, -C(=O)OH, -NH2, imidazolyl (e.g., imidazol-4-yl), oxazolyl (e.g., oxazol-4-yl), pyridinyl (e.g., pyridin-3-yl and pyridin-4-yl), cyclopropyl and -C(=O)NH2.

[0142] R4 represents hydrogen, halogen, -NH2, -NH(C1-C2alkyl) or -N(C1-C2alkyl)2.

[0143] Preferably, R4 is hydrogen. Specific examples of R4 include hydrogen.

[0144] Ring P is a 3-6-membered (e.g. 5-6-membered) saturated or partially unsaturated carbocyclic ring optionally substituted with one to three R5, or is a 3-6-membered (e.g. 5-6-membered) saturated or partially unsaturated heterocyclic ring containing one or two heteroatoms selected from N and O, optionally substituted with one to three R5.

[0145] Preferably, the P ring is a 3- to 6-membered (e.g., 6-membered) saturated carbocyclic ring optionally substituted with one to two R5, or is a 5- or 6-membered saturated heterocyclic ring containing one heteroatom selected from N and O, optionally substituted with one to two R5.

[0146] More preferably, the P ring is oxazolidinyl optionally substituted with one or two R5, in particular oxazolidinyl-2-one optionally substituted with one R5, wherein R5 is not oxo.

[0147] Specific examples of the P ring include cyclopropyl, tetrahydropyranyl (e.g., tetrahydropyran-4-yl), and oxazolidinyl (e.g., oxazolidin-5-yl-2-one).

[0148] Each R5 independently represents halogen, -NH2, -OH, -CN, C1-C4alkylene-R5a, -O-C1-C4alkylene-R5a, or oxo.

[0149] Preferably, each R5 is independently -NH2, C1-C2alkyl, -C1-C2alkyl-R5a, or oxo.

[0150] More preferably, each R5 independently represents C1-C2 alkyl, -C1-C2 alkyl-R5a, or oxo. Preferably, when the moiety is substituted with R5, no more than one R5 represents oxo. In particular, it is preferable that the oxazolidinyl-2-one moiety is not further substituted with oxo.

[0151] Each R5a independently represents hydrogen, halogen, -NH2, -OH, -CN, or -O-C1-C2alkyl.

[0152] Ring Q is phenyl optionally substituted with one to three R6, or is a 5-6-membered heteroaryl ring containing one or two heteroatoms selected from N, S and O, optionally substituted with one to three R6.

[0153] Preferably, the Q ring is phenyl optionally substituted with one or two R6, or is a 5-6-membered heteroaryl ring containing one to two heteroatoms selected from N, S and O, optionally substituted with one or two R6.

[0154] More preferably, the Q ring is phenyl optionally substituted with one R6, or is a 5-6-membered heteroaryl ring containing one to two heteroatoms selected from N and O, optionally substituted with one R6.

[0155] Specific examples of the Q ring include phenyl (e.g., 4-fluorophenyl), 1,3,4-oxadiazole (e.g., -1-fluoroeth-1-yl)-(1,3,4-oxadiazol-4-yl), imidazolyl (e.g., imidazol-4-yl), oxazolyl (e.g., oxazol-4-yl), and pyridinyl (e.g., pyridin-3-yl and pyridin-4-yl).

[0156] Each R6 independently represents halogen, -NH2, -OH, -CN, C1-C4alkylene-R6a, or -O-C1-C4alkylene-RGa.

[0157] Preferably, each R6 is independently -NH2, -OH, -CN, C1-C2alkylene-R6a (e.g., -CH3) or -O-C1-C2alkyl (e.g., -O-CH3).

[0158] Specific examples of R6 include fluorine and 1-fluoro-eth-1-yl.

[0159] Each R6a independently represents hydrogen, halogen, -NH2, -OH, -CN, or -O-C1-C2alkyl.

[0160] Preferably, each R6a independently represents hydrogen, halogen, or -CN.

[0161] Specific examples of R6a include hydrogen and fluorine.

[0162] X is -O-, -C(=O)-, -C(=CH2)-, -N(R10a)-, or -CH(R10b)-, and where X is a bond when R2 is halogen or -CN, and where when X is -C(=O)-, then R2 is not hydrogen, or where X-R2 is hydrogen.

[0163] Preferably, X is -O- or -N(R10a)-, or X-R2 is halogen or hydrogen.

[0164] More preferably, X is -O- or N(R10a)- or X-R2 is halogen.

[0165] Specific examples of X include -O- and -N(R10a)-, where R10a and R2 can together form a piperazine ring, such as 4-methylpiperazinyl, as well as bromine and hydrogen as X-R2.

[0166] R10a is hydrogen or C1-C4 alkyl, or R2 and R10a may together form a 4-7-membered saturated or partially unsaturated heterocyclic ring optionally containing an -N(R9)- moiety as a ring member in addition to the nitrogen atom X and, otherwise, containing only carbon atoms as ring members, optionally substituted with one or two R8.

[0167] Preferably, R10a is hydrogen or -CH3, or R2 and R10a may together form a 4-7-membered saturated heterocyclic ring, optionally containing an N(R9)- moiety as a ring member in addition to the nitrogen atom X and, otherwise, containing only carbon atoms as ring members, and wherein, if the heterocyclic ring does not contain an -N(R9)- moiety, it is optionally substituted with one R8. More preferably, R10a is hydrogen or -CH3, or R2 and R10a may together form a 6-7-membered saturated heterocyclic ring containing one -N(R9)- moiety as a ring member at position 3 relative to the nitrogen atom X (the position of the nitrogen atom X is position 0) and, otherwise, containing only carbon atoms as ring members, and wherein, if the heterocyclic ring does not contain an -N(R9)- moiety, it is substituted with one R8 at position 3 relative to the nitrogen atom X.

[0168] In some embodiments, R10a is hydrogen or -CH3, or R2 and R10a can together form a 6-membered saturated heterocyclic ring containing one -N(R9)- moiety as a ring member at the 3 ("para") position with respect to the nitrogen atom X or substituted with one R8 at the 3 ("para") position with respect to the nitrogen atom X. Specific examples of the ring formed from R2 and R10a include piperazinyl, such as 1-methylpiperazin-4-yl.

[0169] R10b is hydrogen or C1-C4 alkyl, or R2 and R10b together may form a 4- to 7-membered saturated or partially unsaturated carbocyclic ring or a 4- to 7-membered saturated or partially unsaturated heterocyclic ring containing the moiety -N(R9)- as a ring member and, otherwise, containing only carbon atoms as ring members, optionally substituted with one or two R8.

[0170] Preferably R10b is hydrogen.

[0171] R2 is hydrogen, halogen, -CN, C1-C4 alkyl optionally substituted with one or two R7, or is a 4- to 7-membered saturated or partially unsaturated carbocyclic ring optionally substituted with one or two R8, or is a 4- to 7-membered saturated or partially unsaturated heterocyclic ring containing one -N(R9)- moiety as a ring member and, otherwise, containing only carbon atoms as ring members (when R2 does not form a ring with R10a, R10b, R11, R12 or R14).

[0172] Preferably, R2 (when R2 does not form a ring with R10a, R10b, R11, R12 or R14) is C1-C4 alkyl optionally substituted with R7, or is a 4- to 7-membered saturated carbocyclic ring (e.g., a 6- to 7-membered saturated carbocyclic ring) optionally substituted with one R8, or is a 4- to 7-membered saturated heterocyclic ring (e.g., a 6- to 7-membered saturated heterocyclic ring) containing one -N(R9)- moiety as a ring member and, otherwise, containing only carbon atoms as ring members, or where X-R2 is halogen or hydrogen.

[0173] More preferably, R2 (when R2 does not form a ring with R10a, R10b, R11, R12 or R14) is C1-C4 alkyl optionally substituted with R7, or is a 6- to 7-membered saturated carbocyclic ring substituted with one R8 at position 3 relative to X (the carbocyclic ring atom bonded to X is at position 0), or R2 is a 6- to 7-membered saturated heterocyclic ring containing one -N(R9)- moiety as a ring member at position 3 relative to X and otherwise containing only carbon atoms as ring members, or where X-R2 is halogen or hydrogen;

[0174] In some embodiments, R2 (when R2 does not form a ring with R10a, R10b, R11, R12, or R14) is C1-C4 alkyl optionally substituted with R7, or is a 6-membered saturated carbocyclic ring substituted with one R8 at the 3-position {"para") relative to X, or R2 is a 6-membered saturated heterocyclic ring containing one -N(R9)- moiety as a ring member at the 3-position {"para") relative to X and otherwise containing only carbon atoms as ring members, or where X-R2 is bromo.

[0175] Specific examples of R2 when it does not form a ring with R10a, B10b, R11, R12 or R14 include azepan-4-yl, -CH3, OH2OH2N (CH3)2, 4-aminocyclohexyl (e.g., cis-4-aminocyclohexyl and trans-4-aminocyclohexyl), 4-morpholin-4-yl-cyclohexyl (e.g., trans-4-morpholin-4-ylcyclohexyl), 4-NH (CH2CH2OCH3)-cyclohexyl (e.g., trans-4-N(CH2CH2OCH3)-cyclohexyl), 4-N(CH3)2-cyclohexyl (e.g., trans-4-N(CH3)2-cyclohexyl), 4-NH(CH3)-cyclohexyl (e.g., trans-4-NH(CH3)-cyclohexyl) and piperidin-4-yl.

[0176] Specific examples of -X-R2 (when R2 does not form a ring with R10a, R10b, R11, R12 or R14) include hydrogen, bromine, -O-CH3, -O-azepan-4-yl, -O-CH3, -O-(4-aminocyclohexyl) (e.g., -O-(cis-4-aminocyclohexyl), -O-(trans-4-aminocyclohexyl)), -O-CH2CH2N(CH3)2, -O-(4-(morpholin-4-yl)cyclohexyl) (e.g., -O-(trans-4-morpholin-4-yl-cyclohexyl)), -O-(4-NH(CH2CH2OCH3)-cyclohexyl) (e.g., -O-(trans-4-NH(CH2CH2OCH3)-cyclohexyl)), -O-(4-N(CH3)2-cyclohexyl) (e.g. -O-(trans-4-N (CH3)2-cyclohexyl)), -O-(4-NH(CH3)-cyclohexyl) (e.g. -O-(trans-4-NH(CH3)-cyclohexyl)) and -O-piperidin-4-yl.

[0177] Each R7 independently represents -CN, -OH, halogen, -N(R7a)R7b, or -NH(-C(=O)-C1-C4alkyl).

[0178] In some embodiments, R7 is -N(R7a)R7b.

[0179] Specific examples of R7 include -N(CH3)2.

[0180] Each R7a is independently hydrogen, C1-C4alkylene-R7s, or C1-C4haloalkylene-R7s (when R7a does not form a ring with R7b).

[0181] In some embodiments, each R7a, if not forming a ring with R7b, is independently hydrogen or C1-C4 alkyl-R7c.

[0182] Specific examples of R7a include -CH3.

[0183] Each R7b is independently hydrogen, C1-C4alkylene-R7c, or C1-C4haloalkylene-R7c (when R7b does not form a ring with R7a).

[0184] In some embodiments, each R7b, if not forming a ring with R7a, is independently hydrogen or C1-C4 alkyl.

[0185] Specific examples of R7b include -CH3.

[0186] Each R7c independently represents hydrogen, halogen, -O-C1-C2alkyl, or -O-C1-C2haloalkyl.

[0187] R7a and R7b together may form a 4-7-membered saturated or partially unsaturated heterocyclic ring, optionally containing one or two additional heteroatoms as ring members selected from N, O and S, and wherein the heterocyclic ring is optionally substituted with one or two R7d.

[0188] Each R7d independently represents halogen, -OH, -CN, -NH2, C1-C2alkyl, C1-C2haloalkyl, -O-C1-C2alkyl, -O-C1-C2haloalkyl, -NH(C1-C2alkyl) or -N(C1-C2alkyl)2.

[0189] Each R8 independently represents -CN, -OH, halogen, -N(R8a)R8b, -NH(-C(=O)-C1-C4alkyl), C1-C4alkyl, or C1-C4haloalkyl.

[0190] Preferably, each R8 is -N(R8a)R8b.

[0191] Specific examples of R8 include -NH2, -NH(CH3), -N(CH3)2, NH(CH2CH2OCH3), and morpholin-4-yl.

[0192] Each R8a independently represents hydrogen, C1-C4alkylene-R8c, or C1-C4haloalkylene-R8c (when R8a does not form a ring with R8b).

[0193] Preferably, each R8a, if it does not form a ring with R8b, is independently hydrogen or C1-C4 alkyl-R8c.

[0194] Specific examples of R8a include hydrogen, -CH3, and -CH2CH2OCH3.

[0195] Each R8b is independently hydrogen, C1-C4alkylene-R8s, or C1-C4haloalkylene-R8s (when R8b does not form a ring with R8a).

[0196] Preferably, R8b, if it does not form a ring with R8a, is independently hydrogen or C1-C4 alkyl.

[0197] Specific examples of R8b include hydrogen and -CH3.

[0198] Each R8c independently represents hydrogen, halogen, -O-C1-C2alkyl or -O-C1-C2haloalkyl.

[0199] Specific examples of R8c include hydrogen.

[0200] R8a and R8b together may form a 4-7-membered saturated or partially unsaturated heterocyclic ring, optionally containing one or two additional heteroatoms as ring members selected from N, O and S, and wherein the heterocyclic ring is optionally substituted with one or two R8d.

[0201] Preferably, R8a and R8b together may form a 6-membered saturated heterocyclic ring, optionally containing one or two additional heteroatoms as ring members selected from N and O.

[0202] Specific examples of the ring formed by R8a and R8b include morpholin-4-yl.

[0203] Each R8d independently represents halogen, -OH, -CN, -NH2, C1-C2alkyl, C1-C2haloalkyl, -O-C1-C2alkyl, -O-C1-C2haloalkyl, -NH(C1-C2alkyl) or -N(C1-C2alkyl)2.

[0204] R9 represents hydrogen, C1-C4 alkylene-R9a, C1-C4 haloalkylene-R9a, or -C(=O)-C1-C4 alkyl.

[0205] Preferably, R9 is hydrogen or C1-C4 alkyl.

[0206] Specific examples of R9 include -CH3.

[0207] R9a represents hydrogen, halogen, -O-C1-C2alkyl or -O-C1-C2haloalkyl.

[0208] In some embodiments, Ra and Rb are both -CH3.

[0209] In some embodiments, Ra and Rb together form a bridging moiety -CH2-CH2-CH2-CH2-.

[0210] In some embodiments, A is -CH2-.

[0211] In some embodiments, A is -C(=O)-.

[0212] In some embodiments, T is -N(R11)-.

[0213] In some embodiments, T is -N(R11)-C(=O)-.

[0214] In some embodiments, T is -N(R11)-S(O2)-.

[0215] In some embodiments, T is -O-.

[0216] In some embodiments, T is -C(R12)(R13)-.

[0217] In some embodiments, T is -C=C(R12)2.

[0218] In some embodiments, T is -C(=O)-N(R14)-.

[0219] In some embodiments, T is -S-.

[0220] In some embodiments, T is -S(O2)-.

[0221] In some embodiments, T is -S(O2)-N(R14)-.

[0222] In some embodiments, X is -O-.

[0223] In some embodiments, X is -N(R10a)-.

[0224] In some embodiments, X-R2 is hydrogen.

[0225] In some embodiments, X-R2 is halogen.

[0226] In some embodiments, T is -N(R11)- and X is -O-.

[0227] In some embodiments, T is -N(R11)-C(=O)- and X is -O-.

[0228] In some embodiments, T is -N(R11)-S(O2)- and X is -O-.

[0229] In some embodiments, T is -N(R11)- and X is -NH(R10a)-.

[0230] In some embodiments, T is -N(R11)- and X-R2 is hydrogen.

[0231] In some embodiments, T is -N(R11)- and X-R2 is halogen.

[0232] In some embodiments, T is -O- and X is -O-.

[0233] In some embodiments, T is -C(R12)(R13)- and X is -O-.

[0234] In some embodiments, T is -C=C(R12)2 and X is -O-.

[0235] In some embodiments, T is -C(=O)-N(R14)- and X is -O-.

[0236] In some embodiments, T is -O- and X is -O-.

[0237] In some embodiments, T is -S- and X is -O-.

[0238] In some embodiments, T is -S(O2)- and X is -O-.

[0239] In some embodiments, T is -S(O2)-N(R14)- and X is -O-.

[0240] In some embodiments, T is -N(R11)- and X is -N(R10a)-.

[0241] In some embodiments, A is -CH2- and T is -N(R11)-.

[0242] In some embodiments, A is -CH2- and T is -N(R11)-C(=O)-.

[0243] In some embodiments, A is -CH2- and T is -N(R11)-S(O2)-.

[0244] In some embodiments, A is -CH2- and T is -O-.

[0245] In some embodiments, A is -CH2- and T is -C(R12)(R13)-.

[0246] In some embodiments, A is -CH2- and T is -C=C(R12)2.

[0247] In some embodiments, A is -CH2- and T is -C(=O)-N(R14)-.

[0248] In some embodiments, A is -CH2- and T is -S-.

[0249] In some embodiments, A is -CH2- and T is -S(O2)-.

[0250] In some embodiments, A is -CH2- and T is -S(O2)-N(R14)-.

[0251] In some embodiments, A is -C(=O)- and T is -N(R11)-.

[0252] In some embodiments, A is -CH2- and X is -O-.

[0253] In some embodiments, A is -CH2- and X is -N(R10a)-.

[0254] In some embodiments, A is -CH2- and X-R2 is hydrogen.

[0255] In some embodiments, A is -CH2- and X-R2 is halogen.

[0256] In some embodiments, A is -C(=O)- and X is -O-.

[0257] In some embodiments, A is -CH2-, T is -N(R11)-, and X is -O-.

[0258] In some embodiments, A is -CH2-, T is -N(R11)-C(=O)-, and X is -O-.

[0259] In some embodiments, A is -CH2-, T is -N(R11)-S(O2)-, and X is -O-.

[0260] In some embodiments, A is -CH2-, T is -O-, and X is -O-.

[0261] In some embodiments, A is -CH2-, T is -C(R12)(R13)-, and X is -O-.

[0262] In some embodiments, A is -CH2-, T is -N(R11)- and -N(R10a)-.

[0263] In some embodiments, A is -CH2-, T is -C=C(R12)2, and X is -O-.

[0264] In some embodiments, A is -CH2-, T is -C(=O)-N(R14)-, and X is -O-.

[0265] In some embodiments, A is -CH2-, T is -O-, and X is -O-.

[0266] In some embodiments, A is -CH2-, T is -S-, and X is -O-.

[0267] In some embodiments, A is -CH2-, T is -S(O2)-, and X is -O-.

[0268] In some embodiments, A is -CH2-, T is -S(O2)-N(R14)-, and X is -O-.

[0269] In some embodiments, A is -C(=O)-, T is -N(R11)-, and X is -NH(R10a)-.

[0270] In some embodiments, Ra and Rb are both -CH3 and A is -CH2-.

[0271] In some embodiments, Ra and Rb together form a bridging moiety -CH2-CH2-CH2-CH2-, and A is -CH2-.

[0272] In some embodiments, Ra and Rb are both -CH3 and A is -C(=O)-.

[0273] In some embodiments, Ra and Rb are both -CH3 and T is -N(R11)-.

[0274] In some embodiments, Ra and Rb are both -CH3 and T is -N(R11)-C(=O)-.

[0275] In some embodiments, Ra and Rb are both -CH3 and T is -N(R11)-S(O2)-.

[0276] In some embodiments, Ra and Rb are both -CH3 and T is -O-.

[0277] In some embodiments, Ra and Rb are both -CH3 and T is -C(R12)(R13)-.

[0278] In some embodiments, Ra and Rb are both -CH3 and T is -C=C(R12)2.

[0279] In some embodiments, Ra and Rb are both -CH3r and T is -C(=O)-N(R14)-.

[0280] In some embodiments, Ra and Rb are both -CH3 and T is -S-.

[0281] In some embodiments, Ra and Rb are both -CH3 and T is -S(O2)-.

[0282] In some embodiments, Ra and Rb are both -CH3 and T is -S(O2)-N(R14)-.

[0283] In some embodiments, Ra and Rb together form a bridging moiety -CH2-CH2-CH2-CH2-, and T is -N(R11)-.

[0284] In some embodiments, Ra and Rb are both -CH3, A is -CH2-, and T is -N(R11)-.

[0285] In some embodiments, Ra and Rb are both -CH3, A is -CH2-, and T is -N(R11)-C(=O)-.

[0286] In some embodiments, Ra and Rb are both -CH3, A is -CH2-, and T is -N(R11)-S(O2)-.

[0287] In some embodiments, Ra and Rb are both -CH3, A is -CH2-, and T is -O-.

[0288] In some embodiments, Ra and Rb are both -CH3, A is -CH2-, and T is -C(R12)(R13)-.

[0289] In some embodiments, Ra and Rb are both -CH3, A is -CH2-, and T is -C=C(R12)2.

[0290] In some embodiments, Ra and Rb are both -CH3, A is -CH2-, and T is -C(=O)-N(R14)-.

[0291] In some embodiments, Ra and Rb are both -CH3, A is -CH2-, and T is -S-.

[0292] In some embodiments, Ra and Rb are both -CH3, A is -CH2-, and T is -S(O2)-.

[0293] In some embodiments, Ra and Rb are both -CH3, A is -CH2-, and T is -S(O2)-N(R14)-.

[0294] In some embodiments, Ra and Rb together form a bridging moiety -CH2-CH2-CH2-CH2-, A is -CH2-, and T is -N(R11)-.

[0295] In some embodiments, Ra and Rb are both -CH3, A is -C(=O)-, and T is -N(R11)-.

[0296] In some embodiments, the R1 substituent is not hydrogen when T is -N(R11), -O-, C(R12)(R13)-, -S-, -S(O)-, or -S(O2)- (i.e., for the avoidance of doubt, this means that neither R1 nor the Y-R3 moiety in this case can be hydrogen).

[0297] In some embodiments, the R1 substituent is not hydrogen.

[0298] In some embodiments, the R1 substituent comprises at least 1 atom other than hydrogen.

[0299] In some embodiments, the R1 substituent comprises at least 2 atoms other than hydrogen.

[0300] In some embodiments, the R1 substituent comprises at least 3 atoms other than hydrogen.

[0301] In some embodiments, the R1 substituent comprises at least 4 atoms other than hydrogen.

[0302] In some embodiments, the R1 substituent comprises at least 5 atoms other than hydrogen.

[0303] In some embodiments, R1, if it does not form a ring with R11 or R14, is -Y-R3, provided that Y is not a bond and R3 is hydrogen.

[0304] In some embodiments, R1, if it does not form a ring with R11 or R14, is -Y-R3;

[0305] Y is C1-C6 alkylene, wherein one non-terminal -CH2- moiety may be replaced by -O- and wherein the alkylene moiety may be substituted with one or two moieties independently selected from -OH, -O-C1-C4 alkyl and -O-C1-C4 haloalkyl, and wherein the alkylene moiety may include a 3-5-membered saturated or partially unsaturated carbocyclic ring as part of the moiety, or wherein R1 is a P ring or a Q ring.

[0306] In some embodiments, R1, if it does not form a ring with R11 or R14, is C1-C6 alkylene-R3, wherein the alkylene moiety may be substituted with one -OH, wherein the alkylene moiety may include a 3-membered saturated carbocyclic ring as part of the moiety, and wherein there are no more than three intervening carbon atoms between the compound with T and the compound with R3, or wherein R1 is a P ring or a Q ring

[0307] In some embodiments, R1, if it does not form a ring with R11 or R14, is C1-C3 alkylene-P3, a P ring, or a Q ring.

[0308] In some embodiments, R1 is C1-C3 alkylene-P3;

[0309] R3 is hydrogen, -CN, -OH, C1-C4haloalkyl, -O-C1-C4alkylene-R4, -O-C1-C4haloalkyl, -NH2, -NH(C1-C4alkylene-R4) or -N(C1-C4alkylene-R4)2, -C(=O)-OH, -C(=O)-NH2, P cycle or Q cycle;

[0310] R11 is hydrogen, C1-C4alkylene-R11a, C1-C4haloalkylene-R11a, or C3-C4cycloalkyl;

[0311] Ring P is oxazolidinyl, optionally substituted with one or two R5;

[0312] each R5 is independently C1-C2alkyl, -C1-C2alkyl-R5a or oxo, wherein the P ring is not substituted with two oxos;

[0313] each R5a independently represents hydrogen, halogen, -NH2, -OH, -CN or -O-C1-C2alkyl.

[0314] In some embodiments, X is -O-, -C(=O)-, -N(R10a)-, or -CH(R10b)-, and where X is a bond when R2 is halogen or -CN, and where when X is -C(=O)-, then R2 is not hydrogen, or where X-R2 is hydrogen.

[0315] In some embodiments, R2 and R10a together form a 4-7-membered saturated or partially unsaturated heterocyclic ring, optionally containing an N(R9)- moiety as a ring member in addition to the nitrogen atom X and, otherwise, containing only carbon atoms as ring members, optionally substituted with one or two R8.

[0316] In some embodiments, R2 and R10a together do not form a heterocyclic ring.

[0317] In some embodiments, R2 and R10b together may form a 4-7-membered saturated or partially unsaturated carbocyclic ring or a 4-7-membered saturated or partially unsaturated heterocyclic ring containing an N(R9)- moiety as a ring member and, otherwise, containing only carbon atoms as ring members, optionally substituted with one or two R8.

[0318] In some embodiments, R2 and R10b together do not form a heterocyclic ring.

[0319] In some embodiments, R2 and R11 together form a partially unsaturated 6-7-membered heterocyclic ring containing no additional heteroatoms as ring members, wherein the heterocyclic ring is optionally substituted with one or two R2a.

[0320] In some embodiments, R2 and R11 together do not form a heterocyclic ring.

[0321] In some embodiments, R2 and R12 together form a partially unsaturated 6-7-membered heterocyclic ring containing no additional heteroatoms as ring members, wherein the heterocyclic ring is optionally substituted with one or two R2a.

[0322] In some embodiments, R2 and R12 together do not form a heterocyclic ring.

[0323] In some embodiments, R2 and R14 together form a partially unsaturated 6-7-membered heterocyclic ring containing no additional heteroatoms as ring members, wherein the heterocyclic ring is optionally substituted with one or two R2a.

[0324] In some embodiments, R2 and R14 together do not form a heterocyclic ring.

[0325] In some embodiments, R2 and R11, R2 and R12, and R2 and R14 together do not form a heterocyclic ring.

[0326] In some embodiments, R1 and R11 together form a saturated or partially unsaturated 4-7-membered heterocyclic ring optionally containing one or two additional heteroatoms as ring members selected from N, O, and S, wherein the heterocyclic ring is optionally substituted with one to three R1a, or R1 and R11 together form a 5-6-membered heteroaryl ring optionally containing one to three additional heteroatoms as ring members selected from N and O, wherein the heteroaryl ring is optionally substituted with one to three R1b.

[0327] In some embodiments, R1 and R11 together do not form a heterocyclic ring or a heteroaryl ring.

[0328] In some embodiments, R1 and R14 together form a saturated or partially unsaturated 4-7-membered heterocyclic ring optionally containing one or two additional heteroatoms as ring members selected from N, O, and S, wherein the heterocyclic ring is optionally substituted with one to three R1a, or R1 and R14 together form a 5-6-membered heteroaryl ring optionally containing one to three additional heteroatoms as ring members selected from N and O, wherein the heteroaryl ring is optionally substituted with one to three R1b.

[0329] In some embodiments, R1 and R14 together do not form a heterocyclic ring or a heteroaryl ring.

[0330] In some embodiments, R2 and R10a, R2 and R10b, R2 and R11, R2 and R12, R2 and R14, R1 and R11, and R1 and R14 together do not form a heterocyclic ring or a heteroaryl ring.

[0331] In some embodiments, R1 and R11 may together form a heterocyclic ring or a heteroaryl ring as defined herein (particularly when T is -N(R11)-), but R2 and R10a, R2 and R10b, R2 and R11, R2 and R12, R2 and R14, and R1 and R14 together do not form a heterocyclic ring.

[0332] In some embodiments, R2 is C1-C4 alkyl or is a 6-membered saturated carbocyclic ring substituted with one R8 at the 3 ("para") position relative to X, and R8 is -N(R8a)R8b.

[0333] In some embodiments

[0334] X is -O- or -NH(R10a)-, or X-R2 is halogen or hydrogen;

[0335] R10a represents hydrogen or -CH3;

[0336] R2 is C1-C4 alkyl or is a 6-membered saturated carbocyclic ring substituted with one R8 at the 3 ("para") position with respect to X;

[0337] R8 is -N(R8a)R8b;

[0338] R8a, if it does not form a ring with R8b, is hydrogen or C1-C4alkyl-R8c;

[0339] R8b, if it does not form a ring with R8a, is hydrogen or C1-C4 alkyl;

[0340] R8a and R8b together may form a 6-membered saturated heterocyclic ring optionally containing one or two additional heteroatoms as ring members selected from N and O; and

[0341] R8c represents hydrogen, halogen, -O-C1-C2alkyl or -O-C1-C2haloalkyl.

[0342] In some embodiments:

[0343] T represents -N(R11)-, -N(R11)-C(=O)- or -N(R11)-S(O2)-;

[0344] R1, if it does not form a ring with R11, is -Y-R3;

[0345] or wherein R1 and R11 may together form a saturated or partially unsaturated 4-7-membered heterocyclic ring optionally containing one or two additional heteroatoms as ring members selected from N, O and S, wherein the heterocyclic ring is optionally substituted with one to three R1a, or R1 and R11 may together form a 5-6-membered heteroaryl ring optionally containing one to three additional heteroatoms as ring members selected from N and O, wherein the heteroaryl ring is optionally substituted with one to three R1b; and

[0346] R11 is C1-C4alkylene-H11a, C1-

[0347] C4haloalkylene-R11a or C3-C6cycloalkyl, wherein the cycloalkyl is optionally substituted with one or two R11b.

[0348] In some embodiments:

[0349] T represents -N(R11)-, -N(R11)-C(=O)-, or -N(R11)-S(O2)-;

[0350] R1, if it does not form a ring with R11, is -Y-R3;

[0351] Y is C1-C6 alkylene, wherein one non-terminal -CH2- moiety may be replaced by -O- and wherein the alkylene moiety may be substituted with one or two moieties independently selected from -OH, -O-C1-C4 alkyl and -O-C1-C4 haloalkyl, wherein the alkylene moiety may include a 3-5-membered saturated or partially unsaturated carbocyclic ring as part of this moiety;

[0352] or wherein R1 and R11 may together form a saturated or partially unsaturated 4-7-membered heterocyclic ring optionally containing one or two additional heteroatoms as ring members selected from N, O and S, wherein the heterocyclic ring is optionally substituted with one to three R1a, or R1 and R11 may together form a 5-6-membered heteroaryl ring optionally containing one to three additional heteroatoms as ring members selected from N and O, wherein the heteroaryl ring is optionally substituted with one to three R1b; and

[0353] R11 is C1-C4alkylene-R11a, C1-C4haloalkylene-R11a, or C3-C6cycloalkyl, wherein the cycloalkyl is optionally substituted with one or two R11b.

[0354] In some embodiments:

[0355] T represents -N(R11)- or -N(R11)-S(O2)-;

[0356] R11, if it does not form a ring with R1, is hydrogen, C1-C4alkylene-R11a, C1-C4haloalkylene-R11a, or C3-C6cycloalkyl;

[0357] R11a represents hydrogen, halogen, -CN or -OH;

[0358] R1 and R11 may together form a 4- to 6-membered saturated or partially unsaturated heterocyclic ring, optionally containing one additional heteroatom as a ring member selected from N and O, wherein the heterocyclic ring is optionally substituted with one or two R1a or R1 and R11 together may form a 5-membered heteroaryl ring, optionally containing one additional heteroatom as a ring member selected from N, and wherein the heteroaryl ring is optionally substituted with one or two R1b;

[0359] each R1a independently represents halogen, -OH, -CN, C1-C4alkylene-R1c, -O-C1-C4haloalkyl, -C(=O)NH2, or oxo;

[0360] each R1b is independently halogen, -OH, -CN, C1-C4alkylene-R1c, or -O-C1-C4haloalkyl;

[0361] each R1c independently represents hydrogen or -OH;

[0362] R1, if it does not form a ring with R11, is -Y-R3;

[0363] Y is C1-C6 alkylene, wherein the alkylene moiety may be substituted with one -OH, wherein the alkylene moiety may include a 3-membered saturated carbocyclic ring as part of the moiety, and wherein there are not more than three intermediate carbon atoms between the compound with T and the compound with R3;

[0364] R3 is hydrogen, -CN, -OH, C1-C4haloalkyl, -O-C1-C4alkylene-R4, -O-C1-C4haloalkyl, -NH2, -NH(C1-C4alkylene-R4), -N(C1-C4alkylene-R4)2, -C(=O)-NH2, -C(=O)-NH(C1-C4alkylene-R4), -C(=O)-OH, -C(=O)-O-C1-C4alkylene-R4, -C(=O)-N(C1-C4alkylene-R4)2, -NH-C (=O)-C1-C4alkylene-R4, -N(C1-C4alkyl) -C (=O)-C1-C4alkylene-R4, P ring, Q ring, -NH-S(O2) -C1-C4alkylene-R4, -N(C1-C4alkyl)-S(O2)-C1-C4alkylene-R4, -S-C1-C4alkylene-R4 or -S(O2)-C1-C4alkyl-R4;

[0365] R4 is hydrogen;

[0366] Ring P is a 3- to 6-membered saturated carbocyclic ring optionally substituted with one to two R5, or is a 5- or 6-membered saturated heterocyclic ring containing one heteroatom selected from N and O, optionally substituted with one to two R5;

[0367] each R5 is independently -NH2, C1-C2alkyl, -C1-C2alkyl-R5a, or oxo;

[0368] each R5a independently represents hydrogen, halogen, -NH2, -OH, -CN, or -O-C1-C2alkyl;

[0369] Ring Q is phenyl optionally substituted with one or two R6, or is a 5-6-membered heteroaryl ring containing one or two heteroatoms selected from N, S and O, optionally substituted with one or two R6;

[0370] each R6 independently represents -NH2, -OH, -CN, C1-C2alkylene-R6a, or -O-C1-C2alkyl; and

[0371] each R6a independently represents hydrogen, halogen or -CN.

[0372] In some embodiments: T is -N(R11)- or -N(R11)-S(O2)-; R11, when not forming a ring with R1, is C1-C4 alkylene-R11a, C1-C4 haloalkylene-R11a, or C3-C4 cycloalkyl; R11a is hydrogen, halogen, -CN, or -OH; R1 and R11 may be taken together to form a 5-6-membered saturated heterocyclic ring containing no additional heteroatoms as ring members, wherein the heterocyclic ring is optionally substituted with one R1a, or R1 and R11 may be taken together to form a 5-membered heteroaryl ring containing no additional heteroatoms as ring members, and wherein the heteroaryl ring is optionally substituted with one R1b;

[0373] R1a represents halogen, -OH or -CN; R1b represents halogen, -OH or -CN;

[0374] R1, if it does not form a ring with R11, is C1-C3alkylene-R3, P ring or Q ring;

[0375] R3 represents hydrogen, -CN, -OH, C1-C4haloalkyl, -O-C1-C4alkylene-R4, -O-C1-C4haloalkyl, -NH2, -NH(C1-C4alkylene-R4) or -N(C1-C4alkylene-R4)2, -C(=O)-OH, -C(=O)-NH2, P cycle or Q cycle;

[0376] Ring P is oxazolidinyl, optionally substituted with one or two R5;

[0377] each R5 is independently C1-C2alkyl, -C1-C2alkyl-R5a, or oxo, wherein the P ring is not substituted with two oxo (e.g., the P ring is optionally substituted with only one R5 when R5 is oxo);

[0378] Ring Q is phenyl optionally substituted with one R6, or is a 5-6-membered heteroaryl ring containing one to two heteroatoms selected from N and O, optionally substituted with one R6;

[0379] R6 independently represents -NH2, -OH, -CN, C1-C2alkylene-R6a, or -O-C1-C2alkyl; and

[0380] R6a independently represents hydrogen, halogen or -CN.

[0381] In some embodiments, T is -N(R11)-, and R11, if not forming a ring with R1, is C1-C4 alkyl, such as methyl or ethyl.

[0382] In an embodiment (embodiment A1), the compound is a compound of formula (I), wherein

[0383] Ra and Rb are both -CH3 or together form a bridging moiety -CH2-CH2-CH2-CH2-;

[0384] A represents -CH2- or -C(=O)-;

[0385] T is -N(R11)-, -N(R11)-S(O2)-, -O-, -C(R12)(R13)-, -C=C(R12)2, -S-, -S(O2)-, -S(O2)-N(R14)- or -C(=O)-N(R14)-;

[0386] R11, if it does not form a ring with R1 or R2, is hydrogen, C1-C4alkylene-H11a, C1-C4haloalkylene-R11a, or C3-C6cycloalkyl;

[0387] R11a represents hydrogen, halogen, -CN or -OH;

[0388] each R12 is independently hydrogen or C1-C4 alkylene-R12a;

[0389] each R12a independently represents hydrogen, halogen, -CN or -OH;

[0390] R13 is hydrogen;

[0391] R14 represents hydrogen or C1-C4 alkyl;

[0392] R2 and R11 can together form a partially unsaturated 6-membered heterocyclic ring containing no further heteroatoms when T is -N(R11)- and X is -O-;

[0393] R1 and R11 may together form a 4- to 6-membered saturated or partially unsaturated heterocyclic ring optionally containing one additional heteroatom as a ring member selected from N and O, for example, a ring selected from piperidinyl, morpholinyl, pyrrolidinyl, azetidinyl, 2,5-dihydropyrrolyl and 1,1-dioxide-1,2-thiazolidin-2-yl, wherein the heterocyclic ring is optionally substituted with one or two R1a, or R1 and R11 together may form a 5-membered heteroaryl ring optionally containing one additional heteroatom as a ring member selected from N, for example, selected from pyrrolyl, and wherein the heteroaryl ring is optionally substituted with one or two R1b;

[0394] each R1a independently represents halogen, -OH, -CN, C1-C4alkylene-R1c, -O-C1-C4haloalkyl, -C(=O)NH2, or oxo;

[0395] each R1b is independently halogen, -OH, -CN, C1-C4alkylene-R1c, or -O-C1-C4haloalkyl;

[0396] each R1c independently represents hydrogen or -OH;

[0397] R1, if it does not form a ring with R11, is -Y-R3;

[0398] Y represents a bond or C1-C6 alkylene, wherein the alkylene moiety may be substituted with one -OH, wherein the alkylene moiety may include a 3-membered saturated carbocyclic ring as part of the moiety, and wherein there are not more than three intermediate carbon atoms between the compound with T and the compound with R3;

[0399] R3 is hydrogen, -CN, -OH, C1-C4haloalkyl, -O-C1-C4alkylene-R4, -O-C1-C4haloalkyl, -NH2, -NH(C1-C4alkylene-R4), -N(C1-C4alkylene-R4)2, -C(=O)-NH2, -C(=O)-NH(C1-C4alkylene-R4), -C(=O)-0H, -C(=O)-O-C1-C4alkylene-R4, -C(=O)-N(C1-C4alkylene-R4)2, -NH-C (=O)-C1-C4alkylene-R4, -N(C1-C4alkyl)-C(=O)-C1-C4alkylene-R4, P ring, Q ring, -NH-S(O2)-C1-C4alkylene-R4, -N(C1-C4alkyl)-S(O2)-C1-C4alkylene-R4, -S-C1-C4alkylene-R4 or -S(O2)-C1-C4alkyl-R4;

[0400] R4 is hydrogen;

[0401] Ring P is a 3- to 6-membered saturated carbocyclic ring optionally substituted with one to two R5, or is a 5- or 6-membered saturated heterocyclic ring containing one heteroatom selected from N and O, optionally substituted with one to two R5;

[0402] each R5 independently represents -NH2, C1-C2alkyl, -C1-C2alkyl-R5a, or oxo;

[0403] each R5a independently represents hydrogen, halogen, -NH2, -OH, -CN, or -O-C1-C2alkyl;

[0404] Ring Q is phenyl optionally substituted with one or two R6, or is a 5-6-membered heteroaryl ring containing one or two heteroatoms selected from N, S and O, optionally substituted with one or two R6;

[0405] each R6 independently represents -NH2, -OH, -CN, C1-C2alkylene-R6a, or -O-C1-C2alkyl;

[0406] each R6a independently represents hydrogen, halogen or -CN;

[0407] X is -O- or -N(R10a)- or X-R2 is halogen or hydrogen;

[0408] R10a represents hydrogen or -CH3, or R2 and R10a may together form a 4- to 7-membered saturated heterocyclic ring optionally containing an -N(R9)- moiety as a ring member in addition to the nitrogen atom X and otherwise containing only carbon atoms as ring members, and wherein, when the heterocyclic ring does not contain an N(R9)- moiety, it is optionally substituted with one R8;

[0409] R2, if it does not form a ring with R10a or R11, is C1-C4 alkyl optionally substituted with R7, or is a 4- or 7-membered saturated carbocyclic ring optionally substituted with one R8, or is a 4- or 7-membered saturated heterocyclic ring containing one -N(R9)- moiety as a ring member and, otherwise, containing only carbon atoms as ring members, or X-R2 is halogen or hydrogen; R7 is -N(R7a)R7b;

[0410] R7a represents hydrogen or C1-C4 alkyl-R7 c; R7b represents hydrogen or C1-C4 alkyl;

[0411] R7c represents hydrogen, halogen, -O-C1-C2alkyl or -O-C1-C2haloalkyl;

[0412] R8 is -N(R8a)R8b;

[0413] R8a, if it does not form a ring with R8b, is hydrogen or C1-C4 alkyl-R8c;

[0414] R8b, if it does not form a ring with R8a, is hydrogen or C1-C4 alkyl;

[0415] R8a and R8b together may form a 6-membered saturated heterocyclic ring optionally containing one or two additional heteroatoms as ring members selected from N and O;

[0416] R8c represents hydrogen, halogen, -O-C1-C2alkyl or -O-C1-C2haloalkyl; and

[0417] R9 represents hydrogen or C1-C4 alkyl.

[0418] In an embodiment (embodiment A2), the compound is a compound of formula (I), wherein

[0419] Ra and Rb are both -CH3 or together form a bridging moiety -CH2-CH2-CH2-CH2-;

[0420] A represents -CH2- or -C(=O)-;

[0421] T represents -N(R11)-, -N(R11)-S(O2)-, -O-, -C(R12)(R13)-, -C=C(R12)2, -S-, -S(O2)-, -S (O2)-N(R14)- or -C(=O)-N(R14)-;

[0422] R11, if it does not form a ring with R1 or R2, is hydrogen, C1-C4alkylene-H11a, C1-C4haloalkylene-R11a, or C3-C6cycloalkyl;

[0423] R11a represents hydrogen, halogen, -CN or -OH;

[0424] each R12 is independently hydrogen or 01-C4 alkylene-R12a;

[0425] each R12a independently represents hydrogen, halogen, -CN or -OH;

[0426] R13 is hydrogen;

[0427] R14 represents hydrogen or C1-C4 alkyl;

[0428] R2 and R11 can together form a partially unsaturated 6-membered heterocyclic ring containing no further heteroatoms when T is -N(R11)- and X is -O-;

[0429] R1 and R11 may together form a 4- to 6-membered saturated or partially unsaturated heterocyclic ring optionally containing one additional heteroatom as a ring member selected from N and O, for example a ring selected from piperidinyl, morpholinyl, pyrrolidinyl, azetidinyl, 2,5-dihydropyrrolyl and 1,1-dioxide-1,2-thiazolidin-2-yl, wherein the heterocyclic ring is optionally substituted with one or two R1a, or a 5-membered heteroaryl ring optionally containing one additional heteroatom as a ring member selected from N, for example selected from pyrrolyl, and wherein the heteroaryl ring is optionally substituted with one or two R1b;

[0430] each R1a independently represents halogen, -OH, -CN, C1-C4alkylene-R1c, -O-C1-C4haloalkyl, -C(=O)NH2, or oxo;

[0431] each R1b is independently halogen, -OH, -CN, C1-C4alkylene-R1c, or -O-C1-C4haloalkyl;

[0432] each R1c independently represents hydrogen or -OH;

[0433] R1, if it does not form a ring with R11, is hydrogen or C1-C6alkylene-R3, wherein the alkylene moiety may be substituted with one -OH, wherein the alkylene moiety may include a 3-membered saturated carbocyclic ring as part of the moiety and wherein there are no more than three intermediate carbon atoms between the compound with T and the compound with R3, or wherein R1 is a P ring or a Q ring;

[0434] R3 is hydrogen, -CN, -OH, C1-C4haloalkyl, -O-C1-C4alkylene-R4, -O-C1-C4haloalkyl, -NH2, -NH(C1-C4alkylene-R4), -N (C1-C4alkylene-R4)2, -C(=O)-NH2, -C (=O)-NH (C1-C4alkylene-R4), -C(=O)-0H, -C(=O)-O-C1-C4alkylene-R4, -C(=O)-N(C1-C4alkylene-R4)2, -NH-C(=O)-C1-C4alkylene-R4, -N(C1-C4alkyl)-C(=O)-C1-C4alkylene-R4, P ring, Q ring, -NH-S(O2)-C1-C4alkylene-R4, -N(C1-C4alkyl)-S(O2)-C1-C4alkylene-R4, -S-C1-C4alkylene-R4 or -S(O2)-C1-C4alkyl-R4;

[0435] R4 is hydrogen;

[0436] Ring P is a 3- to 6-membered saturated carbocyclic ring optionally substituted with one to two R5, or is a 5- or 6-membered saturated heterocyclic ring containing one heteroatom selected from N and O, optionally substituted with one to two R5;

[0437] each R5 is independently -NH2, C1-C2alkyl, -C1-C2alkyl-R5a, or oxo;

[0438] each R5a independently represents hydrogen, halogen, -NH2, -OH, -CN, or -O-C1-C2alkyl;

[0439] Ring Q is phenyl optionally substituted with one or two R6, or is a 5-6-membered heteroaryl ring containing one or two heteroatoms selected from N, S and O, optionally substituted with one or two R6;

[0440] each R6 independently represents -NH2, -OH, -CN, C1-C2alkylene-R6a, or -O-C1-C2alkyl;

[0441] each R6a independently represents hydrogen, halogen or -CN;

[0442] X is -O- or -NH(R10a)-, or X-R2 is halogen or hydrogen;

[0443] R10a represents hydrogen or -CH3, or R2 and R10a may together form a 4- to 7-membered saturated heterocyclic ring optionally containing an -N(R9)- moiety as a ring member in addition to the nitrogen atom X and otherwise containing only carbon atoms as ring members, and wherein, when the heterocyclic ring does not contain an N(R9)- moiety, it is optionally substituted with one R8;

[0444] R2, if it does not form a ring with R10a or R11, is C1-C4 alkyl optionally substituted with R7, or is a 4- to 7-membered saturated carbocyclic ring optionally substituted with one R8, or is a 4- to 7-membered saturated heterocyclic ring containing one -N(R9)- moiety as a ring member and, otherwise, containing only carbon atoms as ring members, or X-R2 is halogen or hydrogen;

[0445] R7 is -N(R7a)R7b;

[0446] R7a is hydrogen or C1-C4 alkyl-R7c; R7b is hydrogen or C1-C4 alkyl;

[0447] R7c represents hydrogen, halogen, -O-C1-C2alkyl or -O-C1-C2haloalkyl; R8 represents -N(R8a)R8b;

[0448] R8a, if it does not form a ring with R8b, is hydrogen or C1-C4alkyl-R8 c;

[0449] R8b, if it does not form a ring with R8a, is hydrogen or C1-C4 alkyl;

[0450] R8a and R8b together may form a 6-membered saturated heterocyclic ring optionally containing one or two additional heteroatoms as ring members selected from N and O;

[0451] R8c represents hydrogen, halogen, -O-C1-C2alkyl or -O-C1-C2haloalkyl; and

[0452] R9 represents hydrogen or C1-C4 alkyl.

[0453] In an embodiment (embodiment B), the compound is a compound of formula (I), wherein Ra and Rb are both -CH3;

[0454] A is -CH2-;

[0455] T represents -N(R11)-, -N(R11)-S(O2)-, -C=C(R12)2, -S- or -C(=O)-N(R14)-;

[0456] R11, if it does not form a ring with R1, is hydrogen, C1-C4alkylene-R11a, C1-C4haloalkylene-R11a, or C3-C4cycloalkyl;

[0457] R11a is hydrogen, halogen, -CN or -OH; each R12 independently is hydrogen or C1-C4 alkylene-R12a;

[0458] each R12a independently represents hydrogen, halogen, -CN or -OH;

[0459] R14 represents hydrogen or C1-C4 alkyl;

[0460] R1 and R11 may together form a 5-6-membered saturated heterocyclic ring containing no further heteroatoms as ring members, for example, a ring selected from piperidinyl, pyrrolidinyl and 1,1-dioxide-1,2-thiazolidin-2-yl, wherein the heterocyclic ring is optionally substituted with one R1a, or R1 and R11 may together form a 5-membered heteroaryl ring containing no further heteroatoms as ring members, for example, selected from pyrrolyl, and wherein the heteroaryl ring is optionally substituted with one R1b;

[0461] R1a represents halogen, -OH or -CN; R1b represents halogen, -OH or -CN;

[0462] R1, if it does not form a ring with R11, is hydrogen, C1-C3alkylene-R3, P ring or Q ring;

[0463] R3 is hydrogen, -CN, -OH, C1-C4haloalkyl, -O-C1-C4alkylene-R4, -O-C1-C4haloalkyl, -NH2, -NH(C1-C4alkylene-R4) or -N(C1-C4alkylene-R4)2, -C(=O)-0H, -C(=O)-NH2, P cycle or Q cycle;

[0464] R4 is hydrogen;

[0465] Ring P is oxazolidinyl, optionally substituted with one or two R5;

[0466] each R5 is independently C1-C2alkyl, -C1-C2alkyl-R5a, or oxo, wherein the P ring is not substituted with two oxo (e.g., the P ring is optionally substituted with only one R5 when R5 is oxo);

[0467] each R5a independently represents hydrogen, halogen, -NH2, -OH, -CN, or -O-C1-C2alkyl;

[0468] Ring Q is phenyl optionally substituted with one R6, or is a 5-6-membered heteroaryl ring containing one to two heteroatoms selected from N and O, optionally substituted with one R6;

[0469] R6 independently represents -NH2, -OH, -CN, C1-C2alkylene-R6a, or -O-C1-C2alkyl;

[0470] R6a independently represents hydrogen, halogen or -CN;

[0471] X is -O- or -N(R10a)- or X-R2 is halogen;

[0472] R10a represents hydrogen or -CH3 or R2 and R10a together can form a 6-7-membered saturated

[0473] a heterocyclic ring containing one -N(R9)- moiety as a ring member at position 3 with respect to the nitrogen atom X and otherwise containing only carbon atoms as ring members and wherein, if the heterocyclic ring does not contain the -N(R9)- moiety, it is substituted with one R8 at position 3 with respect to the nitrogen atom X;

[0474] R2, if it does not form a ring with R10a, is C1-C4 alkyl optionally substituted with R7, or is a 6-7-membered saturated carbocyclic ring substituted with one R8 at position 3 relative to X, or R2 is a 6-7-membered saturated heterocyclic ring containing one -N(R9)- moiety as a ring member at position 3 relative to X and, otherwise, containing only carbon atoms as ring members, or where X-R2 is halogen or hydrogen;

[0475] R7 is -N(R7a)R7b;

[0476] R7a represents hydrogen or C1-C4 alkyl-R7 c; R7b represents hydrogen or C1-C4 alkyl;

[0477] R7c represents hydrogen, halogen, -O-C1-C2alkyl or -O-C1-C2haloalkyl;

[0478] R8 is -N(R8a)R8b;

[0479] R8a, if it does not form a ring with R8b, is hydrogen or C1-C4alkyl-R8c;

[0480] R8a, if it does not form a ring with R8a, is hydrogen or C1-C4 alkyl;

[0481] R8a and R8b together may form a 6-membered saturated heterocyclic ring optionally containing one or two additional heteroatoms as ring members selected from N and O;

[0482] R8c represents hydrogen, halogen, -O-C1-C2alkyl or -O-C1-C2haloalkyl; and

[0483] R9 represents hydrogen or C1-C4 alkyl.

[0484] In an embodiment (embodiment C), the compound is a compound of formula (I), wherein

[0485] Ra and Rb are both -CH3 or Ra and Rb together form a bridging moiety -CH2-CH2-CH2-CH2-;

[0486] A represents -CH2- or -C(=O)-;

[0487] T is -N(R11)-, -N(R11)-C(=O)-, -N(R11)-S(O2)-, -O- or -C(R12)(R13)-, -C=C(R12)2, -S-, -S(O2)-, -S(O2)-N(R14)- or -C(=O)-N(R14)-; R11, when not forming a ring with R1 or R2, is -CH3; cyclopropyl, -CH2CH2CH3, CH2CH2CN, -CH2CH2OH, -CH2CH3, or hydrogen;

[0488] each R12 independently represents hydrogen, -CH3, or -CH2OH;

[0489] R13 is hydrogen;

[0490] R14 represents hydrogen or -CH3;

[0491] R2 and R11 can together form a bridging moiety -CH2CH2- when T is -N(R11)- and X is -O-;

[0492] R1 and R11 may together form a heterocyclic ring when T is -N(R11)- selected from piperidinyl, morpholinyl, pyrrolidinyl azetidinyl, 2,5-dihydropyrrolyl and 1,1-dioxide-1,2-thiazolidin-2-yl, each of which is optionally substituted with one to two R1a;

[0493] each R1a independently represents -OH, -CN, -OCH3, -CH2OH, -C(=O)NH2, or oxo;

[0494] R1 and R11 may together form a heteroaryl ring when T is -N(R11)- selected from pyrrolyl optionally substituted with one or two R1b;

[0495] each R1b is independently selected from -OH, -CN, -OCH3, and -CH2OH;

[0496] R1, if it does not form a ring with R11, is hydrogen or -Y-R3;

[0497] Y represents a bond, -CH2-, -CH2C (-CH2CH2-)-, CH2C(CH3)2-, -CH2CH (OH)CH2-, -CH2CH2- or -CH2CH2CH2-, -C(CH3)2-, -CH2CH2C(CH3)2-, -CH2CH2CH2CH2-, -CH2C(CH3)2- or -CH2C (CH3)2CH2-;

[0498] R3 is hydrogen, 1-tetrahydropyran-4-yl, -CN, -OH, -C(=O)NHCH3, -CF3, -NHC(=O)CH3, -NHS(O2)CH3, -OCF3, -OCH3, -oxazolidin-5-yl-2-one, -S(O2)CH3, -SCH3, -OCH2CH3, 4-fluorophenyl, 1,3,4-oxadiazol-4-yl, -C(=O)OCH2CH3, -C (=O)OH, -NH2, imidazolyl, oxazolyl, pyridinyl, cyclopropyl or -C(=O)NH2;

[0499] X is -O- or -N(R10a)-, or X-R2 is bromine or hydrogen;

[0500] R2 and R10a can form a piperazinyl ring together;

[0501] and

[0502] R2, if it does not form a ring with R10a or R11, is azepan-4-yl, -CH3, -CH2CH2N(CH3)2, 4-aminocyclohexyl (e.g., cis-4-aminocyclohexyl and trans-4-aminocyclohexyl), 4-morpholin-4-ylcyclohexyl (e.g., trans-4-morpholin-4-yl-cyclohexyl), 4-NH(CH2CH2OCH3)-cyclohexyl (e.g., trans-4-N(CH2CH2OCH3)-cyclohexyl), 4-N (CH3)2-cyclohexyl (e.g., trans-4-N(CH3)2-cyclohexyl), 4-NH(CH3)-cyclohexyl (e.g., trans-4-NH(CH3)-cyclohexyl) or piperidin-4-yl, or where X-R2 represents bromine or hydrogen.

[0503] In further embodiments, the invention provides the following compounds and pharmaceutically acceptable salts thereof:

[0504] 8-methoxy-5,5,7-trimethyl-6H-benzo[h]quinazolin-4-amine;

[0505] 8-methoxy-5,5-dimethyl-6H-benzo[h]quinazoline-4,7-diamine;

[0506] 6,6-dimethyl-2,3,4,5-tetrahydroquinazolino[7,8-f][1,4]benzoxazin-7-amine;

[0507] 4,6,6-trimethyl-3,5-dihydro-2H-quinazolino[7,8-f][1,4]benzoxazin-7-amine;

[0508] 8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazoline-4,7-diamine;

[0509] N-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]acetamide;

[0510] 8-(trans-4-aminocyclohexoxy)-N7,N7-diethyl-5,5-dimethyl-6H-benzo[h]quinazoline-4,7-diamine;

[0511] 8-(trans-4-aminocyclohexoxy)-N7-ethyl-5,5-dimethyl-6H-benzo[h]quinazoline-4,7-diamine;

[0512] 8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-7-(1-piperidyl)-6H-benzo[h]quinazolin-4-amine;

[0513] 8-(grans-4-aminocyclohexoxy)-5,5-dimethyl-7-morpholino-6H-benzo[h]quinazolin-4-amine;

[0514] 2-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-(2-hydroxyethyl)amino]ethanol;

[0515] 2-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]methylamino]ethanol;

[0516] 8-(trans-4-aminocyclohexoxy)-N7-(2-methoxyethyl)-N7,5,5-trimethyl-6H-benzo[h]quinazoline-4,7-diamine;

[0517] 2-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]amino]ethanol;

[0518] 1-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]pyrrolidin-3-ol - isomer 1;

[0519] 1-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]pyrrolidin-3-ol - isomer 2;

[0520] 8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-7-pyrrol-1-yl-6H-benzo[h]quinazolin-4-amine;

[0521] 8-(trans-4-aminocyclohexoxy)-N7-(2-methoxyethyl)-5,5-dimethyl-6H-benzo[h]quinazoline-4,7-diamine;

[0522] 8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-7-propoxy-6H-benzo[h]quinazolin-4-amine;

[0523] 8-(trans-4-aminocyclohexoxy)-N7,N7,5,5-tetramethyl-6H-benzo[h]quinazoline-4,7-diamine;

[0524] 1-(4-amino-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-9-yl)piperidin-4-ol;

[0525] 2-[[4-amino-8-(cis-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]ethylamino]ethanol;

[0526] 2-[[4-amino-8-(cis-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]propylamino]ethanol;

[0527] 2-[[4-amino-8-(cis-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methylamino]ethanol;

[0528] 1-(4-amino-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)azetidin-3-ol;

[0529] 2-[[4-amino-8-(cis-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methylamino]-N-methylacetamide;

[0530] 3-[(4-amino-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)amino]propane-1,2-diol;

[0531] [1-(4-amino-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)azetidin-3-yl]methanol;

[0532] 8-(cis-4-aminocyclohexoxy)-N7,5,5-trimethyl-N7-(tetrahydropyran-4-ylmethyl)-6H-benzo[h]quinazoline-4,7-diamine;

[0533] 2-[[4-amino-8-(cis-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methylamino]acetonitrile;

[0534] 8-(cis-4-aminocyclohexoxy)-N7,5,5-trimethyl-N7-(2-methylsulfanylethyl)-6H-benzo[h]quinazoline-4,7-diamine;

[0535] 8-(cis-4-aminocyclohexoxy)-N7,5,5-trimethyl-N7-(2-methylsulfonylethyl)-6H-benzo[h]quinazoline-4,7-diamine;

[0536] 2-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methylamino]acetonitrile;

[0537] 4,7-diamino-8-(trans-4-aminocyclohexoxy)-5,5-dimethylbenzo[h]quinazolin-6-one;

[0538] 2-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]amino]acetonitrile;

[0539] 8-(trans-4-aminocyclohexoxy)-N7-(2-ethoxyethyl)-N7,5,5-trimethyl-6H-benzo[h]quinazoline-4,7-diamine;

[0540] 8-(trans-4-aminocyclohexoxy)spiro[6H-benzo[h]quinazoline-5,1'-cyclopentane]-4,7-diamine;

[0541] N-[2-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methylamino]ethyl]acetamide;

[0542] N-[2-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methylamino]ethyl]methanesulfonamide;

[0543] 1-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methylamino]-2-methylpropan-2-ol;

[0544] N-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-2-hydroxy-N-methylacetamide;

[0545] N-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-2-hydroxyethanesulfonamide;

[0546] 8-(trans-4-aminocyclohexoxy)-N7,5,5-trimethyl-N7-(3,3,3-trifluoropropyl)-6H-benzo[h]quinazoline-4,7-diamine;

[0547] N-[4-amino-8-(4-trans-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-2-hydroxy-N-methylethanesulfonamide;

[0548] N-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-2-hydroxyacetamide;

[0549] 3-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methylamino]propanenitrile;

[0550] 8-(trans-4-aminocyclohexoxy)-N7,5,5-trimethyl-N7-[2-(trifluoromethoxy)ethyl]-6H-benzo[h]quinazoline-4,7-diamine.

[0551] 1-[[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methylamino]methyl]cyclopropanecarbonitrile;

[0552] 1-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]pyrrolidin-3-carbonitrile - isomer 1;

[0553] 1-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]pyrrolidin-3-carbonitrile - isomer 2;

[0554] 3-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-cyclopropylamino]propanenitrile;

[0555] 3-[[4-amino-5,5-dimethyl-8-(trans-4-morpholinocyclohexoxy)-6H-benzo[h]quinazolin-7-yl]-methylamino]propanenitrile;

[0556] 3-[[4-amino-8-[trans-4-(2-methoxyethylamino)cyclohexoxy]-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methylamino]propanenitrile;

[0557] 8-(trans-4-aminocyclohexoxy)-N7-but-3-ynyl-N7,5,5-trimethyl-6H-benzo[h]quinazoline-4,7-diamine;

[0558] 1-(4-amino-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)pyrrolidine-3-carbonitrile.

[0559] 1-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-2H-pyrrol-5-one;

[0560] 8-(trans-4-aminocyclohexoxy)-7-(3-methoxypyrrol-1-yl)-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine;

[0561] 4-[[4-amino-8-(4-trans-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methylamino]butanenitrile;

[0562] 2-[[4-amino-8-(4-trans-aminocyclohexoxy)spiro[6H-benzo[h]quinazolin-5,1'-cyclopentan]-7-yl]methylamino]ethanol;

[0563] 2-[[4-amino-8-(4-trans-aminocyclohexoxy)spiro[6H-benzo[h]quinazolin-5,1'-cyclopentane]-7-yl]amino]ethanol;

[0564] 8-methoxy-7-(3-methoxypropyl)-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine;

[0565] 8-(trans-4-aminocyclohexoxy)-N7-(2-methoxyethyl)spiro[6H-benzo[h]quinazoline-5,1'-cyclopentane]-4,7-diamine;

[0566] 8-(trans-4-aminocyclohexoxy)-7-(3-methoxypyrrolidin-1-yl)-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine - isomer 1;

[0567] N-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-2-methoxy-N-methylethanesulfonamide;

[0568] ethyl 2-[[4-amino-8-(cis-4-aminocyclohexoxy)spiro[6H-benzo[h]quinazolin-5,1'-cyclopentane]-7-yl]amino]acetate;

[0569] 1-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]pyrrolidine-3-carbonitrile;

[0570] 8-(trans-4-aminocyclohexoxy)-N7-ethyl-N7,5,5-trimethyl-6H-benzo[h]quinazoline-4,7-diamine;

[0571] 8-(trans-4-aminocyclohexoxy)-N7,5,5-trimethyl-6H-benzo[h]quinazoline-4,7-diamine;

[0572] 3-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methylsulfamoyl]propanoic acid;

[0573] 2-[[4-amino-8-(cis-4-aminocyclohexoxy)spiro[6H-benzo[h]quinazolin-5,1'-cyclopentane]-1-yl]amino]ethanol;

[0574] 3-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]oxy]propanenitrile;

[0575] 8-(trans-4-aminocyclohexoxy)-N7-(2-methoxyethyl)-N7-methylspiro[6H-benzo[h]quinazoline-5,1'-cyclopentane]-4,7-diamine;

[0576] 8-(trans-4-aminocyclohexoxy)-7-(3-methoxypyrrolidin-1-yl)-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine - isomer 2;

[0577] N-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-2-cyano-N-methylethanesulfonamide;

[0578] 8-(cis-4-aminocyclohexoxy)-N7-(2-methoxyethyl)-N7-methyl-spiro[6H-benzo[h]quinazoline-5,1'-cyclopentane]-4,7-diamine;

[0579] 1-[[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]amino]methyl]cyclopropanecarbonitrile;

[0580] 1-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]pyrrolidine-3-carboxamide;

[0581] 3-[[4-amino-8-(azepan-4-yloxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]methylamino]propanenitrile;

[0582] 2-[[4-amino-8-(cis-4-aminocyclohexoxy)spiro[6H-benzo[h]quinazolin-5,1'-cyclopentan]-7-yl]amino]acetic acid;

[0583] 8-(trans-4-aminocyclohexoxy)-N7-(2-aminoethyl)-N7,5,5-trimethyl-6H-benzo[h]quinazoline-4,7-diamine;

[0584] 4-[4-amino-8-(grane-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]butanenitrile;

[0585] (5R)-5-[[(4-amino-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)amino]methyl]oxazolidin-2-one;

[0586] 2-[[4-amino-8-(cis-4-aminocyclohexoxy)spiro[6H-benzo[h]quinazolin-5,1'-cyclopentan]-7-yl]-methylamino]ethanol;

[0587] 8-(trans-4-aminocyclohexoxy)-N7-cyclopropyl-5,5-dimethyl-6H-benzo[h]quinazoline-4,7-diamine;

[0588] 3-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methylamino]propanoic acid;

[0589] 3-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methylsulfamoyl]propanamide;

[0590] 8-(cis-4-aminocyclohexoxy)-N7-(2-methoxyethyl)spiro[6H-benzo[h]quinazoline-5,1'-cyclopentane]-4,7-diamine;

[0591] 3-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]methylamino]-2,2-dimethylpropanamide;

[0592] (5R)-5-[2-[(4-amino-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)amino]ethyl]oxazolidin-2-one;

[0593] 4-amino-8-(trans-4-aminocyclohexoxy)-N-(cyanomethyl)-5,5-dimethyl-6H-benzo[h]quinazoline-7-carboxamide;

[0594] 3-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]methylamino]-2,2-dimethylpropanenitrile;

[0595] 3-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]butan-1-ol;

[0596] 3-[[4-amino-5,5-dimethyl-8-(4-piperidyloxy)-6H-benzo[h]quinazolin-7-yl]-methylamino]propanenitrile;

[0597] 4-amino-8-(trans-4-aminocyclohexoxy)-N-(cyanomethyl)-N,5,5-trimethyl-6H-benzo[h]quinazoline-7-carboxamide;

[0598] 3-[(4-amino-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)-methylamino]propanenitrile;

[0599] 3-[[4-amino-8-trans-4-(dimethylamino)cyclohexoxy]-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methylamino]propanenitrile;

[0600] 4-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]pentanenitrile;

[0601] (E)-3-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]but-2-en-1-ol;

[0602] 3-[[4-amino-5,5-dimethyl-8-[trans-4-(methylamino)cyclohexoxy]-6H-benzo[h]quinazolin-7-yl]-methylamino]propanenitrile;

[0603] 8-(trans-4-aminocyclohexoxy)-N7-butyl-N7,5,5-trimethyl-6H-benzo[h]quinazoline-4,7-diamine;

[0604] 8-(trans-4-aminocyclohexoxy)-N7,5,5-trimethyl-N7-(4-pyridylmethyl)-6H-benzo[h]quinazoline-4,7-diamine;

[0605] 8-(trans-4-aminocyclohexoxy)-N7-isopropyl-N7,5,5-trimethyl-6H-benzo[h]quinazoline-4,7-diamine;

[0606] 8-(trans-4-aminocyclohexoxy)-N7-(1H-imidazol-4-ylmethyl)-N7,5,5-trimethyl-6H-benzo[h]quinazoline-4,7-diamine;

[0607] 8-(trans-4-aminocyclohexoxy)-N7-isopentyl-N7,5,5-trimethyl-6H-benzo[h]quinazoline-4,7-diamine;

[0608] 8-(trans-4-aminocyclohexoxy)-N7,5,5-trimethyl-N7-(oxazol-4-ylmethyl)-6H-benzo[h]quinazoline-4,7-diamine;

[0609] 8-(trans-4-aminocyclohexoxy)-N7-isobutyl-N7,5,5-trimethyl-6H-benzo[h]quinazoline-4,7-diamine;

[0610] 8-(trans-4-aminocyclohexoxy)-N7,5,5-trimethyl-N7-(3-pyridylmethyl)-6H-benzo[h]quinazoline-4,7-diamine;

[0611] 3-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]sulfanyl]propanenitrile;

[0612] 3-[(4-amino-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)methylamino]propanenitrile;

[0613] 3-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methylamino]-2,2-dimethylpropan-1-ol;

[0614] 4-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methylamino]-2-methylbutan-2-ol;

[0615] 3-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]sulfonyl]propanenitrile;

[0616] 4-amino-8-(trans-4-aminocyclohexoxy)-N-(cyanomethyl)-N,5,5-trimethyl-6H-benzo[h]quinazoline-7-sulfonamide;

[0617] N-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-4-fluoro-N-methylbenzenesulfonamide;

[0618] 3-[(4-amino-8-bromo-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)-methylamino]propanenitrile;

[0619] 4-amino-8-(trans-4-aminocyclohexoxy)-N-(cyanomethyl)-5,5-dimethyl-6H-benzo[h]quinazoline-7-sulfonamide;

[0620] 3-(7-amino-6,6-dimethyl-3,5-dihydro-2H-quinazolino[7,8-f][1,4]benzoxazin-4-yl)propanenitrile;

[0621] 3-[[4-amino-5,5-dimethyl-8-(4-methylpiperazin-1-yl)-6H-benzo[h]quinazolin-7-yl]-methylamino]propanenitrile;

[0622] 8-(trans-4-aminocyclohexoxy)-7-(1,1-dioxo-1,2-thiazolidin-2-yl)-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine;

[0623] 1-(4-amino-8-bromo-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)pyrrolidine-3-carbonitrile;

[0624] (5R)-5-[[(4-amino-8-bromo-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)amino]methyl]oxazolidin-2-one;

[0625] N7-[[5-(1-fluoroethyl)-1,3,4-oxadiazol-2-yl]methyl]-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazoline-4,7-diamine;

[0626] 3-[[4-amino-8-[2-(dimethylamino)ethoxy]-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methylamino]propanenitrile;

[0627] 3-[(4-amino-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)-[[5-(1-fluoroethyl)-1,3,4-oxadiazol-2-yl]methyl]amino]propanenitrile;

[0628] 3-[(4-amino-5,5-dimethyl-8-piperazin-1-yl-6H-benzo[h]quinazolin-7-yl)-methylamino]propanenitrile;

[0629] (5S)-5-[[(4-amino-8-bromo-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)-methylamino]methyl]oxazolidin-2-one;

[0630] (5R)-5-[[(4-amino-8-bromo-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)amino]methyl]-3-(2-hydroxyethyl)oxazolidin-2-one;

[0631] (5R)-5-[[[4-amino-8-(cis-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]amino]methyl]oxazolidin-2-one;

[0632] (5R)-5-[[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]amino]methyl]oxazolidin-2-one;

[0633] (5R)-5-[[[4-amino-5,5-dimethyl-8-(cis-4-morpholinocyclohexoxy)-6H-benzo[h]quinazolin-7-yl]amino]methyl]oxazolidin-2-one;

[0634] (5R)-5-[[[4-amino-5,5-dimethyl-8-(trans-4-morpholinocyclohexoxy)-6H-benzo[h]quinazolin-7-yl]amino]methyl]oxazolidin-2-one; and

[0635] 3-[(4-amino-8-bromo-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)-[[(5S)-2-oxooxazolidin-5-yl]methyl]amino]propanenitrile.

[0636] Certain intermediates useful for preparing compounds of formula (I) are novel and constitute further aspects of the invention. Accordingly, in a further aspect, the invention provides compounds of formula (B)

[0637]

[0638] and their salts, where

[0639] A, Ra and Rb have the meanings defined for the compounds of formula (I), including their preferred meanings (including the meanings defined in Embodiment A1, Embodiment A2, Embodiment B or Embodiment C);

[0640] E1 represents -OH, -halogen, -O-C1-C4alkyl, boronic acid, boronic acid ester (such as dimethyl boronic acid ester or pinacol boronic acid ester) or O-L1;

[0641] L1 is methanesulfonyl, p-toluenesulfonyl or trifluoromethanesulfonyl; and

[0642] E2 is -OH, halogen, -NO2or -SO2Cl.

[0643] In a further aspect, the invention provides compounds of formula (C)

[0644]

[0645] and their salts, where

[0646] A, X, Ra and Rb have the meanings defined for the compounds of formula (I), including their preferred meanings (including the meanings defined in Embodiment A1, Embodiment A2, Embodiment B or Embodiment C);

[0647] E2 is -OH, halogen, -NO2, or -SO2Cl; and

[0648] R2' has the meanings defined for R2 for the compounds of formula (I), including their preferred meanings (including the meanings defined in Embodiment A1, Embodiment A2, Embodiment B or Embodiment C), wherein any functional group in R2 is optionally protected with a suitable protecting group.

[0649] Preferably, in the compounds of formula (C), in the substituent R2', the amino group may optionally be protected with a suitable amino-protecting group such as allyloxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethylcarbonyl, tert-butoxycarbonyl or benzyl and / or the hydroxyl group may optionally be protected with a suitable hydroxyl-protecting group such as methyl, benzyl or g-para-methoxybenzyl.

[0650] In a further aspect, the present invention provides compounds of formula (D)

[0651]

[0652] and its salts, where

[0653] A, X, Ra and Rb have the meanings defined for the compounds of formula (I), including their preferred meanings (including the meanings defined in Embodiment A1, Embodiment A2, Embodiment B or Embodiment C);

[0654] T' represents -N(R11')-, -N(R11')-C(=O)-, -N(R11')-S(O2)-, -O-, -C(R12')(R13)-, -C=C(R12')2, -S-, -S(O)-, -S(O2)-, -S (O2)-N(R14')- or -C(=O)-N(R14')-;

[0655] R11' has the meanings defined for R11 in the compounds of formula (I), including its preferred meanings (including the meanings defined in Embodiment A1, Embodiment A2, Embodiment B or Embodiment C), wherein any functional group in R11 is optionally protected with a suitable protecting group;

[0656] R12' has the meanings defined for R12 in the compounds of formula (I), including its preferred meanings (including the meanings defined in Embodiment A1, Embodiment A2, Embodiment B or Embodiment C), wherein any functional group in R12 is optionally protected with a suitable protecting group;

[0657] R13 has the meanings defined for the compounds of formula (I), including their preferred meanings (including the meanings defined in Embodiment A1, Embodiment A2, Embodiment B or Embodiment C);

[0658] R14' has the meanings defined for R14 in the compounds of formula (I), including its preferred meanings (including the meanings defined in Embodiment A1, Embodiment A2, Embodiment B or Embodiment C), wherein any functional group within R14 is optionally protected with a suitable protecting group;

[0659] R1' has the meanings defined for R1 in the compounds of formula (I), including their preferred meanings (including the meanings defined in Embodiment A1, Embodiment A2, Embodiment B or Embodiment C), wherein any functional group within R1 is optionally protected with a suitable protecting group; and

[0660] R2' has the meanings defined for R2 in the compounds of formula (I), including their preferred meanings (including the meanings defined in Embodiment A1, Embodiment A2, Embodiment B or Embodiment C), wherein any functional group in R2 is optionally protected with a suitable protecting group.

[0661] Preferably, the compounds of formula (D) include at least one protecting group.

[0662] Preferably, in the compounds of formula (D), in one or more substituents R1', R2', R11', R12' and R14', the amino group may optionally be protected with a suitable amino-protecting group such as allyloxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethylcarbonyl, tert-butoxycarbonyl or benzyl and / or the hydroxyl group may optionally be protected with a suitable hydroxyl-protecting group such as methyl, benzyl or para-methoxybenzyl.

[0663] In a further aspect, the invention provides compounds of formula (E)

[0664]

[0665] and its salts, where

[0666] A, Ra and Rb have the meanings defined for the compounds of formula (I), including their preferred meanings (including the meanings defined in Embodiment A1, Embodiment A2, Embodiment B or Embodiment C);

[0667] T' represents -N(R11')-, -N(R11')-C(=O)-, -N(R11')-S(O2)-, -O-, -C(R12')(R13)-, -C=C(R12')2, -S-, -S(O)-, -S(O2)-, -S (O2)-N(R14')- or -C(=O)-N(R14')-;

[0668] R11' has the meanings defined for R11 in the compounds of formula (I), including its preferred meanings (including the meanings defined in Embodiment A1, Embodiment A2, Embodiment B or Embodiment C), wherein any functional group in R11 is optionally protected with a suitable protecting group;

[0669] R12' has the meanings defined for R12 in the compounds of formula (I), including its preferred meanings (including the meanings defined in Embodiment A1, Embodiment A2, Embodiment B or Embodiment C), wherein any functional group in R12 is optionally protected with a suitable protecting group;

[0670] R13 has the meanings defined for the compounds of formula (I), including their preferred meanings (including the meanings defined in Embodiment A1, Embodiment A2, Embodiment B or Embodiment C);

[0671] R14' has the meanings defined for R14 in the compounds of formula (I), including its preferred meanings (including the meanings defined in Embodiment A1, Embodiment A2, Embodiment B or Embodiment C), wherein any functional group within R14 is optionally protected with a suitable protecting group;

[0672] R1' has the meanings defined for R1 in the compounds of formula (I), including their preferred meanings (including the meanings defined in Embodiment A1, Embodiment A2, Embodiment B or Embodiment C), wherein any functional group within R1 is optionally protected with a suitable protecting group;

[0673] E1 represents -OH, -halogen, -O-C1-C4alkyl, boronic acid, boronic acid ester (e.g. dimethyl boronic acid ester or pinacol boronic acid ester) or O-L1; and

[0674] L1 is methanesulfonyl, p-toluenesulfonyl or trifluoromethanesulfonyl.

[0675] Preferably, in the compounds of formula (E), in one or more substituents R1', R11', R12' and R14', the amino group may optionally be protected with a suitable amino-protecting group such as allyloxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethylcarbonyl, tert-butoxycarbonyl or benzyl, and / or the hydroxyl group may be protected with a suitable hydroxyl-protecting group such as methyl, benzyl or para-methoxybenzyl.

[0676] The present invention also relates to pharmaceutical compositions that contain a compound of formula (I) as an active ingredient or a pharmaceutically acceptable salt thereof, which can be used, in particular, in the treatment of neoplastic diseases, in particular cancer, as described herein. The compositions can be formulated for non-parenteral administration, such as nasal, buccal, rectal, pulmonary, vaginal, sublingual, topical, transdermal, ophthalmic or, in particular, for oral administration, such as in the form of solid oral dosage forms such as.Granules, pellets, powders, tablets, film-coated or sugar-coated tablets, effervescent tablets, hard and soft gelatin or hydroxypropyl methylcellulose (HPMC) capsules coated, if applicable, with orally disintegrating tablets, oral solutions, lipid emulsions or suspensions, or for parenteral administration, for example, intravenous, intramuscular or subcutaneous, intrathecal, intradermal or epidural administration to mammals, especially humans, for example in the form of solutions, for example in the form of solutions, lipid emulsions or suspensions containing microparticles or nanoparticles. The compositions may contain the active ingredient alone or, preferably, together with a pharmaceutically acceptable carrier.

[0677] The compounds of formula (I) or pharmaceutically acceptable salts thereof can be processed with pharmaceutically inert, inorganic or organic excipients to produce solid oral dosage forms, such as granules, pellets, powders, tablets, film-coated or sugar-coated tablets, effervescent tablets, hard gelatin or HPMC capsules or orally disintegrating tablets.Fillers such as lactose, cellulose, mannitol, sorbitol, calcium phosphate, starch or its derivatives, binders such as cellulose, starch, polyvinylpyrrolidone or their derivatives, lubricants such as talc, stearic acid or its salts, anti-caking agents such as colloidal silicon dioxide can be used as such excipients for the formulation and production of solid oral dosage forms such as granules, pellets, powders, tablets, film-coated or sugar-coated tablets, effervescent tablets, hard gelatin capsules or HPMC capsules or orally disintegrating tablets. Suitable excipients for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols, etc.

[0678] Suitable excipients for the production 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, lecithin, surfactants, etc. In addition, pharmaceutical preparations may contain preservatives, solubilizers (e.g., cyclodextrin), stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorings, salts for changing the osmotic pressure, buffers, masking agents or antioxidants. They may also contain other therapeutically valuable substances.

[0679] Pharmaceutical compositions suitable for injection use include sterile aqueous solutions (if soluble in water) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include saline, bacteriostatic water, Cremophor® EL, or phosphate-buffered saline (PBS). The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, a polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, etc.), and suitable mixtures thereof. For intravenous injection of highly lipophilic molecules, it may be advisable to include solubilizers, such as surfactants, polymeric surfactants, polymers, complexing agents, and / or cosolvents, which can significantly increase the solubility of the compounds in water.Examples of solubilizers include polyethylene glycol, propylene glycol, ethanol, glycerol, and cyclodextrins (e.g., sulfobutyl ether β-cyclodextrin).

[0680] The dosage can vary widely and is, of course, individualized. Generally, when administered orally, the daily dose of the compound of general formula (I) is approximately 1-1000 mg per person, although the lower or upper limits specified above may also be exceeded if necessary.

[0681] Compounds of formula (I) can also be used in combination with one or more other pharmaceutically active compounds that are either effective against the same disease, preferably with a different mechanism of action, or that reduce or prevent potential undesirable side effects of the compound of formula (I). In such treatment, the combination partners can be administered either simultaneously, for example by including them in a single pharmaceutical formulation, or sequentially by administering two or more different dosage forms, each containing one or more of the combination partners.

[0682] The compounds of formula (I) according to the invention, as described above, or pharmaceutically acceptable salts thereof, are particularly useful for the treatment of neoplastic diseases such as cancer, in particular when administered in therapeutically effective amounts, for example, to a subject in need thereof. In some embodiments, cancer to be treated with the compounds of the present invention can be treated by inhibiting one or more CLK enzymes. In some embodiments, cancer to be treated with the compounds of the present invention can be treated by inhibiting aberrant splicing. Cancer can be caused by aberrant splicing, for example, the cancer can be a cancer with a mutant splicing factor. Cancer can be dependent on an oncogenic splicing variant.

[0683] In some embodiments, the compounds of the present invention are potent inhibitors of CLK kinase and exhibit high selectivity for the kinase, for example, as evidenced by a low selectivity index. In some embodiments, the compounds of the present invention exhibit potent cellular activity, for example, as evidenced by antiproliferative activity and / or cell death. In some embodiments, the compounds of the present invention effectively inhibit phosphorylation of the SR protein. In some embodiments, the compounds of the present invention exhibit a long retention time of the CLK enzyme, as demonstrated by a target interaction assay, for example, resulting in potent antiproliferative activity against cancer cells even after short-term exposure. In some embodiments, the compounds of the present invention exhibit good metabolic stability.In some embodiments, the compounds of the present invention exhibit good permeability, for example, as demonstrated by the Caco-2 permeability assay. In some embodiments, the compounds of the present invention exhibit good leakage prevention. In some embodiments, the compounds of the present invention exhibit high bioavailability when administered orally.

[0684] In some embodiments, a compound of the present invention inhibits CLK3 in an in vitro assay with an IC50 of no more than 100 nM. In some embodiments, a compound of the invention inhibits CLK3 in an in vitro assay with an IC50 of no more than 30 nM. The in vitro assay for determining CLK3 inhibition is described in the examples below (CLK3 kinase assay).

[0685] Examples of neoplastic diseases for treatment with the compounds of the present invention include, but are not limited to, epithelial neoplasms, squamous cell neoplasms, basal cell neoplasms, transitional cell papillomas and carcinomas, adenomas and adenocarcinomas, neoplasms of the adnexa and appendages of the skin, mucoepidermoid neoplasms, cystic neoplasms, mucinous and serous neoplasms, ductal, lobular and medullary neoplasms, acinar cell neoplasms, complex epithelial neoplasms, specialized gonadal neoplasms, paragangliomas and glomus tumors, nevi and melanomas, soft tissue tumors and sarcomas, fibromatous neoplasms, myxomatous neoplasms, lipomatous neoplasms, myomatous neoplasms, complex mixed and stromal neoplasms, fibroepithelial neoplasms, synovial-like neoplasms, mesothelial neoplasms,Embryonal cell neoplasms, trophoblastic neoplasms, mesonephromas, angiomas, lymphatic tumors, bone and chondromatous neoplasms, giant cell tumors, various bone tumors, odontogenic tumors, gliomas, neuroepitheliomatous and neuroendocrine neoplasms, meningiomas, nerve sheath tumors, granular cell tumors and alveolar sarcomas of the soft tissues, Hodgkin's disease and non-Hodgkin's lymphomas, B-cell lymphoma, T-cell lymphoma, hairy cell lymphoma, Burkitt's lymphoma and other lymphoreticular neoplasms, plasma cell tumors, mast cell tumors, immunoproliferative disorders, leukemias, various myeloproliferative disorders, lymphoproliferative disorders, and myelodysplastic syndromes.

[0686] Examples of cancer in terms of the organs and body parts affected include, but are not limited to, breast, cervix, ovary, colon, rectum (including both 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 gland, liver, stomach (gastric cancer), intestine, pancreas, bone marrow, hematological malignancies (such as lymphoma, leukemia, myeloma, or lymphoid malignancies), bladder, urinary tract, kidney, skin, thyroid gland, brain, head, neck, prostate, and testicles.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, kidney cancer, bladder cancer, mesothelioma, hematological malignancies, melanoma, and sarcoma.

[0687] Further examples of neoplastic diseases treatable with the compounds of the invention include hematological malignancies such as acute myeloid leukemia, myelodysplastic syndromes, chronic myelomonocytic leukemia, chronic lymphocytic leukemia, non-Hodgkin's lymphoma; solid tumors such as mucosal melanoma, uveal melanoma, medulloblastoma, hepatocellular carcinoma, endometrial carcinoma, bladder cancer, skin melanoma, lung adenocarcinoma, pancreatic cancer, breast cancer; Cancers with mutations in splicing genes, such as cancers with amplification or fusion of splicing factors, cancers caused by signaling of oncogenic transcription factors, cancers caused by oncogenic splicing variants, cancers with partial or complete deletion of splicing factors and / or genes involved in the regulation of splicing.

[0688] The term "therapy" or "treatment," or as used herein in the context of treating a pathological condition, generally refers to treatment and therapy, whether in humans or animals (e.g., veterinary use), that achieves some desired therapeutic effect, such as inhibiting the progression of a pathological disease or disorder, and includes reducing the rate of progression, stopping the rate of progression, alleviating the symptoms of a disease or disorder, mitigating the disease or disorder, and curing the disease or disorder. Treatment as a preventive measure (i.e., prophylaxis) is also included. For example, the term "treatment" encompasses use in patients who have not yet developed a disease or disorder but are at risk of developing the disease or disorder. For example, treatment includes the prevention of cancer, reducing the incidence of cancer, alleviating the symptoms of cancer, etc.

[0689] As used herein, the term "therapeutically effective amount" refers to that amount of a compound or a material, composition, or dosage form containing the compound that is effective to produce some desired therapeutic effect commensurate with a reasonable benefit / risk ratio when administered in accordance with the desired treatment regimen.

[0690] The term "pharmaceutical composition" is defined herein to refer to a solid or liquid composition containing at least one therapeutic agent, to be administered to a subject, such as a mammal or a human, optionally with one or more pharmaceutically acceptable excipients, for the purpose of preventing or treating a particular disease or condition affecting the mammal.

[0691] As used in this document, the term "pharmaceutically acceptable" refers to entities such as compounds and their salts, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for contact with the tissues of a warm-blooded animal, such as a mammal or a human, without undue toxicity or other morbidity proportionate to a reasonable benefit / risk ratio.

[0692] Compounds of formula (I) can be synthesized by the methods presented below or by analogous methods, for example as shown in Scheme I, as well as using synthetic routes via intermediate (E), as described in the claims, which will be understood by one skilled in the art. The scheme described herein is not an exhaustive list of methods for preparing compounds of formula (I); rather, additional methods known to a skilled chemist can be used to synthesize the compounds.

[0693] One skilled in organic synthesis will appreciate that optimal reaction conditions may vary depending on the specific reagents or solvents used, but such conditions can be determined using routine optimization procedures. In some cases, the order of the following reaction schemes and / or reaction steps may be altered to facilitate the reaction or avoid the formation of undesirable byproducts. Furthermore, the functionality present at various positions on the molecule must be compatible with the proposed reagents and reactions. Such restrictions on substituents compatible with the reaction conditions will be readily apparent to one skilled in the art, and alternative methods should then be employed. Furthermore, in some of the reactions mentioned herein, it may be necessary or desirable to protect any sensitive groups in the compounds, and it is envisaged that such protecting groups (PGs) are present as needed.Conventional protecting groups can be used according to standard practice well known in the art (for an illustration, see Wuts, PGM, Greene's Protective Groups in Organic Synthesis, 5th Edition, Publisher: John Wiley & Sons, 2014). Protecting groups can be removed at any convenient stage of the synthesis using conventional methods well known in the art, or they can be removed at a later stage of the reaction or workup.

[0694] In the general reaction sequence shown in Scheme 1 below, the abbreviations A, T and X and the characteristic groups Ra, Rb, R1 and R2 have the same meanings as defined for formula (I), unless otherwise indicated. The characteristic group E1 has the same meaning as defined in the claims and is typically -OH or a methoxy group, or a halogen atom, a boronic acid, a boronic acid ester or -O-L1, and -O-L1 is a leaving group, in which L1 is selected from perfluoroalkylsulfonyl, such as triflyl (trifluoromethanesulfonyl), and sulfonyl, such as tosyl (p-toluenesulfonyl) or mesyl (methanesulfonyl). The characteristic group E2 is a halogen atom, -OH, -NO2 or -SO2Cl.The characteristic groups R1', R2', R11', R12' and R14' are as defined in the claims for R1, R2, R11, R12 and R14, respectively, with any suitable CG or functional groups allowing the formation of R1, R2, R11, R12 and R14, respectively, and in step 4 of synthesis scheme 1. Other abbreviations used herein are expressly defined or have the meanings defined in the experimental section.

[0695] The compounds of the present invention, their pharmaceutically acceptable salts, solvates and hydrates can be prepared according to the general reaction sequence described below in Scheme 1, followed, if necessary, by:

[0696] - manipulation of substituents to obtain a new end product. These manipulations may include, but are not limited to, reduction, oxidation, alkylation, acylation, substitution, coupling, including coupling reactions with a transition metal catalyst, and hydrolysis reactions, which are generally known to those skilled in the art;

[0697] - removal of any protective groups;

[0698] - formation of a pharmaceutically acceptable salt; or

[0699] - formation of a pharmaceutically acceptable solvate or hydrate.

[0700]

[0701] The necessary starting materials for the synthetic methods described herein, if not commercially available, can be prepared using procedures described in the scientific literature or can be prepared from commercially available compounds using adaptations of processes described in the scientific literature. The reader is further referred to, for example, March J., Smith M., Advanced Organic Chemistry, 7th Edition, Publisher: John Wiley & Sons, 2013, for general recommendations on reaction conditions and reagents.

[0702] Compounds of formula (A), wherein A is -CH2-, are prepared according to methods described in the literature (see, for example, Fukuda et al., Bioorg Med. Chem. Lett. 2018, 28(20), 3333-3337) or by methods known to a person skilled in the art.

[0703] Compounds of formula (A), wherein A is -C(=O)-, can be prepared from compounds of formula (A), wherein A is -CH2-, by oxidation carried out at a temperature of from 0°C to 100°C using an oxidizing agent such as potassium permanganate or tert-butyl hydroperoxide, in a polar solvent such as water, acetone or acetonitrile, or a mixture thereof.

[0704] Compounds of formula (A) wherein E1 is -OH can be prepared from compounds of formula (A) wherein E1 is a methoxy group by demethylation performed at a temperature of from 0°C to 100°C in the presence of a Lewis acid such as aluminum chloride, boron tribromide or boron trifluoride in a solvent such as dichloromethane.

[0705] Compounds of formula (A), wherein E1 is a halogen atom, can be prepared from compounds of formula (A), wherein E1 is an -O-L1 group, through a coupling reaction with a transition metal catalyst. Typical catalysts include palladium(II) acetate, tris(dibenzylideneacetone)dipalladium(0), or the like. The reaction is usually carried out at a temperature of from 0°C to 150°C, more often from 80°C to 120°C.Typically, the reaction is carried out in the presence of a ligand such as di-tert-butyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphane, di-tert-butyl-[2,3,4,5-tetramethyl-6-(2,4,6-triisopropylphenyl)phenyl]phosphane, 2-(dicyclohexylphosphino)biphenyl, 4,5-bis(diphenylphospheno)-9,9-dimethylxanthene or the like and a base such as sodium tert-butoxide, cesium carbonate, potassium carbonate, most commonly cesium carbonate in a wide variety of inert solvents such as toluene, tetrahydrofuran, dioxane, 1,2-dichloroethane, N,N-dimethylformamide, dimethyl sulfoxide, water and acetonitrile or a mixture of solvents, most commonly dioxane. Since coupling reactions between catalysts and transition metals involve numerous components, such as the specific palladium catalyst, ligand, additives, solvent, and temperature, numerous protocols have been established. A skilled artisan can determine a satisfactory protocol without undue experimentation.

[0706] Alternatively, compounds of formula (A), wherein E1 is a halogen atom, can be prepared from compounds of formula (A), wherein E1 is a boronic acid or a boronic acid ester, via a halogenodebonation reaction. The reaction is typically carried out in the presence of copper(II) halides in methanol at a temperature of from 0°C to 100°C, more commonly at 90°C.

[0707] Stage 1:

[0708] Compounds of formula (B), where E2 is a halogen atom and E1 is -OH or a methoxy group, can be prepared from compounds of formula (A), where E1 is -OH or a methoxy group, via an electrophilic aromatic halogenation reaction. The reaction is typically carried out in a mixture of acetic acid and trifluoroacetic acid, using NCS for chlorination, NBS for bromination, and NIS for iodination.

[0709] Compounds of formula (B) wherein E2 is -OH can be prepared from compounds of formula (B) wherein E2 is a halogen atom by a coupling reaction with a transition metal catalyst using the conditions previously described.

[0710] Compounds of formula (B), where E2 is -NO2, can be prepared from compounds of formula (A) by an aromatic nitration reaction. Typically, the nitration reaction is carried out using fuming nitric acid in an acidic solvent such as acetic acid or sulfuric acid.

[0711] Compounds of formula (B), wherein E2 is -SO2Cl, can be prepared from compounds of formula (A), wherein and E1 are -OH or a methoxy group, by an aromatic sulfonylation reaction, usually carried out at a temperature of from -10°C to 110°C using chlorosulfonic acid.

[0712] Stage 2:

[0713] Compounds of formula (C), wherein X is -O-, can be prepared from compounds of formula (B), wherein E1 is -OH, by a substitution reaction with compounds of formula R2'-E3, wherein E3 is a halogen atom or a leaving group -O-L1, wherein L1 is a methanesulfonyl, p-toluenesulfonyl or trifluoromethanesulfonyl group. The reaction is usually carried out at a temperature of from -20°C to 100°C in a dry aprotic solvent such as dichloromethane, acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide or tetrahydrofuran, with or without an inorganic base such as potassium carbonate or cesium carbonate or an organic base such as triethylamine or N,N-diisopropylethylamine.The formation of a mesylate, tosylate or triflate can be achieved by reacting the corresponding alcohol with methanesulfonyl chloride or methanesulfonic anhydride, p-toluenesulfonyl chloride, trifluoromethanesulfonyl chloride or trifluoromethanesulfonic 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 of from -30°C to 80°C.

[0714] Alternatively, compounds of formula (C) wherein X is -O- can be prepared from compounds of formula (B) wherein E1 is -OH and an alcohol via the Mitsunobu coupling (as described in O. Mitsunobu, Synthesis, Vol. 1, pp. 1-28, 1981). The reaction is carried out in the presence of diethyl or diisopropyl azodicarboxylate and triphenylphosphine, in a wide range of solvents such as N,N-dimethylformamide, tetrahydrofuran, 1,2-dimethoxyethane or dichloromethane, and over a wide range of temperatures such as -20°C to 60°C. The reaction can also be carried out using triphenylphosphine on a polymer support.

[0715] Compounds of formula (C), wherein X is -NH- or -N(C1-C4alkyl)-, can be prepared from compounds of formula (B), wherein E1 is a halogen atom or -O-L1, and an amine by a substitution reaction using the conditions previously described.

[0716] Alternatively, compounds of formula (C), wherein X is -NH- or -N(C1-C4alkyl)-, can be prepared from compounds of formula (B), wherein E1 is a halogen atom or -O-L1, and an amine by reacting the compound with a transition metal catalyst using the conditions previously described.

[0717] Alternatively, compounds of formula (C) wherein X is -N(C1-C4 alkyl)- can be prepared from compounds of formula (C) wherein X is -NH- and an alkyl halide via a substitution reaction using the conditions previously described.

[0718] Alternatively, compounds of formula (C), wherein X is -N(C1-C4 alkyl)-, can be prepared from compounds of formula (C), wherein X is -NH-, and an aldehyde, via reductive amination. The reaction is carried out in a solvent system that allows the formed water to be removed by physical or chemical means (e.g., by distillation of a solvent-water azeotrope or in the presence of drying agents such as molecular sieves, magnesium sulfate, or sodium sulfate). Such a solvent is typically toluene, n-hexane, tetrahydrofuran, dichloromethane, N,N-dimethyl formamide, N,N-dimethylacetamide, acetonitrile, 1,2-dichloroethane, or a solvent mixture such as methanol-1,2-dichloroethane. The reaction can be catalyzed by a trace of acid (usually acetic acid). The intermediate imine is reduced sequentially or simultaneously with a suitable reducing agent (e.g. sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride; RO and M.K.Hutchins, Comprehensive Organic Synthesis, B. M. Trost, I. Fleming, Eds; Pergamon Press: New York (1991), vol. 8, pp. 25–78) or by hydrogenation over a noble metal catalyst such as palladium on activated carbon. The reaction is typically carried out at temperatures from -10°C to 110°C, preferably from 0°C to 60°C. The reaction can also be carried out in a single vessel. It can also be carried out in protic solvents such as methanol or water in the presence of a picoline-borane complex (Tetrahedron, 2004, 60, 7899).

[0719] Compounds of formula (C), wherein X is -CH2- or -C(=CH2)-, can be prepared from compounds of formula (B), wherein E1 is a halogen atom or -O-L1, and a boronic acid via the Suzuki reaction. The Suzuki reaction is a palladium-catalyzed cross-coupling of organoboronic acids with aryl or vinyl halides or triflates. Typical catalysts include palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium(II) dichloride, and [1,1'bis(diphenylphosphino)ferrocene]dichloropalladium(II). The reaction can be carried out in a variety of organic solvents, including toluene, tetrahydrofuran, dioxane, 1,2-dichloroethane, N,N-dimethylformamide, dimethyl sulfoxide, and acetonitrile, as well as aqueous solvents and under biphasic conditions. Reactions are typically carried out at temperatures ranging from room temperature to 150°C. Additives such as cesium fluoride, potassium fluoride, potassium hydroxide, or sodium ethoxide often accelerate the coupling reaction.Potassium trifluoroborates and organoboranes or boronate esters can be used instead of boronic acids. Although the Suzuki reaction involves numerous components, such as the specific palladium catalyst, ligand, additives, solvent, and temperature, numerous protocols have been developed. A skilled artisan will be able to determine a satisfactory protocol without undue experimentation.

[0720] Alternatively, compounds of formula (C), wherein X is -CH2- or -C(=CH2)-, can be prepared from compounds of formula (B), wherein E1 is a boronic acid, and compounds of formula R2'-E3, wherein E3 is a halogen or triflate, by a Suzuki reaction using the conditions previously described.

[0721] Compounds of formula (C), wherein X is -C(=O)- or -CN, can be prepared from compounds of formula (B), wherein E1 is a halogen atom, by a coupling reaction with a transition metal catalyst using the conditions previously described.

[0722] Stage 3a:

[0723] Compounds of formula (D-1), wherein R12' and R13 are as defined in the claims for R12 and R13, with any suitable CG or functional groups allowing the formation of R12 at a later stage of the synthesis, can be prepared from compounds of formula (C), wherein E2 is a halogen atom, by a Suzuki reaction using the conditions previously described.

[0724] Stage 3b:

[0725] Compounds of formula (D-2) wherein R1' is not -H can be prepared from compounds of formula (C) wherein E2 is -OH by a substitution reaction using the conditions previously described.

[0726] Stage 3c:

[0727] Compounds of formula (D-3), wherein R1' and R11' are -H, can be prepared from compounds of formula (C), wherein E2 is -NO2, by reducing the nitro group. Typical reducing agents that can be used for such a reaction are an alkali metal hydride such as lithium aluminum hydride or sodium borohydride in the presence of cobalt(II) chloride or nickel(II) chloride, or a metal such as iron or zinc in an acidic medium such as hydrochloric acid or acetic acid. Alternatively, the nitro group can be reduced to an amine by hydrogenation over a noble metal catalyst such as palladium on activated carbon, Raney nickel, or platinum oxide. The catalytic hydrogenation reaction can be carried out in a solvent such as ethanol, methanol, or ethyl acetate at ambient temperature. In addition, additional reagents such as aluminum amalgam or iron sulfate can also be used to reduce the nitro group.

[0728] Compounds of formula (D-3), wherein R1' has the meaning defined in the claims for R1, with any suitable CG or functional groups allowing R1 to be formed later in the synthesis, and R11' is -H, can be prepared from compounds of formula (D-3) wherein R1' and R11' are -H, via reductive amination, substitution or coupling reactions.

[0729] In the case of amide coupling reactions, the reaction occurs with a carboxylic acid derivative in the presence of an activating agent such as N,N'-dicyclohexylcarbodiimide or N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride with the optional addition of 1-hydroxybenzotriazole. Other suitable coupling agents such as O-(7-azabenzotriazol-1-yl)-N, N, N', N'-tetramethyluronium hexafluorophosphate, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, carbonyldiimidazole or diethylphosphoryl cyanide can be used. A base such as triethylamine, N,N-diisopropylethylamine or pyridine can be optionally added to achieve the coupling. The amide coupling is carried out at a temperature from -20°C to 100°C in an inert solvent, preferably a dry aprotic solvent such as dichloromethane, acetonitrile, N,N-dimethylformamide and chloroform.Alternatively, the carboxylic acid can be activated by conversion to the corresponding acid chloride (by reaction with oxalyl chloride or thionyl chloride) or to the corresponding activated ester, such as N-hydroxysuccinimidyl ester (Org. Process Res. & Dev., 2002, 863) or benzothiazolyl thioester (J. Antibiotics, 2000, 1071). The formed activated entity can be reacted at a temperature of from -20°C to 100°C with a compound of formula (D-3), where R1' and R11' are -H, in an aprotic solvent such as dichloromethane, chloroform, acetonitrile, N,N-dimethylformamide and tetrahydrofuran. To achieve coupling, a base such as triethylamine, N,N-diisopropylethylamine, pyridine, sodium hydroxide, sodium carbonate or potassium carbonate can be optionally added.

[0730] Compounds of formula (D-3), wherein R1' and R11' are as defined in the claims for R1 and R11, with any suitable CG or functional groups that allow the formation of R1 and R11 at a later stage of the synthesis, can be prepared from compounds of formula (D-3), wherein R1' and R11' are -H, by reductive amination, substitution or coupling reactions.

[0731] Furthermore, compounds of formula (D-3), wherein R1' is -H and R11' has the meaning defined in the claims for R11, with any suitable CG or functional groups that provide the formation of R11 at a later stage of the synthesis, can be reacted with sulfonyl chlorides. Subsequent removal of any CG or modification of functional groups can lead to the preparation of compounds of formula (I), wherein T is -N(R11)-S(O)2- .

[0732] Stage 3d:

[0733] Compounds of formula (D-4) can be prepared from compounds of formula (C) wherein E2 is a halogen atom by a substitution reaction or a coupling reaction with a transition metal catalyst using the conditions described above.

[0734] A compound of formula (D-4) wherein R1' is not -H can be obtained from compounds of formula (D-4) wherein R1' is -H through a substitution reaction.

[0735] Stage 3e:

[0736] In the compounds of formula (D-5), R1' is not -H. Compounds of formula (D-5) can be prepared from compounds of formula (D-4), wherein R1' is not -H, by an oxidation reaction carried out at a temperature of from 0°C to 100°C using oxidizing agents such as hydrogen peroxide, potassium permanganate, sodium perborate, potassium hydropersulfate in polar solvents such as water, acetone, acetonitrile, dichloromethane or ethanol. Depending on the oxidation conditions, the corresponding sulfoxide analogs (D-5) and (I-e) can also be obtained.

[0737] Stage 3f:

[0738] Compounds of formula (D-6), wherein R1' and R14' are as defined in the claims for R1 and R14, with any suitable CG or functional groups that provide for the formation of R1 and R14, can be prepared from compounds of formula (C), wherein E2 is -SO2Cl and an amine via a coupling reaction.

[0739] Stage 3g:

[0740] Compounds of formula (D-7), wherein R1' and R14' are as defined in the claims for R1 and R14, with any suitable CG or functional groups providing for the formation of R1 and R14, can be prepared from compounds of formula (C), wherein E2 is a halogen atom, by an aryl carbonylation reaction followed by a coupling reaction with an amine using the conditions previously described.

[0741] Stage 4a-g:

[0742] Compounds of formula (Iag) can be prepared from compounds of formula (D-1-7) respectively after removing any protecting groups or further modifying the substituents R1', R2', R11', R12' and R14'.

[0743] All aspects and embodiments of the invention described herein may be combined in any combination where possible.

[0744] This document cites a number of publications to more fully describe and disclose the invention and the prior art to which the invention pertains. Each of these references is hereby incorporated by reference in its entirety, to the same extent as if each individual reference were specifically and individually indicated to be incorporated by reference.

[0745] Specific embodiments of the invention are described in the following examples, which serve to illustrate the invention in more detail and should not be construed as limiting the invention in any way.

[0746] Brief description of graphic materials

[0747] Figure 1: Figure 1 shows a representative Western blot showing the reduction of phosphorylated-SRSFG (P-SRSF6) in MDA-MB 468 cells in response to compounds of the invention. GAPDH was tested by Western blotting to control for equal protein loading and sample normalization. Numbers below the blots indicate the percentage inhibition of P-SRSF6 signal at 100 nM (A) or 10 nM (B) compared to the DMSO control.

[0748] Figure 2: Figure 2 shows the changes in tumor volume (TV) and body weight (BW) of female NOD / SCID mice treated with vehicle or 45 mg / kg sample 13 twice daily* twice a week on days 1 to 10 and 50 mg / kg sample 13 twice daily* twice a week on days 11 to 22. NOD / SCID mice weighing approximately 23 g were inoculated with 1×10 7 SW480 human colorectal cancer cells in 50% Matrigel™ subcutaneously in the flank. Pairs were compared when the tumors reached an average volume of 100-150 mm 3to assign animals to treatment and vehicle control groups (n=8 / group). Tumor volumes (expressed in mm 3 ) were measured twice weekly with a caliper on days 1, 4, 8, 11, 15, 18, 22, and 23 of the treatment period. (A) Mean VO values ​​(± standard error of the mean (SEM)) for each treatment group are shown. Tumor volumes treated with sample 13, 45 mg / kg twice daily* twice weekly, decreased continuously during the treatment period compared with tumor volumes in the vehicle group. (B) Percent changes in BW (expressed in g, ± SEM) on days 1, 4, 8, 11, 15, 18, 22, and 23 of the treatment period. (C) Changes in VO after treatment with vehicle and sample 13, expressed in mm 3 The ratio of OO after treatment with sample 13 and the control vehicle (K / N) is indicated.

[0749] Sample preparation

[0750] All reagents and solvents are generally used as received from the commercial supplier;

[0751] Reactions are generally carried out with anhydrous solvents in well-dried glassware under argon or nitrogen atmosphere unless otherwise stated;

[0752] evaporation is carried out by rotary evaporation under reduced pressure, and the processing procedures are carried out after removing the residual solids by filtration;

[0753] All temperatures are in degrees Celsius (°C) and are approximate; unless otherwise stated, experiments are conducted at room temperature (RT), which is generally in the range of 18°C ​​- 25°C;

[0754] Column chromatography (flash method) is used to purify compounds;

[0755] Classical flash chromatography is often replaced by automated systems. This does not change the separation process itself. A specialist in this field can replace the classical flash chromatography process with an automated one, and vice versa. Typical automated systems can be used, such as those provided by or Isco (combif1ash);

[0756] The reaction mixture can often be separated by preparative HPLC, using, for example, water and acetonitrile as the eluent system, unless otherwise specified. Those skilled in the art will find suitable conditions for each separation; the compounds are isolated after purification as the starting compound or as the corresponding trifluoroacetic acid (TFA) salt or the corresponding formate salt;

[0757] Reactions requiring higher temperatures are usually carried out using classical heating devices; but they can also be carried out using microwave equipment (CEM Explorer) at a power of 250 W, unless otherwise specified;

[0758] The hydrogenation or hydrogenolysis reactions can be carried out using hydrogen gas in a cylinder or using a Parr apparatus system or other suitable hydrogenation equipment;

[0759] Concentration of solutions and drying of solids are carried out under reduced pressure unless otherwise specified;

[0760] In general, the progress of reactions is monitored by TLC, HPLC or LC / MS, and the reaction times are for illustrative purposes only; the yield is for illustrative purposes only and is not necessarily the maximum achievable;

[0761] The structure and purity of the final products of the invention are usually confirmed by NMR spectroscopy, HPLC and mass spectroscopy.

[0762] Proton NMR spectra were recorded on a Brucker 400 MHz spectrometer. Chemical shifts (δ) are reported in ppm relative to Me4Si or the solvent peak as an internal standard, and NMR coupling constants (J values) are reported in Hertz (Hz). Each peak is designated as a broad singlet (b), singlet (s), doublet (d), triplet (t), quadruplet (q), doublet of doublets (dd), triplet of doublets (td), or multiplet (m).

[0763] HPLC analysis of the final products was performed using a Dionex Ultimate 3000 instrument in combination with the Dionex MSQ ESI mode and the following conditions:

[0764]

[0765] Mass spectra were obtained on a q-Tof Ultima mass spectrometer (Waters AG or Thermo Scientific MSQ Plus) in positive or negative ESI mode. The system is equipped with a standard Lockspray interface;

[0766] Each intermediate is purified to the standard required for the subsequent step and characterized in sufficient detail to confirm the correctness of the determined structure;

[0767] Analytical and preparative HPLC on non-chiral phases is carried out on columns based on RP-C18;

[0768] The following abbreviations may be used (you may also refer to the Guide for Authors of the Journal of Organic Chemistry for a complete list of standard abbreviations and acronyms):

[0769]

[0770]

[0771]

[0772]

[0773] The following examples refer to compounds of formula (I) as shown in Table 1.

[0774] The examples listed in the following table can be prepared using the procedures described above, and the detailed synthesis methodology is described below. Example numbers used in the leftmost column are used throughout the application to identify the corresponding compounds.

[0775]

[0776]

[0777]

[0778]

[0779]

[0780]

[0781]

[0782]

[0783]

[0784]

[0785]

[0786]

[0787]

[0788]

[0789]

[0790]

[0791]

[0792]

[0793]

[0794]

[0795]

[0796]

[0797]

[0798]

[0799]

[0800]

[0801]

[0802]

[0803]

[0804]

[0805]

[0806]

[0807]

[0808]

[0809]

[0810]

[0811]

[0812]

[0813]

[0814]

[0815] Preparation of Example 1: 8-methoxy-5,5,7-trimethyl-6H-benzo[h]quinazolin-4-amine:

[0816]

[0817] Step 1: Preparation of 2-[2-(3-methoxyphenyl)-1,1-dimethylethyl]propane dinitrile:

[0818] 3-Methoxybenzylmagnesium chloride (96 mL, 24 mmol, 0.25 M in THF) was added dropwise at 0 °C to a stirred solution of isopropylidenemalononitrile (2 g, 18.5 mmol) in THF (50 mL). The resulting solution was stirred at room temperature for 3 h. Then, 1 N aqueous HCl solution was added at 0 °C, and the resulting mixture was concentrated. The residue was extracted with EA and H2O. The combined organic layers were dried over Na2SO4, filtered, concentrated, and purified by column chromatography (silica gel; PE:EA; 5:1; v:v) to give 2-[2-(3-methoxyphenyl)-1,1-dimethylethyl]propane dinitrile as a yellow oil (1.69 g, yield 38%).

[0819] 1 H NMR (400 MHz, CDCl3) δ ppm: 7.27 (m, 1H), 6.86 (m, 1H), 6.79 (d, J=7.6 Hz, 1H), 6.74 (m, 1H), 3.82 (s, 3H), 3.44 (s, 1H), 2.81 (s, 2H), 1.29 (s, 6H).

[0820] MS m / z (+IER): 229.1 [M+H] + .

[0821] Step 2: Preparation of 1-amino-6-methoxy-3,3-dimethyl-4H-naphthalene-2-carbonitrile:

[0822] TfOH (1.04 g, 6.24 mmol) was added to a stirred solution of 2-[2-(3-methoxyphenyl)-1,1-dimethylethyl]propane dinitrile (300 mg, 1.25 mmol) in DCM (6 mL) at 0 °C, and the resulting mixture was stirred at 0 °C for 2 h. Saturated aqueous NaHCO3 solution was added, and the mixture was extracted with DCM. The combined organic layers were dried over Na2SO4, filtered, and concentrated to give 1-amino-6-methoxy-3,3-dimethyl-4H-naphthalene-2-carbonitrile as a yellow solid (300 mg, 95% yield), which was used in the next step without further purification.

[0823] 1 H NMR (400 MHz, CDCl3) δ ppm: 7.31 (d, J=8.8 Hz, 1H), 6.81 (m, 1H), 6.74 (d, J=2.4 Hz, 1H), 4.51 (br., 2H), 3.85 (s, 3H), 2.69 (s, 2H), 1.17 (s, 6H).

[0824] MS m / z (+IER): 229.1 [M+H] + .

[0825] Step 3: Preparation of 8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine:

[0826] A suspension of 1-amino-6-methoxy-3,3-dimethyl-4H-naphthalene-2-carbonitrile (1 g, 3.94 mmol) and formamide (19 mL, 473 mmol) was stirred at 180°C for 8 h. After cooling to room temperature, the reaction mixture was diluted with H2O and extracted with EA. The combined organic layers were dried over Na2SO4, filtered, concentrated, and purified by column chromatography (silica gel; PE:EA; 1:1; v:v) to give 8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine as a light yellow solid (700 mg, yield 63%).

[0827] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 8.24 (s, 1H), 7.99 (d, J=8.8 Hz, 1H), 6.86 (m, 1H), 6.79 (d, J=2.8 Hz, 1H), 6.37 (br., 2H), 3.79 (s, 3H), 2.75 (s, 2H), 1.28 (s, 6H).

[0828] MS m / z (+IER): 256.1 [M+H] + .

[0829] Step 4: Preparation of 7-iodo-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine and 9-iodo-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine:

[0830] NIS (1.21 g, 5.29 mmol) was added portionwise to a stirred solution of 8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine (300 mg, 1.06 mmol) in AcOH (5 mL) and TFA (0.3 mL). After 20 h, the solvent was removed, the residue was dissolved in H2O and neutralized with saturated aqueous K2CO3 before extraction with EA. The combined organic layers were dried over Na2SO4, filtered, and concentrated to give a mixture of 7-iodo-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine and 9-iodo-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine (1:4 ratio) as a light yellow solid (403 mg, 79% yield).

[0831] MS m / z (+IER): 276.1,278.1 [M+H] + .

[0832] Step 5: Preparation of 8-methoxy-5,5,7-trimethyl-6H-benzo[h]quinazolin-4-amine:

[0833] CH3B(OH)2(22 mg, 0.35 mmol) was added to a stirred solution of a mixture of 7-iodo-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine and 9-iodo-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine (ratio 1:4) in dioxane (5 mL) and H2O (1 mL), followed by the addition of K3PO4(63 mg, 0.30 mmol) and Pd(dppf)Cl2(219 mg, 0.30 mmol). After stirring for 20 h at 90°C, the reaction mixture was filtered through decalite, concentrated and purified by preparative HPLC to give 8-methoxy-5,5,7-trimethyl-6H-benzo[h]quinazolin-4-amine as a white solid (79 mg, 6% yield).

[0834] 1 H NMR (400 MHz, DMSO-d6+D2O) δ ppm: 8.28 (s, 1H), 7.89 (d, J=8.8 Hz, 1H), 6.94 (d, J=8.8 Hz, 1H), 3.82 (s, 3H), 2.75 (s, 2H), 2.13 (s, 3H), 1.27 (s, 6H).

[0835] MS m / z (+IER): 270.1 [M+H] + .

[0836] Preparation of Example 2: 8-methoxy-5,5-dimethyl-6H-benzo[h]quinazoline-4,7-diamine:

[0837]

[0838] Step 1: Preparation of 8-methoxy-5,5-dimethyl-7-nitro-6H-benzo[h]quinazolin-4-amine:

[0839] HNO3 (14.6 mL, 228.2 mmol) was added dropwise at 0°C to a stirred solution of 8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine (4.5 g, 17.55 mmol) in H2SO4 (29 mL), followed by the addition of H2O (14.5 mL). After stirring for 2 h at room temperature, the reaction mixture was poured into a saturated aqueous NaHCO3 solution and extracted with EA. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel; DCM:EA; 10:1 to 0:1; v:v) to give 8-methoxy-5,5-dimethyl-7-nitro-6H-benzo[h]quinazolin-4-amine as an off-white solid (640 mg, 11% yield).

[0840] 1 H NMR (400 MHz, DMSO-d6+D2O) δ ppm: 8.51 (s, 1H), 8.11 (d, J=8.8 Hz, 1H), 7.41 (d, J=8.8 Hz, 1H), 3.95 (s, 3H), 2.71 (s, 2H), 1.27 (s, 6H).

[0841] MS m / z (+IER): 301.2 [M+H]+ .

[0842] Step 2: Preparation of 8-methoxy-5,5-dimethyl-6H-benzo[h]quinazoline-4,7-diamine:

[0843] Zinc (300 mg, 4.49 mmol) was added to a stirred solution of 8-methoxy-5,5-dimethyl-7-nitro-6H-benzo[h]quinazolin-4-amine (300 mg, 0.15 mmol) in EtOH (10 mL) and AcOH (3 mL). After stirring for 4 h, the reaction mixture was filtered, concentrated, and purified by preparative HPLC to afford 8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-4,7-diamine as a light yellow solid (178 mg, 66% yield).

[0844] 1 H NMR (400 MHz, DMSO-d6+D2O) δ ppm: 8.53 (s, 1H), 7.19 (d, J=8.4 Hz, 1H), 6.96 (d, J=8.4 Hz, 1H), 3.87 (s, 3H), 2.72 (s, 2H), 1.29 (s, 6H).

[0845] MS m / z (+IER): 271.1 [M+H] + .

[0846] Preparation of Examples 3 and 4: 6,6-dimethyl-2,3,4,5-tetrahydroquinazolino[7,8-f][1,4]benzoxazin-7-amine and 4,6,6-trimethyl-3,5-dihydro-2H-quinazolino[7,8-f][1,4]benzoxazin-7-amine:

[0847]

[0848] Step 1: Preparation of 4-amino-5,5-dimethyl-6H-benzo[h]quinazolin-8-ol:

[0849] BBr3 (1 M in DCM, 4.8 mL, 4.80 mmol) was added dropwise at -40°C to a stirred solution of 8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine (450 mg, 1.58 mmol) in DCM (30 mL). The resulting solution was stirred at rt for 18 h. Saturated aqueous NaHCO3 was added, and the resulting green solid was collected by filtration, washed with H2O, and dried under reduced pressure to give 4-amino-5,5-dimethyl-6H-benzo[h]quinazolin-8-ol (350 mg, yield 82%).

[0850] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 8.21 (s, 1H), 7.88 (d, J=8.4 Hz, 1H), 6.67 (m, 1H), 6.59 (s, 1H), 6.29 (b, 2H), 2.67 (s, 2H), 1.26 (s, 6H).

[0851] MS m / z (+IER): 242.2 [M+H] + .

[0852] Step 2: Preparation of 4-amino-7-chloro-5,5-dimethyl-6H-benzo[h]quinazolin-8-ol:

[0853] NCS (1.07 g, 7.96 mmol) was added portionwise to a stirred solution of 4-amino-5,5-dimethyl-6H-benzo[h]quinazolin-8-ol (2 g, 6.63 mmol) in AcOH (40 mL) and TFA (10 mL). After stirring for 3 h, the solvent was removed and the residue was purified by Combiflash to give 4-amino-7-chloro-5,5-dimethyl-6H-benzo[h]quinazolin-8-ol as a white solid (1.83 g, 15% yield).

[0854] MS m / z (+IER): 276.1, 278.1 [M+H] + .

[0855] Step 3: Preparation of tert-butyl N-[2-[(4-amino-7-chloro-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl)oxy]ethyl]carbamate:

[0856] tert-Butyl N-(2-bromoethyl)carbamate (226 mg, 0.98 mmol) was added to a stirred solution of 4-amino-7-chloro-5,5-dimethyl-6H-benzo[h]quinazolin-8-ol (250 mg, 0.82 mmol) in DMF (5 mL), followed by the addition of Cs2CO3 (543 mg, 1.63 mmol). After stirring for 20 h, the solvent was removed and the residue was purified by Combiflash to give tert-butyl N-[2-[(4-amino-7-chloro-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl)oxy]ethyl]carbamate as a white solid (342 mg, yield 79%).

[0857] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 8.27 (s, 1H), 8.02 (d, J=8.4 Hz, 1H), 7.11 (d, J=8.4 Hz, 1H), 6.98 (b, 1H), 6.50 (b, 2H), 4.09 (t, J=5.2 Hz, 2H), 3.33 (t, J=5.2 Hz, 2H), 2.91 (s, 2H), 1.38 (s, 9H), 1.30 (s, 6H).

[0858] MS m / z (+IER): 419.2, 421.3 [M+H] + .

[0859] Step 4: Preparation of 8-(2-aminoethoxy)-7-chloro-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine:

[0860] A solution of tert-butyl N-[2-[(4-amino-7-chloro-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl)oxy]ethyl]carbamate (300 mg, 0.64 mmol) in TFA (3 mL) was stirred for 1 h before concentration and purification by preparative HPLC to give 8-(2-aminoethoxy)-7-chloro-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine as a white solid (300 mg, yield 98%).

[0861] MS m / z (+IER): 319.2, 321.2 [M+H] + .

[0862] Step 5: Preparation of 6,6-dimethyl-2,3,4,5-tetrahydroquinazolino[7,8-f][1,4]benzoxazin-7-amine:

[0863] t-BuOK (285 mg, 2.94 mmol) was added to a stirred solution of 8-(2-aminoethoxy)-7-chloro-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine (280 mg, 0.59 mmol) in dioxane (10 mL), followed by the addition of Pd2(dba)3 (55 mg, 0.06 mmol) and Xant-Phos (70 mg, 0.12 mmol). After stirring for 18 h at 120°C, the reaction mixture was filtered through decalite, concentrated and purified by preparative HPLC to give 6,6-dimethyl-2,3,4,5-tetrahydroquinazolino[7,8-f][1,4]benzoxazin-7-amine as a light yellow solid (166 mg, 36% yield).

[0864] 1 H NMR (400 MHz, DMSO-d6+D2O) δ ppm: 8.52 (s, 1H), 7.10 (d, J=8.4 Hz, 1H), 6.79 (d, J=8.4 Hz, 1H), 4.18 (t, J=4.4 Hz, 2H), 3.33 (t, J=4.4 Hz, 2H), 2.66 (s, 2H), 1.29 (s, 6H).

[0865] MS m / z (+IER): 283.2 [M+H] + .

[0866] Step 6: Preparation of 4,6,6-trimethyl-3,5-dihydro-2H-quinazolino[7,8-f][1,4]benzoxazin-7-amine:

[0867] To a stirred solution of 6,6-dimethyl-2,3,4,5-tetrahydroquinazolino[7,8-f][1,4]benzoxazin-7-amine (38 mg, 0.13 mmol) in MeOH (5 mL) was added H2CO (11 mg, 0.13 mmol), followed by NaBH3CN (9 mg, 0.13 mmol). After stirring for 1 h, the reaction mixture was concentrated and purified by preparative HPLC to give 4,6,6-trimethyl-3,5-dihydro-2H-quinazolino[7,8-f][1,4]benzoxazin-7-amine as a white solid (29 mg, yield 72%).

[0868] 1 H NMR (400 MHz, DMSO-d6+D2O) δ ppm: 8.54 (s, 1H), 7.42 (d, J=8.4 Hz, 1H), 6.92 (d, d=8.4 Hz, 1H), 4.20 (t, J=4.4 Hz, 2H), 3.09 (t, J=4.4 Hz, 2H), 2.84 (s, 2H), 2.63 (s, 3H), 1.28 (s, 6H).

[0869] MS m / z (+IER): 297.2 [M+H] + .

[0870] Preparation of Example 5: 8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazoline-4,7-diamine:

[0871]

[0872] Step 1: Preparation of [cis-4-(tert-butoxycarbonylamino)cyclohexyl]4-methylbenzenesulfonate:

[0873] TsCl (139 g, 721 mmol) was added portionwise to a stirred solution of tert-butyl N-(cis-4-hydroxycyclohexyl)carbamate (80 g, 360 mmol) in DCM (300 mL), followed by the addition of TEA (152 mL, 1081 mmol) and DMAP (4.5 g, 36 mmol). After stirring for 24 h, the reaction mixture was filtered. The filtrate was concentrated, and the residue was purified by column chromatography (silica gel; PE:EA; 10:1; v:v) to give [cis-4-(tert-butoxycarbonylamino)cyclohexyl]4-methylbenzenesulfonate as a white solid (105 g, yield 71%).

[0874] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.78 (d, J=8.0 Hz, 2H), 7.47 (d, J=8.0 Hz, 2H), 6.81 (d, J=7.2 Hz, 1H), 4.58 (m, 1H), 3.24 (m, 1H), 2.41 (s, 3H), 1.66 (m, 2H), 1.51 (m, 4H), 1.41 (m, 2H), 1.36 (s, 9H).

[0875] MS m / z (+IER): 370.1 [M+H] + .

[0876] Step 2: Preparation of 4-amino-5,5-dimethyl-7-nitro-6H-benzo[h]quinazolin-8-ol:

[0877] The title compound was obtained as a light yellow solid (260 mg, yield 35%) according to Scheme 1 and in analogy with Example 2 (step 1) using 4-amino-5,5-dimethyl-6H-benzo[h]quinazolin-8-ol (700 mg, 2.32 mmol) as a starting material.

[0878] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 12.76 (br, 1H), 8.27 (s, 1H), 8.09 (d, J=8.4 Hz, 1H), 7.01 (d, J=8.4 Hz, 1H), 6.54 (br, 2H), 2.62 (s, 2H), 1.27(s, 6H).

[0879] MS m / z (+IER): 287.2 [M+H] + .

[0880] Step 3: Preparation of tert-butyl N-[trans-4-[(4-amino-5,5-dimethyl-7-nitro-6H-benzo[h]quinazolin-8-yl)oxy]cyclohexyl]carbamate:

[0881] Cs2CO3(820 mg, 2.45 mmol) was added to a stirred solution of 4-amino-5,5-dimethyl-7-nitro-6H-benzo[h]quinazolin-8-ol (260 mg, 0.82 mmol) and [cis-4-(tert-butoxycarbonylamino)cyclohexyl]4-methylbenzenesulfonate (2.0 g, 4.90 mmol) in DMF (8 mL) and ACN (8 mL). After stirring for 40 h at 80°C, the reaction mixture was filtered. The filtrate was concentrated and the residue was purified using Combiflash to give tert-butyl N-[trans-4-[(4-amino-5,5-dimethyl-7-nitro-6H-benzo[h]quinazolin-8-yl)oxy]cyclohexyl]carbamate as a light yellow solid (400 mg, 91% yield).

[0882] MS m / z (+IER): 484.4 [M+H] + .

[0883] Step 4: Preparation of tert-butyl N-[trans-4-[(4,7-diamino-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl)oxy]cyclohexyl]carbamate:

[0884] Pd(OH)2(20% on carbon, 52 mg, 0.07 mmol) was added to a stirred solution of tert-butyl N-[trans-4-[(4-amino-5,5-dimethyl-7-nitro-6H-benzo[h]quinazolin-8-yl)oxy]cyclohexyl]carbamate (400 mg, 0.74 mmol) in MeOH (10 mL) and EA (10 mL). After stirring for 20 h under a stream of hydrogen, the catalyst was removed by filtration and the solution was concentrated to give tert-butyl N-[trans-4-[(4,7-diamino-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl)oxy]cyclohexyl]carbamate as a light yellow solid (340 mg, 96% yield), which was used in the next step without further purification.

[0885] MS m / z (+IER): 454.3 [M+H] + .

[0886] Step 5: Preparation of 8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazoline-4,7-diamine:

[0887] The title compound was obtained as a light yellow solid (246 mg, yield 97%) according to Scheme 1 and in analogy with Example 4 (step 4) using tert-butyl N-[trans-4-[(4,7-diamino-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl)oxy]cyclohexyl]carbamate (340 mg, 0.71 mmol) as a starting material.

[0888] 1 H NMR (400 MHz, DMSO-d6+D2O) δ ppm: 8.54 (s, 1H), 7.18 (d, J=8.8 Hz, 1H), 7.04 (d, J=8.8 Hz, 1H), 4.39 (m, 1H), 3.09 (m, 1H), 2.72 (s, 2H), 2.12 (m, 2H), 2.00 (m, 2H), 1.50 (m, 4H), 1.29 (s, 6H).

[0889] MS m / z (+IER): 354.3 [M+H] + .

[0890] Preparation of Example 6: N-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]acetamide:

[0891]

[0892] HATU (75 mg, 0.19 mmol) was added to a stirred solution of tert-butyl N-[trans-4-[(4,7-diamino-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl)oxy]cyclohexyl]carbamate (80 mg, 0.16 mmol) in DMF (2 mL), followed by the addition of NaHCO3 (26.9 mg, 0.32 mmol) and AcOH (19.3 mg, 0.32 mmol). After stirring for 1 h, the reaction mixture was extracted with EA and H2O. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was dissolved in DCM (1 mL) and TFA (1 mL). After stirring for 1 h, the reaction mixture was concentrated and purified by preparative HPLC to give N-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]acetamide as a white solid (29 mg, 44% yield).

[0893] 1 H NMR (400 MHz, DMSO-d6+D2O) δ ppm: 8.52 (s, 1H), 7.77 (d, J=8.8 Hz, 1H), 7.21 (d, J=8.8 Hz, 1H), 4.39 (m, 1H), 3.09 (m, 1H), 2.62 (s, 2H), 2.07 (m, 2H), 2.04 (s, 3H), 1.97 (m, 2H), 1.48 (m, 4H), 1.26 (s, 6H).

[0894] MS m / z (+IER): 396.2 [M+H] + .

[0895] Preparation of Example 7: 8-(trans-4-aminocyclohexoxy)-N7,N7-diethyl-5,5-dimethyl-6H-benzo[h]quinazoline-4,7-diamine:

[0896]

[0897] Stage 1: Preparation of tert-butyl N-[trans-4-[[4-amino-7-(diethylamino)-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate:

[0898] NaBH3CN (8 mg, 0.12 mmol) was added to a stirred solution of acetaldehyde (27 μL, 0.48 mmol) and tert-butyl N-[trans-4-[(4,7-diamino-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl)oxy]cyclohexyl]carbamate (60 mg, 0.12 mmol) in MeOH (5 mL). After stirring for 2 h, the solvent was removed and the crude product was extracted with EA and H2O. The combined organic layers were dried over Na2SO4, filtered, and concentrated to give tert-butyl N-[trans-4-[[4-amino-7-(diethylamino)-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate as a white solid (60 mg, 89% yield), which was used in the next step without further purification.

[0899] MS m / z (+IER): 510.3 [M+H] + .

[0900] Step 2: Preparation of 8-(trans-4-aminocyclohexoxy)-N7,N7-diethyl-5,5-dimethyl-6H-benzo[h]quinazoline-4,7-diamine:

[0901] The title compound was obtained as a light yellow solid (44 mg, yield 99%) according to Scheme 1 and in analogy with Example 4 (step 4), using tert-butyl N-[trans-4-[[4-amino-7-(diethylamino)-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate (60 mg, 0.11 mmol) as a starting material.

[0902] 1 H NMR (400 MHz, DMSO-d6+D2O) δ ppm: 8.54 (s, 1H), 7.71 (d, J=8.8 Hz, 1H), 7.20 (d, J=8.8 Hz, 1H), 4.49 (m, 1H), 3.20 (m, 2H), 3.11 (m, 1H), 2.98 (m, 4H), 2.14 (m, 2H), 1.98 (m, 2H), 1.50 (m, 4H), 1.26 (s, 6H), 0.84 (t, J=7.2 Hz, 6H).

[0903] MS m / z (+IER): 410.3 [M+H] + .

[0904] Preparation of Example 8: 8-(trans-4-aminocyclohexoxy)-N7-ethyl-5,5-dimethyl-6H-benzo[h]quinazoline-4,7-diamine:

[0905]

[0906] Step 1: Preparation of tert-butyl N-[trans-4-[[4-amino-7-(ethylamino)-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate:

[0907] To a stirred solution of tert-butyl N-[trans-4-[(4,7-diamino-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl)oxy]cyclohexyl]carbamate (60 mg, 0.12 mmol) in MeOH (5 mL) was added acetaldehyde (5 mg, 0.12 mmol). After stirring for 2 h, NaBH3CN (8 mg, 0.12 mmol) was added. After stirring for 1 h, the solvent was removed and the crude product was extracted with EA and H2O. The combined organic layers were dried over Na2SO4, filtered and concentrated to give tert-butyl N-[trans-4-[[4-amino-7-(ethylamino)-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate as a white solid (60 mg, 84% yield).

[0908] MS m / z (+IER): 482.2 [M+H] + .

[0909] Step 2: Preparation of 8-(trans-4-aminocyclohexoxy)-N7-ethyl-5,5-dimethyl-6H-benzo[h]quinazoline-4,7-diamine:

[0910] The title compound was obtained as an off-white solid (38 mg, yield 97%) according to Scheme 1 and in analogy with Example 4 (step 4), using tert-butyl N-[trans-4-[[4-amino-7-(ethylamino)-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate (60 mg, 0.10 mmol) as a starting material.

[0911] 1 H NMR (400 MHz, DMSO-d6+D2O) δ ppm: 8.50 (s, 1H), 7.68 (d, J=8.8 Hz, 1H), 7.25 (d, J=8.8 Hz, 1H), 4.49 (m, 1H), 3.12 (m, 3H), 2.86 (s, 2H), 2.13 (m, 2H), 2.00 (m, 2H), 1.52 (m, 4H), 1.28 (s, 6H), 1.10 (t, J=7.2 Hz, 3H).

[0912] MS m / z (+IER): 382.2 [M+H] + .

[0913] Preparation of Example 9: 8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-7-(1-piperidyl)-6H-benzo[h]quinazolin-4-amine:

[0914]

[0915] Step 1: Preparation of tert-butyl N-[trans-4-[[4-amino-5,5-dimethyl-7-(1-piperidyl)-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate:

[0916] Glutaraldehyde (90 μL, 0.16 mmol) was added to a stirred solution of tert-butyl N-[trans-4-[(4,7-diamino-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl)oxy]cyclohexyl]carbamate (80 mg, 0.16 mmol) in MeOH (10 mL), followed by the addition of a drop of AcOH and NaBH3CN (31 mg, 0.16 mmol). After stirring for 2 h, the reaction mixture was extracted with DCM and H2O. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (silica gel; EA:DCM; 1:2 to 3:1; v:v) to give tert-butyl N-[trans-4-[[4-amino-5,5-dimethyl-7-(1-piperidyl)-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate as a colorless oil (73 mg, 79% yield).

[0917] MS m / z (+IER): 522.3 [M+H] + .

[0918] Step 2: Preparation of 8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-7-(1-piperidyl)-6H-benzo[h]quinazolin-4-amine:

[0919] A solution of tert-butyl N-[trans-4-[[4-amino-5,5-dimethyl-7-(1-piperidyl)-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate (85 mg, 0.15 mmol) in HCO2H (2 mL) was stirred for 16 h before concentration and purification by preparative HPLC to give 8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-7-(1-piperidyl)-6H-benzo[h]quinazolin-4-amine as an off-white solid (33 mg, 52% yield).

[0920] 1 H NMR (400 MHz, DMSO-d6+D2O) δ ppm: 8.20 (s, 1H), 7.79 (d, J=8.8 Hz, 1H), 6.96 (d, J=8.8 Hz, 1H), 4.34 (m, 1H), 3.20 (m, 2H), 3.10 (m, 1H), 2.87 (s, 2H), 2.67 (m, 2H), 2.13 (m, 2H), 1.99 (m, 2H), 1.75 (m, 1H), 1.52 (m, 9H), 1.24 (s, 6H).

[0921] MS m / z (+IER): 422.3 [M+H] + .

[0922] Preparation of Example 11: 2-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-(2-hydroxyethyl)amino]ethanol:

[0923]

[0924] Step 1: Preparation of tert-butyl N-[trans-4-[[4-amino-7-[bis[2-[tert-butyl(dimethyl)silyl]oxyethyl]amino]-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate:

[0925] The title compound was obtained as a colorless oil (120 mg, yield 90%) according to Scheme 1 and in analogy with Example 7 (step 1) using tert-butyl N-[trans-4-[(4,7-diamino-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl)oxy]cyclohexyl]carbamate (70 mg, 0.14 mmol) and (tert-butyldimethylsilyloxy)acetaldehyde as starting materials.

[0926] MS m / z (+IER): 714.5 [M+H] + .

[0927] Step 2: Preparation of 2-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-(2-hydroxyethyl)amino]ethanol:

[0928] TFA (234 μL, 3.12 mmol) and 4 M HCl aqueous solution (1.56 mL, 6.23 mmol) were added to a stirred solution of tert-butyl N-[trans-4-[[4-amino-7-[bis[2-[tert-butyl(dimethyl)silyl]oxyethyl]amino]-5,5-dimethyl-6H-benzo[h]quinazolin-8-l]oxy]cyclohexyl]carbamate (150 mg, 0.16 mmol) in THF (6 mL) and MeOH (100 μL). After stirring for 2 h, the reaction mixture was concentrated and the residue was purified by preparative HPLC to give 2-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-(2-hydroxyethyl)amino]ethanol as a white solid (49 mg, 72% yield).

[0929] 1 H NMR (400 MHz, DMSO-d6+D2O) δ ppm: 8.55 (s, 1H), 7.73 (d, J=8.8 Hz, 1H), 7.20 (d, J=8.8 Hz, 1H), 4.49 (m, 1H), 3.32 (m, 4H), 3.09 (m, 5H), 3.02 (s, 2H), 2.16 (m, 2H), 2.00 (m, 2H), 1.53 (m, 4H), 1.27 (s, 6H).

[0930] MS m / z (+IER): 442.4 [M+H] + .

[0931] Preparation of Examples 15, 16 and 17: 1-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]pyrrolidin-3-ol isomer 1,1-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]pyrrolidin-3-ol isomer 2 and 8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-7-pyrrol-1-yl-6H-benzo[h]quinazolin-4-amine:

[0932]

[0933] Step 1: Preparation of tert-butyl N-[trans-4-[[4-amino-7-(3-hydroxypyrrolidin-1-yl)-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate and tert-butyl N-[trans-4-[(4-amino-5,5-dimethyl-7-pyrrol-1-yl-6H-benzo[h]quinazolin-8-yl)oxy]cyclohexyl]carbamate:

[0934] 1,4-Dibromo-2-butanol (727 mg, 2.98 mmol) was added to a stirred solution of tert-butyl N-[trans-4-[(4,7-diamino-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl)oxy]cyclohexyl]carbamate (150 g, 0.30 mmol) in DMSO (6 mL), followed by the addition of KOH (136 g, 2.38 mmol). After stirring for 16 h at 40 °C, the reaction mixture was concentrated and the residue was purified by preparative HPLC to give tert-butyl N-[trans-4-[[4-amino-7-(3-hydroxypyrrolidin-1-yl)-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate as a yellow oil (90 mg, 46% yield) and tert-butyl N-[trans-4-[(4-amino-5,5-dimethyl-7-pyrrol-1-yl-6H-benzo[h]quinazolin-8-yl)oxy]cyclohexyl]carbamate as a yellow oil (50 mg, 30% yield).

[0935] MS m / z (+IER): 524.4 [M+H] + and 504.4 [M+N] + .

[0936] Step 2: Preparation of tert-butyl N-[trans-4-[[4-amino-7-(3-hydroxypyrrolidin-1-yl)-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate - isomer 1 and tert-butyl N-[trans-4-[[4-amino-7-(3-hydroxypyrrolidin-1-yl)-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate - isomer 2:

[0937] tert-Butyl N-[trans-4-[[4-amino-7-(3-hydroxypyrrolidin-1-yl)-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate (430 g, 0.66 mmol) was purified by chiral preparative HPLC to give tert-butyl N-[trans-4-[[4-amino-7-(3-hydroxypyrrolidin-1-yl)-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate - isomer 1 as a yellow viscous oil (226 mg, yield 39%) and N-[trans-4-[[4-amino-7-(3-hydroxypyrrolidin-1-yl)-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate - isomer 2 as a yellow semi-solid (91 mg, yield 21%).

[0938] MS m / z (+IER): 524.3 [M+H] + .

[0939] Step 3: Preparation of 1-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]pyrrolidin-3-ol - isomer 1:

[0940] The title compound was obtained as a white solid (37 mg, yield 34%) according to Scheme 1 in analogy with Example 4 (step 4) using tert-butyl N-[trans-4-[[4-amino-7-(3-hydroxypyrrolidin-1-yl)-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate - isomer 1 (210 mg, 0.24 mmol) as a starting material.

[0941] 1 H NMR (400 MHz, DMSO-d6+D2O) δ ppm: 8.55 (s, 1H), 7.72 (d, J=8.8 Hz, 1H), 7.22 (d, J=8.8 Hz, 1H), 4.48 (m, 1H), 4.40 (m, 1H), 3.26 (m, 2H), 3.09 (m, 2H), 2.96 (m, 3H), 2.12 (m, 3H), 1.99 (m, 2H), 1.82 (m, 1H), 1.52 (m, 4H), 1.26 (s, 6H).

[0942] MC m / z (+IER): 424.4 [M+H] + .

[0943] [α] D 26 =-6° (c=0.1, MeOH).

[0944] Step 4: Preparation of 1-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]pyrrolidin-3-ol - isomer 2:

[0945] The title compound was obtained as a white solid (27 mg, yield 44%) according to Scheme 1 in analogy with Example 4 (step 4) using tert-butyl N-[trans-4-[[4-amino-7-(3-hydroxypyrrolidin-1-yl)-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate - isomer 2 (90 mg, 0.14 mmol) as a starting material.

[0946] 1 H NMR (400 MHz, DMSO-d6+D2O) δ ppm: 8.56 (s, 1H), 7.74 (d, J=8.8 Hz, 1H), 7.23 (d, J=8.8 Hz, 1H), 4.48 (m, 1H), 4.39 (m, 1H), 3.26 (m, 2H), 3.08 (m, 2H), 2.96 (m, 3H), 2.12 (m, 3H), 1.99 (m, 2H), 1.82 (m, 1H), 1.53 (m, 4H), 1.26 (s, 6H).

[0947] MS m / z (+IER): 424.4 [M+H] + .

[0948] [α] D 26 =+7.5° (c=0.1, MeOH).

[0949] Step 5: Preparation of 8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-7-pyrrol-1-yl-6H-benzo[h]quinazolin-4-amine:

[0950] The title compound was obtained as a white solid (36 mg, yield 37%) according to Scheme 1 and in analogy with Example 4 (step 4), using tert-butyl N-[trans-4-[(4-amino-5,5-dimethyl-7-pyrrol-1-yl-6H-benzo[h]quinazolin-8-yl)oxy]cyclohexyl]carbamate (130 mg, 0.23 mmol) as a starting material.

[0951] 1 H NMR (400 MHz, DMSO-d6+D2O) δ ppm: 8.26 (s, 1H), 8.07 (d, J=8.8 Hz, 1H), 7.15 (d, J=8.8 Hz, 1H), 6.68 (t, J=2.0 Hz, 2H), 6.19 (t, J=2.0 Hz, 2H), 4.22 (m, 1H), 2.55 (m, 1H), 2.34 (s, 2H), 1.90 (m, 2H), 1.70 (m, 2H), 1.16 (m, 10H).

[0952] MS m / z (+IER): 404.3 [M+H] + .

[0953] Preparation of Example 19: 8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-7-propoxy-6H-benzo[h]quinazolin-4-amine:

[0954]

[0955] Step 1: Preparation of 7-chloro-8-[(4-methoxyphenyl)methoxy]-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine:

[0956] PMB-Cl (492 mg, 3.05 mmol) was added to a stirred solution of 4-amino-7-chloro-5,5-dimethyl-6H-benzo[h]quinazolin-8-ol (700 mg, 2.03 mmol) in DMF (10 mL), followed by the addition of Cs2CO3 (1.35 g, 4.06 mmol). After stirring for 20 h at 60 °C, the reaction mixture was concentrated and extracted with DCM and H2O. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by CombiFlash to give 7-chloro-8-[(4-methoxyphenyl)methoxy]-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine as a white solid (520 mg, 58% yield).

[0957] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 8.27 (s, 1H), 8.03 (d, J=8.8 Hz, 1H), 7.42 (d, J=8.8 Hz, 2H), 7.22 (d, J=8.8 Hz, 1H), 6.97 (d, J=8.8 Hz, 2H), 6.49 (s, 2H), 5.16 (s, 2H), 3.76 (s, 3H), 2.90 (s, 2H), 1.30 (s, 6H).

[0958] MS m / z (+IER): 396.2 [M+H] + .

[0959] Step 2: Preparation of 4-amino-8-[(4-methoxyphenyl)methoxy]-5,5-dimethyl-6H-benzo[h]quinazolin-7-ol:

[0960] t-BuOK (410 mg, 3.55 mmol) was added to a stirred solution of 7-chloro-8-[(4-methoxyphenyl)methoxy]-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine (520 mg, 1.18 mmol) in t-BuOH (10 mL) and H2O (0.5 mL), followed by the addition of Pd2(dba)3 (110 mg, 0.12 mmol) and t-BuBrettPhos (118 mg, 0.24 mmol). After stirring for 2 h at 110°C, the reaction mixture was filtered through decalite, concentrated and purified by preparative HPLC to give 4-amino-8-[(4-methoxyphenyl)methoxy]-5,5-dimethyl-6H-benzo[h]quinazolin-7-ol as a yellow solid (184 mg, 37% yield).

[0961] MS m / z (+IER): 378.2 [M+H] + .

[0962] Step 3: Preparation of 8-[(4-methoxyphenyl)methoxy]-5,5-dimethyl-7-propoxy-6H-benzo[h]quinazolin-4-amine:

[0963] The title compound was obtained as a light yellow solid (150 mg, yield 73%) according to Scheme 1 and in analogy with Example 4 (step 4) using 4-amino-8-[(4-methoxyphenyl)methoxy]-5,5-dimethyl-6H-benzo[h]quinazolin-7-ol (184 mg, 0.44 mmol) and n-propyl iodide as the starting materials.

[0964] MS m / z (+IER): 420.3 [M+H] + .

[0965] Step 4: Preparation of 4-amino-5,5-dimethyl-7-propoxy-6H-benzo[h]quinazolin-8-ol:

[0966] A solution of 8-[(4-methoxyphenyl)methoxy]-5,5-dimethyl-7-propoxy-6H-benzo[h]quinazolin-4-amine (30 mg, 0.06 mmol) in TFA (1 mL) and DCM (1 mL) was stirred for 1 h before concentration and purification by preparative HPLC to give 4-amino-5,5-dimethyl-7-propoxy-6H-benzo[h]quinazolin-8-ol as a white solid (9 mg, 44% yield).

[0967] 1H NMR (400 MHz, DMSO-d6+ D2O) δ ppm: 8.20 (s, 1H), 7.57 (d, J=8.4 Hz, 1H), 6.80 (d, J=8.4 Hz, 1H), 3.79 (t, J=6.8 Hz, 2H), 2.74 (s, 2H), 1.67 (ct, J1=1.2 Hz, J2=6.8 Hz, 2H), 1.23 (s, 6H), 0.95 (t, J=7.2 Hz, 3H).

[0968] MS m / z (+IER): 300.2 [M+H] + .

[0969] Step 5: Preparation of 8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-7-propoxy-6H-benzo[h]quinazolin-4-amine:

[0970] The title compound was obtained as a white solid according to Scheme 1 and in analogy with Example 5 (steps 1 and 3) and Example 9 (step 2), using 4-amino-5,5-dimethyl-7-propoxy-6H-benzo[h]quinazolin-8-ol and using tert-butyl N-(cis-4-hydroxycyclohexyl)carbamate as starting materials.

[0971] 1H NMR (400 MHz, DMSO-d6+D2O) δ ppm: 8.18 (s, 1H), 7.15 (d, J=8.8 Hz, 1H), 7.00 (d, J=8.8 Hz, 1H), 4.32 (m, 1H), 3.82 (t, J=6.8 Hz, 2H), 3.06 (m, 1H), 2.73 (s, 2H), 2.11 (m, 2H), 1.97 (m, 2H), 1.66 (kv.t, J1=7.2 Hz, J2=6.8 Hz, 2H), 1.46 (m, 4H), 1.24 (s, 6H), 0.96 (t, J=7.2 Hz 3H).

[0972] MS m / z (+IER): 397.3 [M+H] + .

[0973] Preparation of Example 21: 1-(4-amino-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-9-yl)piperidin-4-ol:

[0974]

[0975] Step 1: Preparation of 3-[tert-butyl(diphenyl)silyl]oxypentanediol:

[0976] MMNO (3.2 g, 26.51 mmol) was added to a stirred solution of tert-butylcyclopent-3-en-1-yloxydiphenylsilane (3.8 g, 10.60 mmol) in THF (40 mL) and H2O (10 mL), followed by the addition of potassium osmate(VI) dihydrate (40 mg, 0.11 mmol). After stirring for 20 h, NaIO4 (2.74 g, 12.73 mmol) was added and the resulting suspension was stirred for 3 h before filtration. The filtrate was concentrated and the residue was purified by column chromatography (silica gel; EA:PE; 1:3; v:v) to give 3-[tert-butyl(diphenyl)silyl]oxypentanediyal as an off-white viscous oil (2 g, 27% yield).

[0977] 1 H NMR (400 MHz, CDCl3) δ ppm: 9.65 (t, J=1.6 Hz, 2H), 7.66 (m, 4H), 7.42 (m, 6H), 4.72 (m, 1H), 2.66 (m, 4H), 1.05 (s, 9H).

[0978] Step 2: Preparation of 7-[4-[tert-butyl(diphenyl)silyl]oxy-1-piperidyl]-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine:

[0979] 3-[tert-Butyl(diphenyl)silyl]oxypentanedial (1.49 g, 2.11 mmol) was added to a stirred solution of 8-methoxy-5,5-dimethyl-6H-benzo[h]quinazoline-4,7-diamine (200 mg, 0.70 mmol) in MeOH (3 mL), followed by the addition of NaBH3CN (139 mg, 2.11 mmol) and a drop of AcOH. After stirring for 2 h, the reaction mixture was quenched with aqueous NH4Cl and extracted with DCM. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by Combiflash to give 7-[4-[tert-butyl(diphenyl)silyl]oxy-1-piperidyl]-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine as a white solid (350 mg, 76% yield).

[0980] MS m / z (+IER): 593.5 [M+H] + .

[0981] Step 3: Preparation of 1-(4-amino-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-9-yl)piperidin-4-ol:

[0982] TBAF (218 mg, 0.75 mmol) was added to a stirred solution of 7-[4-[tert-butyl(diphenyl)silyl]oxy-1-piperidyl]-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine (330 mg, 0.50 mmol) in THF (3 mL). After stirring for 20 h at 60 °C, the reaction mixture was concentrated, and the residue was purified by preparative HPLC to give 1-(4-amino-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-9-yl)piperidin-4-ol as a white solid (80 mg, yield 45%).

[0983] 1 H NMR (400 MHz, DMSO-d6+D2O) δ ppm: 8.22 (s, 1H), 7.84 (d, J=8.4 Hz, 1H), 6.90 (d, J=8.8 Hz, 1H), 3.79 (s, 3H), 3.46 (m, 1H), 3.23 (m, 2H), 2.88 (s, 2H), 2.68 (m, 2H), 1.8 (m, 2H), 1.49 (m, 2H), 1.25 (s, 6H).

[0984] MS m / z (+IER): 355.3 [M+H] + .

[0985] Preparation of Example 22: 2-[[4-amino-8-(4-cis-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]ethylamino]ethanol:

[0986]

[0987] The starting material was prepared according to the procedure described for Example 5 (steps 1-4) from 8-methoxy-5,5-dimethyl-6H-benzo[h]quinazoline-4,7-diamine and tert-butyl N-(trans-4-hydroxycyclohexyl)carbamate.

[0988] Step 1: Preparation of ethyl 2-[[4-amino-8-[cis-4-(tert-butoxycarbonylamino)cyclohexoxy]-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]amino]acetate:

[0989] Ethyl 2-bromoacetate (504 μL, 4.41 mmol) was added to a stirred solution of tert-butyl N-[cis-4-[(4,7-diamino-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl)oxy]cyclohexyl]carbamate (500 mg, 0.88 mmol) in DMF (5 mL), followed by the addition of Cs2CO3 (880 mg, 2.65 mmol) and KI (74 mg, 0.44 mmol). After stirring for 4 h, the reaction mixture was concentrated and extracted with EA and H2O. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by Combiflash to give ethyl 2-[[4-amino-8-[cis-4-(tert-butoxycarbonylamino)cyclohexoxy]-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]amino]acetate as a yellow solid (390 mg, 70% yield).

[0990] MS m / z (+IER): 540.3 [M+H] + .

[0991] Step 2: Preparation of ethyl 2-[[4-amino-8-[cis-4-(tert-butoxycarbonylamino)cyclohexoxy]-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]ethylamino]acetate:

[0992] Acetaldehyde (31 μL, 5.51 mmol) was added to a stirred solution of ethyl 2-[[4-amino-8-[cis-4-(tert-butoxycarbonylamino)cyclohexoxy]-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]amino]acetate (350 mg, 0.55 mmol) in DCE (6 mL) and EtOH (2 mL), followed by the addition of NaBH3CN (182 mg, 2.75 mmol) and a drop of AcOH. After stirring for 3 h, the reaction mixture was quenched with aqueous NH4Cl and extracted with DCM. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by Combiflash to give ethyl 2-[[4-amino-8-[cis-4-(tert-butoxycarbonylamino)cyclohexoxy]-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]ethylamino]acetate as a yellow solid (2100 mg, 57% yield).

[0993] MS m / z (+IER): 563.8 [M+H] + .

[0994] Step 3: Preparation of ethyl 2-[[4-amino-8-(cis-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]ethylamino]acetate:

[0995] The title compound was obtained as a yellow solid (150 mg, yield 86%) according to Scheme 1 and in analogy with Example 4 (step 4) using ethyl 2-[[4-amino-8-[cis-4-(tert-butoxycarbonylamino)cyclohexoxy]-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]ethylamino]acetate (200 mg, 0.30 mmol) as a starting material.

[0996] MS m / z (+IER): 468.3 [M+H] + .

[0997] Step 4: Preparation of 2-[[4-amino-8-(cis-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]ethylamino]ethanol:

[0998] LiAlH4 (28 mg, 0.72 mmol) was added to a stirred solution of ethyl 2-[[4-amino-8-(cis-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]ethylamino]acetate (140 mg, 0.24 mmol) in THF (5 mL). After stirring for 1 h, the reaction mixture was quenched with H2O and the resulting suspension was filtered. The filtrate was concentrated and the residue was purified by preparative HPLC to give 2-[[4-amino-8-(cis-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]ethylamino]ethanol as an off-white solid (52 mg, 50% yield).

[0999] 1 H NMR (400 MHz, DMSO-d6+D2O) δ ppm: 8.19 (s, 1H), 7.84 (d, J=8.8 Hz, 1H), 6.89 (d, J=8.8 Hz, 1H), 4.62 (m, 1H), 3.35 (m, 2H), 3.04 (m, 7H), 1.98 (m, 2H), 1.70 (m, 6H), 1.24 (s, 6H), 0.84 (t, J=7.2 Hz, 3H).

[1000] MS m / z (+IER): 426.5 [M+H] + .

[1001] Preparation of Example 25: 1-(4-amino-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)azetidin-3-ol:

[1002]

[1003] Step 1: Preparation of (2R)-1-[(4-amino-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)amino]-3-chloropropan-2-ol:

[1004] (R)-(-)-Epichlorohydrin (133 μL, 1.66 mmol) was added to a stirred solution of 8-methoxy-5,5-dimethyl-6H-benzo[h]quinazoline-4,7-diamine (500 mg, 1.66 mmol) in CHCl3 (3 mL), followed by the addition of Zn(ClO4)2 (126 mg, 0.33 mmol). After stirring for 18 h at 80°C, the reaction mixture was extracted with DCM and H2O. The combined organic layers were dried over Na2SO4, filtered and concentrated to give (2R)-1-[(4-amino-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)amino]-3-chloropropan-2-ol as a light yellow solid (490 mg, 32% yield), which was used in the next step without further purification.

[1005] MS m / z (+IER): 363.2, 365.2 [M+H] + .

[1006] Step 2: Preparation of 8-methoxy-5,5-dimethyl-N7-[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-3-chloropropyl]-6H-benzo[h]quinazoline-4,7-diamine:

[1007] Imidazole (74 mg, 1.08 mmol) was added to a stirred solution of (2R)-1-[(4-amino-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)amino]-3-chloropropan-2-ol (490 mg, 0.54 mmol) in DCM (3 mL), followed by the addition of TBSCl (168 mg, 1.08 mmol). After stirring for 8 h, the reaction mixture was extracted with DCM and H2O. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by Combiflash to give 8-methoxy-5, 5-dimethyl-N7-[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-3-chloropropyl]-6H-benzo[h]quinazoline-4,7-diamine as a colorless oil (170 mg, 59% yield).

[1008] MS m / z (+IER): 477.2, 479.2 [M+H] + .

[1009] Step 3: Preparation of 1-[3-[tert-butyl(dimethyl)silyl]oxyazetidin-1-yl]-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine:

[1010] Cs2CO3(188 mg, 0.56 mmol) was added to a stirred solution of 8-methoxy-5,5-dimethyl-N7-[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-3-chloropropyl]-6H-benzo[h]quinazoline-4,7-diamine (150 mg, 0.28 mmol) in DMF (2 mL), followed by the addition of KI (47 mg, 0.28 mmol). After stirring for 3 h at 120°C under microwave irradiation, the reaction mixture was concentrated and extracted with EA and H2O. The combined organic layers were dried over Na2SO4, filtered and concentrated to give 7-[3-[tert-butyl(dimethyl)silyl]oxyazetidin-1-yl]-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine as a yellow solid (140 mg, 78% yield), which was used in the next step without further purification.

[1011] MS m / z (+IER): 441.2 [M+H] + .

[1012] Step 4: Preparation of 1-(4-amino-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)azetidin-3-ol:

[1013] TBAF (95 mg, 0.31 mmol) was added to a stirred solution of 7-[3-[tert-butyl(dimethyl)silyl]oxyazetidin-1-yl]-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine (130 mg, 0.21 mmol) in THF (1.5 mL). After stirring for 2 h, the reaction mixture was concentrated, and the residue was purified by preparative HPLC to give 1-(4-amino-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)azetidin-3-ol as a yellow solid (33 mg, yield 46%).

[1014] 1 H NMR (400 MHz, DMSO-d6+D2O) δ ppm: 8.21 (s, 1H), 7.55 (d, J=8.4 Hz, 1H), 6.85 (d, J=8.8 Hz, 1H), 4.32 (m, 1H), 4.26 (m, 2H), 3.77 (m, 2H), 3.74 (s, 3H), 2.66 (s, 2H), 1.22 (s, 6H).

[1015] MS m / z (+IER): 327.3 [M+H] + .

[1016] Preparation of Example 26: 2-[[4-amino-8-(cis-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]methylamino]-N-methylacetamide:

[1017]

[1018] The starting material was prepared according to the procedure described for Example 23 from 4-amino-5,5-dimethyl-6H-benzo[h]quinazolin-8-ol and using tert-butyl N-(trans-4-hydroxycyclohexyl)carbamate, ethyl bromoacetate and formaldehyde.

[1019] Step 1: Preparation of 2-[[4-amino-8-[cis-4-(tert-butoxycarbonylamino)cyclohexoxy]-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]methylamino]acetic acid:

[1020] LiOH.H2O (11 mg, 0.46 mmol) was added to a stirred solution of ethyl 2-[[4-amino-8-[cis-4-(tert-butoxycarbonylamino)cyclohexoxy]-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]methylamino]acetate (150 mg, 0.23 mmol) in THF (6 mL), MeOH (2 mL), and H2O (2 mL). After stirring for 1 h, the reaction mixture was concentrated. The residue was diluted with H2O, and the pH was adjusted to 5 with 3 M aqueous HCl. The resulting suspension was filtered, the precipitate was washed with water and dried in vacuo to give 2-[[4-amino-8-[cis-4-(tert-butoxycarbonylamino)cyclohexoxy]-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]methylamino]acetic acid as a yellow solid (120 mg, 84% yield), which was used in the next step without further purification.

[1021] MS m / z (+IER): 526.3 [M+H] + .

[1022] Step 2: Preparation of tert-butyl N-[cis-4-[[4-amino-5,5-dimethyl-7-[methyl-[2-(methylamino)-2-oxoethyl]amino]-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate:

[1023] Methylamine (2 M in THF, 445 μL, 0.89 mmol) was added to a stirred solution of 2-[[4-amino-8-[cis-4-(tert-butoxycarbonylamino)cyclohexoxy]-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]methylamino]acetic acid (110 mg, 0.18 mmol) in DMF (5 mL), followed by the addition of HATU (103 mg, 0.27 mmol) and NaHCO3 (76 mg, 0.89 mmol). After stirring for 1 h, the reaction mixture was concentrated and extracted with EA and H2O. The combined organic layers were dried over Na2SO4, filtered and concentrated to give tert-butyl N-[cis-4-[[4-amino-5,5-dimethyl-7-[methyl-[2-(methylamino)-2-oxoethyl]amino]-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate as a yellow solid (95 mg, 84% yield), which was used in the next step without further purification.

[1024] MS m / z (+IER): 539.3 [M+H] + .

[1025] Step 3: Preparation of 2-[[4-amino-8-(cis-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]methylamino]-N-methylacetamide:

[1026] The title compound was obtained as a yellow solid (34 mg, yield 50%) according to Scheme 1 and in analogy with Example 9 (step 2), using tert-butyl N-[cis-4-[[4-amino-5,5-dimethyl-7-[methyl-[2-(methylamino)-2-oxoethyl]amino]-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate (90 mg, 0.14 mmol) as a starting material.

[1027] 1 H NMR (400 MHz, DMSO-d6+D2O) δ ppm: 8.21 (s, 1H), 7.86 (d, J=8.8 Hz, 1H), 6.93 (d, J=8.8 Hz, 1H), 4.66 (m, 1H), 3.64 (m, 1H), 3.45 (m, 1H), 3.09 (m, 1H), 2.94 (s, 2H), 2.73 (s, 3H), 2.68 (s, 3H), 2.03 (m, 2H), 1.72 (m, 6H), 1.29 (s, 3H), 1.27 (s, 3H).

[1028] MS m / z (+IER): 439.4 [M+H] + .

[1029] Preparation of Example 28: [1-(4-amino-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)azetidin-3-yl]methanol:

[1030]

[1031] Step 1: Preparation of N1-[2-(chloromethyl)allyl]-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazoline-4,7-diamine:

[1032] 3-Chloro-2-chloromethyl-1-propene (1.05 mL, 8.78 mmol) was added to a stirred solution of 8-methoxy-5,5-dimethyl-6H-benzo[h]quinazoline-4,7-diamine (500 mg, 1.76 mmol) in DMF (4 mL), followed by the addition of Cs2CO3 (1.17 g, 3.51 mmol) and KI (147 mg, 0.88 mmol). After stirring for 6 h, the reaction mixture was extracted with DCM and H2O. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by Combiflash to give N7-[2-(chloromethyl)allyl]-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazoline-4,7-diamine as a yellow solid (320 mg, 46% yield).

[1033] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 8.23 ​​(s, 1H), 7.67 (d, J=8.8 Hz, 1H), 6.89 (d, J=8.8 Hz, 1H), 6.34 (br, 2H), 5.22 (s, 1H), 5.14 (s, 1H), 4.28 (s, 2H), 4.25 (m, 1H), 3.82 (s, 3H), 3.68 (d, J=6.8 Hz, 2H), 2.75 (s, 2H), 1.26 (s, 6H).

[1034] MS m / z (+IER): 359.2, 361.3 [M+H] + .

[1035] Step 2: Preparation of 2-[[(4-amino-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)amino]methyl]-3-chloropropan-1-ol:

[1036] 1 M borane-THF complex solution (1.6 mL, 1.6 mmol) was added to a stirred solution of N7-[2-(chloromethyl)allyl]-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazoline-4,7-diamine (320 mg, 0.80 mmol) in THF (1 mL) at 0 °C. After stirring for 2 h at room temperature, 2.5 M aqueous NaOH solution (3.2 mL, 8.02 mmol) and then H2O2 (0.82 mL, 8.02 mmol) were added dropwise to the reaction mixture. After stirring for 2 h at room temperature, the resulting solution was extracted with DCM and H2O. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by Combiflash to give 2-[[(4-amino-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)amino]methyl]-3-chloropropan-1-ol as a light yellow solid (180 mg, 53% yield).

[1037] MS m / z (+IER): 377.2, 379.3 [M+H] + .

[1038] Step 3: Preparation of N7-[2-[[tert-butyl(diphenyl)silyl]oxymethyl]-3-chloropropyl]-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazoline-4,7-diamine:

[1039] TBDPSCl (228 μL, 0.86 mmol) was added to a stirred solution of 2-[[(4-amino-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)amino]methyl]-3-chloropropan-1-ol (180 mg, 0.43 mmol) in DCM (2 mL), followed by the addition of imidazole (148 mg, 2.15 mmol). After stirring for 2 h at 120 °C, the reaction mixture was extracted with DCM and H2O. The combined organic layers were dried over Na2SO4, filtered, and concentrated to give N7-[2-[[tert-butyl(diphenyl)silyl]oxymethyl]-3-chloropropyl]-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazoline-4,7-diamine as a light yellow oil (600 mg, 34% yield), which was used in the next step without further purification.

[1040] MS m / z (+ESI): no signal.

[1041] Step 4: Preparation of 7-[3-[[tert-butyl(diphenyl)silyl]oxymethyl]azetidin-1-yl]-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine:

[1042] The title compound was obtained as a yellow oil (560 mg, yield 66%) according to Scheme 1 and in analogy with Example 25 (step 3) using N7-[2-[[tert-butyl(diphenyl)silyl]oxymethyl]-3-chloropropyl]-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazoline-4,7-diamine (600 mg, 0.15 mmol) as a starting material.

[1043] MS m / z (+ESI): no signal.

[1044] Step 5: Preparation of [1-(4-amino-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)azetidin-3-yl]methanol:

[1045] TBAF (63 mg, 0.19 mmol) was added to a stirred solution of 7-[3-[[tert-butyl(diphenyl)silyl]oxymethyl]azetidin-1-yl]-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine (560 mg, 0.09 mmol) in THF (1.5 mL). After stirring for 2 h, the reaction mixture was concentrated. The residue was purified by preparative HPLC to give [1-(4-amino-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)azetidin-3-yl]methanol as a white solid (12 mg, yield 34%).

[1046] 1 H NMR (400 MHz, DMSO-d6+D2O) δ ppm: 8.20 (s, 1H), 7.53 (d, J=8.8 Hz, 1H), 6.84 (d, J=8.4 Hz, 1H), 4.08 (m, 2H), 3.78 (m, 2H), 3.73 (s, 3H), 3.55 (m, 2H), 2.69 (s, 2H), 2.57 (m, 1H), 1.21 (s, 6H).

[1047] MS m / z (+IER): 341.2 [M+H] + .

[1048] Preparation of Example 32: 8-(cis-4-aminocyclohexoxy)-N7,5,5-trimethyl-N7-(2-methylsulfonylethyl)-6H-benzo[h]quinazoline-4,7-diamine:

[1049]

[1050] The starting material was prepared according to the procedures described for Examples 5 and 8 from 4-amino-5,5-dimethyl-6H-benzo[h]quinazolin-8-ol and using tert-butyl N-(trans-4-hydroxycyclohexyl)carbamate, (methylthio)acetaldehyde and formaldehyde.

[1051] Step 1: Preparation of tert-butyl N-[cis-4-[[4-amino-5,5-dimethyl-7-[methyl(2-methylsulfonylethyl)amino]-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate:

[1052] Potassium peroxomonosulfate (4.5% active oxygen, 521 mg, 0.83 mmol) was added to a stirred solution of tert-butyl N-[cis-4-[[4-amino-5,5-dimethyl-7-[methyl(2-methylsulfanylethyl)amino]-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate (250 mg, 0.41 mmol) in MeOH (8 mL) and H2O (2 mL). After stirring for 1 h, the reaction suspension was filtered, the filtrate was concentrated and the crude product was purified using Combiflash to give tert-butyl N-[cis-4-[[4-amino-5,5-dimethyl-7-[methyl(2-methylsulfonylethyl)amino]-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate as a yellow solid (230 mg, 87% yield).

[1053] MS m / z (+IER): 574.3 [M+H] + .

[1054] Step 2: Preparation of 8-(cis-4-aminocyclohexoxy)-N7,5,5-trimethyl-N7-(2-methylsulfonylethyl)-6H-benzo[h]quinazoline-4,7-diamine:

[1055] The title compound was obtained as a yellow solid (83 mg, yield 73%) according to Scheme 1 and in analogy with Example 9 (step 2), using tert-butyl N-[cis-4-[[4-amino-5,5-dimethyl-7-[methyl(2-methylsulfonylethyl)amino]-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate (150 mg, 0.23 mmol) as a starting material.

[1056] 1 H NMR (400 MHz, DMSO-d6+D2O) δ ppm: 8.22 (s, 1H), 7.88 (d, J=8.8 Hz, 1H), 6.94 (d, J=8.8 Hz, 1H), 4.65 (m, 1H), 3.53 (m, 2H), 3.15 (m, 4H), 2.98 (s, 3H), 2.78 (s, 1H), 2.75 (s, 3H), 2.01 (m, 2H), 1.72 (m, 6H), 1.28 (s, 3H), 1.25 (s, 3H).

[1057] MS m / z (+IER): 474.3 [M+H] + .

[1058] Preparation of Example 34: 4,7-diamino-8-(trans-4-aminocyclohexoxy)-5,5-dimethylbenzo[h]quinazolin-6-one:

[1059]

[1060] Step 1: Preparation of 4-amino-8-methoxy-5,5-dimethylbenzo[h]quinazolin-6-one:

[1061] TBAI (7.4 g, 19.5 mmol) was added to a stirred suspension of 8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine (25 g, 97.8 mmol) in ACN (150 mL). The resulting suspension was heated to 45 °C before dropwise addition of TBHP solution (100 g, 782 mmol) over 3 h. After stirring for 16 h at 50 °C, the reaction mixture was cooled to room temperature before dropwise addition of H2O (150 mL) over 30 min. After stirring for 16 h at 0°C, the resulting precipitate was collected by filtration, washed with a mixture of ACN (25 mL) and H2O (75 mL), and dried in vacuo to give 4-amino-8-methoxy-5,5-dimethylbenzo[h]quinazolin-6-one as a light gray solid (26.3 g, 69% yield), which was used in the next step without further purification.

[1062] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 8.56 (d, J=8, 8 Hz, 1H), 8.38 (s, 1H), 7.48 (d, J=2, 8 Hz, 1H), 7.42 (dd, J=8, 8 Hz, 2.8 Hz, 1H), 6.87 (s, 2H), 3.89 (s, 3H), 1.51 (s, 6H)

[1063] MS m / z (+IER): 270.2 [M+H] + .

[1064] Step 2: Preparation of 4-amino-8-methoxy-5,5-dimethyl-7-nitrobenzo[h]quinazolin-6-one:

[1065] KHNO3 (2.53 g, 24.5 mmol) was added portionwise at 0°C to a stirred solution of 4-amino-8-methoxy-5,5-dimethylbenzo[h]quinazolin-6-one (5.1 g, 18.8 mmol) in H2SO4 (10 mL). After stirring for 1 h at room temperature, the reaction mixture was poured into ice water and basified to pH 9 with 2 N aqueous NaOH solution. The resulting precipitate was collected by filtration to give 4-amino-8-methoxy-5,5-dimethyl-7-nitrobenzo[h]quinazolin-6-one as a light yellow solid (5.9 g, yield 65%), which was used in the next step without further purification.

[1066] MS m / z (+IER): 315.1 [M+H] + .

[1067] Step 3: Preparation of 4-amino-8-hydroxy-5,5-dimethyl-7-nitrobenzo[h]quinazolin-6-one:

[1068] LiCl (1.61 g, 36.7 mmol) was added to a stirred suspension of 4-amino-8-methoxy-5,5-dimethyl-7-nitrobenzo[h]quinazolin-6-one (5.5 g, 12.25 mmol) in DMF (30 mL). After stirring for 2 h at 170°C, the solvent was removed to give 4-amino-8-hydroxy-5,5-dimethyl-7-nitrobenzo[h]quinazolin-6-one as a yellow liquid (5.2 g, yield 98%), which was used in the next step without further purification.

[1069] MS m / z (+IER): 301.1 [M+H] + .

[1070] Step 4: Preparation of tert-butyl N-[trans-4-(4-amino-5,5-dimethyl-7-nitro-6-oxobenzo[h]quinazolin-8-yl)oxycyclohexyl]carbamate:

[1071] The title compound was obtained as a yellow solid (6 g, yield 59%) according to Scheme 1 and analogously to Example 5 (step 3) using [cis-4-(tert-butoxycarbonylamino)cyclohexyl]4-methylbenzenesulfonate (14.9 g, 36.3 mmol) as a starting material.

[1072] 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.72 (d, J=9, 2 Hz, 1H), 8.40 (s, 1H), 7.96 (d, J=9.2 Hz, 1H), 7.00 (s, 2H), 6.85 (d, J=1.6 Hz, 1H), 4.61 (m, 1H), 3.35 (m, 1H), 2.02 (m, 2H), 1.79 (m, 2H), 1.49 (s, 6H), 1.38 (m, 13H).

[1073] MS m / z (+IER): 498.2 [M+H] + .

[1074] Step 5: Preparation of tert-butyl N-[trans-4-(4,7-diamino-5,5-dimethyl-6-oxobenzo[h]quinazolin-8-yl)oxycyclohexyl]carbamate:

[1075] 10% Pd / C (19 mg, 0.02 mmol) was added to a stirred solution of tert-butyl N-[trans-4-(4-amino-5,5-dimethyl-7-nitro-6-oxobenzo[h]quinazolin-8-yl)oxycyclohexyl]carbamate (100 mg, 0.18 mmol) in EtOH (10 mL). After stirring for 20 h under hydrogen flow, the catalyst was removed by filtration and the solution was concentrated to give tert-butyl N-[trans-4-(4,7-diamino-5,5-dimethyl-6-oxobenzo[h]quinazolin-8-yl)oxycyclohexyl]carbamate as a yellow solid (90 mg, yield 95%), which was used in the next step without further purification.

[1076] MS m / z (+IER): 468.3 [M+H] + .

[1077] Step 6: Preparation of 4,7-diamino-8-(trans-4-aminocyclohexoxy)-5,5-dimethylbenzo[h]quinazolin-6-one:

[1078] The title compound was obtained as a yellow solid (42 mg, yield 62%) according to Scheme 1 and similarly to Example 9 (step 2) using tert-butyl N-[trans-4-(4,7-diamino-5,5-dimethyl-6-oxobenzo[h]quinazolin-8-yl)oxycyclohexyl]carbamate (90 mg, 0.17 mmol) as a starting material.

[1079] 1 H NMR (400 MHz, DMSO-d6+D2O) δ ppm: 8.30 (s, 1H), 7.82 (d, d=8.4 Hz, 1H), 7.26 (d, d=8.4 Hz, 1H), 4.37 (m, 1H), 3.01 (m, 1H), 2.11 (m, 2H), 1.97 (m, 2H), 1.48 (m, 10H).

[1080] MS m / z (+IER): 368.3 [M+H] + .

[1081] Preparation of Examples 38 and 39 N-[2-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]methylamino]ethyl]acetamide and N-[2-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]methylamino]ethyl]methanesulfonamide:

[1082]

[1083] The starting material was prepared according to the procedures described for Examples 5 and 8 from 4-amino-5,5-dimethyl-6H-benzo[h]quinazolin-8-ol using tert-butyl N-(cis-4-hydroxycyclohexyl)carbamate, 1,3-dihydro-1,3-dioxo-2H-isoindole-2-acetaldehyde and formaldehyde.

[1084] Step 1: Preparation of tert-butyl N-[trans-4-[[4-amino-7-[2-aminoethyl(methyl)amino]-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy] cyclohexyl]carbamate:

[1085] N2H4.H2O (47 mg, 0.93 mmol) was added to a stirred solution of tert-butyl N-[trans-4-[[4-amino-7-[2-(1,3-dioxoisoindolin-2-yl)ethyl-methylamino]-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate (220 mg, 0.31 mmol) in EtOH (2 mL). After stirring for 2 h at 70°C, the solvent was removed and the crude product was purified using Combiflash to give tert-butyl N-[trans-4-[[4-amino-7-[2-aminoethyl(methyl)amino]-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate as a yellow solid (158 mg, 54% yield).

[1086] MS m / z (+IER): 511.4 [M+H] + .

[1087] Step 2: Preparation of tert-butyl N-[trans-4-[[7-[2-acetamidoethyl(methyl)amino]-4-amino-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate:

[1088] Ac2O (15 μL, 0.16 mmol) was added to a stirred solution of tert-butyl N-[trans-4-[[4-amino-7-[2-aminoethyl(methyl)amino]-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate (60 mg, 0.11 mmol) in DCM (1 mL), followed by the addition of pyridine (13 μL, 0.16 mmol). After stirring for 2 h, the reaction mixture was extracted with DCM and H2O. The combined organic layers were dried over Na2SO4, filtered and concentrated to give tert-butyl N-[trans-4-[[7-[2-acetamidoethyl(methyl)amino]-4-amino-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate as a yellow solid (60 mg, 92% yield), which was used in the next step without further purification.

[1089] MS m / z (+IER): 553.3 [M+H] + .

[1090] Step 3: Preparation of N-[2-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]methylamino]ethyl]acetamide:

[1091] The title compound was obtained as a white solid (36 mg, yield 80%) according to Scheme 1 and similarly to Example 9 (step 2) using tert-butyl N-[trans-4-[[7-[2-acetamidoethyl(methyl)amino]-4-amino-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate (55 mg, 0.90 mmol) as a starting material.

[1092] 1 H NMR (400 MHz, DMSO-d6+D2O) δ ppm: 8.20 (s, 1H), 7.84 (d, J=8.8 Hz, 1H), 6.99 (d, J=8.8 Hz, 1H), 4.36 (m, 1H), 3.02 (m, 5H), 2.86 (m, 2H), 2.63 (s, 3H), 2.14 (m, 2H), 1.97 (m, 2H), 1.77 (s, 3H), 1.48 (m, 4H), 1.25 (s, 3H), 1.23 (s, 3H).

[1093] MS m / z (+IER): 453.5 [M+H] + .

[1094] Step 4: Preparation of tert-butyl N-[trans-4-[[4-amino-7-[2-(methanesulfonamido)ethyl-methylamino]-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate:

[1095] MsCl (18 μL, 0.22 mmol) was added to a stirred solution of tert-butyl N-[trans-4-[[4-amino-7-[2-aminoethyl(methyl)amino]-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate (85 mg, 0.15 mmol) in DCM (1 mL), followed by the addition of TEA (42 μL, 0.30 mmol). After stirring for 2 h, the reaction mixture was extracted with DCM and H2O. The combined organic layers were dried over Na2SO4, filtered and concentrated to give tert-butyl N-[trans-4-[[4-amino-7-[2-(methanesulfonamido)ethylmethylamino]-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate as a yellow solid (70 mg, 71% yield), which was used in the next step without further purification.

[1096] MS m / z (+IER): 589.3 [M+H] + .

[1097] Step 5: Preparation of N-[2-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]methylamino]ethyl]methanesulfonamide:

[1098] The title compound was obtained as a white solid (11 mg, yield 20%) according to Scheme 1 and similarly to Example 9 (step 2) using tert-butyl N-[trans-4-[[4-amino-7-[2-(methanesulfonamido)ethylmethylamino]-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate (70 mg, 0.10 mmol) as a starting material.

[1099] 1 H NMR (400 MHz, DMSO-d6+D2O) δ ppm: 8.22 (s, 1H), 7.86 (d, J=8.8 Hz, 1H), 7.00 (d, J=8.8 Hz, 1H), 4.38 (m, 1H), 2.99 (m, 5H), 2.79 (m, 2H), 2.85 (s, 3H), 2.65 (s, 3H), 2.15 (m, 2H), 1.97 (m, 2H), 1.49 (m, 4H), 1.28 (s, 3H), 1.24 (s, 3H)

[1100] MS m / z (+IER): 489.3 [M+H] + .

[1101] Preparation of Example 42: N-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-2-hydroxyethanesulfonamide:

[1102]

[1103] Step 1: Preparation of tert-butyl N-[trans-4-[[4-amino-7-(2-methoxyethylsulfonylamino)-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate:

[1104] 2-Methoxyethanesulfonyl chloride (451 mg, 2.80 mmol) was added to a stirred solution of tert-butyl N-[trans-4-[(4,7-diamino-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl)oxy]cyclohexyl]carbamate (300 mg, 0.56 mmol) in ACN (10 mL), followed by the addition of DMAP (69 mg, 0.5 6 mmol) and pyridine (4 58 μL, 5.60 mmol). After stirring for 16 h at 80°C, the solvent was removed and the residue was extracted with EA and H2O. The combined organic layers were dried over Na2SO4, filtered and concentrated to give tert-butyl N-[trans-4-[[4-amino-7-(2-methoxyethylsulfonylamino)-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate as a yellow solid (140 mg, 28% yield), which was used in the next step without further purification.

[1105] MS m / z (+IER): 576.3 [M+H] + .

[1106] Step 2: Preparation of N-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-2-hydroxyethanesulfonamide:

[1107] The title compound was obtained as a white solid (33 mg, yield 36%) according to Scheme 1 and similarly to Example 4 (step 1) using tert-butyl N-[trans-4-[[4-amino-7-(2-methoxyethylsulfonylamino)-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate (130 mg, 0.15 mmol) as a starting material.

[1108] 1 H NMR (400 MHz, DMSO-d6+D2O) δ ppm: 8.24 (s, 1H), 8.00 (d, J=8.8 Hz, 1H), 7.11 (d, J=8.8 Hz, 1H), 4.42 (m, 1H), 3.82 (t, J=7.2 Hz, 2H), 3.26 (t, J=7.2 Hz, 2H), 3.02 (m, 1H), 2.85 (s, 2H), 2.14 (m, 2H), 2.00 (m, 2H), 1.51 (m, 4H), 1.25 (s, 6H).

[1109] MS m / z (+IER): 462.3 [M+H] + .

[1110] Preparation of Example 48: 1-[[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]methylamino]methyl]cyclopropanecarbonitrile:

[1111]

[1112] Step 1: Preparation of tert-butyl N-[trans-4-[[4-amino-5,5-dimethyl-7-[(2-nitrophenyl)sulfonylamino]-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate:

[1113] 2-Nitrobenzenesulfonyl chloride (2.72 g, 11.90 mmol) was added to a stirred solution of tert-butyl N-[trans-4-[(4,7-diamino-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl)oxy]cyclohexyl]carbamate (2 g, 3.97 mmol) in DCM (200 mL), followed by the addition of DABCO (2.25 g, 19.84 mmol). After stirring for 16 h, the reaction mixture was extracted with DCM and H2O. The combined organic layers were dried over Na2SO4, filtered, concentrated and purified with Combiflash to give tert-butyl N-[trans-4-[[4-amino-5,5-dimethyl-7-[(2-nitrophenyl)sulfonylamino]-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate as a yellow solid (2.53 g, 53% yield).

[1114] MS m / z (+IER): 639.3 [M+H] + .

[1115] Step 2: Preparation of tert-butyl N-[trans-4-[[4-amino-7-[(1-cyanocyclopropyl)methyl-(2-nitrophenyl)sulfonylamino]-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate:

[1116] The title compound was obtained as a light yellow solid (255 mg, yield 76%) according to Scheme 1 and similarly to Example 4 (step 3) using tert-butyl N-[trans-4-[[4-amino-5,5-dimethyl-7-[(2-nitrophenyl)sulfonylamino]-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate (300 mg, 0.42 mmol) and 1-(bromomethyl)cyclopropanecarbonitrile (150 mg, 0.85 mmol) as the starting materials.

[1117] MS m / z (+IER): 718.3 [M+H] + .

[1118] Step 3: Preparation of tert-butyl N-[trans-4-[[4-amino-7-[(1-cyanocyclopropyl)methylamino]-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate:

[1119] p-Toluenethiol (108 mg, 0.86 mmol) was added to a stirred solution of tert-butyl N-[trans-4-[[4-amino-5,5-dimethyl-7-[(2-nitrophenyl)sulfonylamino]-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate (275 mg, 0.34 mmol) in DMF (2 mL), followed by the addition of K2CO3 (120 mg, 0.86 mmol). After stirring for 3 h at 50°C, the reaction mixture was extracted with DCM and H2O. The combined organic layers were dried over Na2SO4, filtered, concentrated and purified with Combiflash to give tert-butyl N-[trans-4-[[4-amino-7-[(1-cyanocyclopropyl)methylamino]-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate as a white solid (184 mg, 66% yield).

[1120] MS m / z (+IER): 533.3 [M+H] + .

[1121] Step 4: Preparation of 1-[[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methylamino]methyl]cyclopropanecarbonitrile:

[1122] The title compound was obtained as a white solid (34 mg, yield 58%) according to Scheme 1 and in analogy with Example 22 (step 2) and Example 9 (step 2) using tert-butyl N-[trans-4-[[4-amino-7-[(1-cyanocyclopropyl)methylamino]-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate (80 mg, 0.14 mmol) as a starting material.

[1123] 1 H NMR (400 MHz, DMSO-d6+D2O) δ ppm: 8.22 (s, 1H), 7.87 (d, J=8.8 Hz, 1H), 7.00 (d, J=8.8 Hz, 1H), 4.35 (m, 1H), 3.24 (m, 2H), 3.06 (m, 1H), 2.86 (m, 2H), 2.69 (s, 3H), 2.12 (m, 2H), 1.96 (m, 2H), 1.48 (m, 4H), 1.31 (s, 3H), 1.25 (m, 1H), 1.23 (s, 3H), 1.03 (m, 1H), 0.94 (m, 1H), 0.66 (m, 1H).

[1124] MS m / z (+IER): 477.2 [M+H] + .

[1125] Preparation of Examples 49 and 50: 1-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]pyrrolidine-3-carbonitrile - isomer 1 and 1-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]pyrrolidine-3-carbonitrile - isomer 2:

[1126]

[1127] Step 1: Preparation of 2,5-dimethoxytetrahydrofuran-3-carbonitrile:

[1128] NH4OH (866 μL, 2.25 mmol) was added to a stirred solution of 2,5-dimethoxytetrahydrofuran-3-carbaldehyde (50 mg, 0.28 mmol) in THF (0.4 mL), followed by the addition of Hanus' solution (109 μL, 0.42 mmol). After stirring for 16 h, the reaction mixture was quenched with a saturated aqueous solution of Na2SO3 and then extracted with EA and H2O. The combined organic layers were dried over Na2SO4, filtered, concentrated, and purified by column chromatography (silica gel; PE:EA; 5:1; v:v) to give 2,5-dimethoxytetrahydrofuran-3-carbonitrile as a yellow oil (44 mg, yield 36%).

[1129] 1 H NMR (400 MHz, CDCl3) δ ppm: 5.27 (d, J=3.2 Hz, 1H), 5.21 (dd, J=5.2 Hz, 2.4 Hz, 1H), 3.46 (s, 3H), 3.41 (s, 3H), 3.24 (m, 1H), 2.39 (m, 2H).

[1130] Step 2: Preparation of 2-formyl-4-oxobutanitrile:

[1131] A solution of 2,5-dimethoxytetrahydrofuran-3-carbonitrile (500 mg, 2.54 mmol) in 1 N aqueous HCl solution (3 mL) was stirred for 1 h at 80°C before being used directly in the next step.

[1132] Step 3: Preparation of tert-butyl N-[trans-4-[[4-amino-7-(3-cyanopyrrolidin-1-yl)-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate:

[1133] The title compound was obtained as a yellow solid (575 mg, yield 51%) according to Scheme 1 and similarly to Example 7 (step 1) using tert-butyl N-[trans-4-[(4,7-diamino-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl)oxy]cyclohexyl]carbamate (150 mg, 1.08 mmol) as a starting material.

[1134] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 8.23 ​​(s, 1H), 7.87 (d, J=8.8 Hz, 1H), 7.00 (d, J=8.8 Hz, 1H), 6.83 (d, J=7.6 Hz, 1H), 6.34 (s, 2H), 4.36 (m, 1H), 3.42 (m, 2H), 3.19 (m, 4H), 2.85 (m, 2H), 2.32 (m, 1H), 2.12 (m, 3H), 1.80 (m, 2H), 1.43 (m, 13H), 1.27 (s, 3H), 1.23 (s, 3H).

[1135] MS m / z (+IER): 533.4 [M+H] + .

[1136] Step 4: Preparation of tert-butyl N-[trans-4-[[4-amino-7-(3-carbamoylpyrrolidin-1-yl)-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate:

[1137] H2O2(132 μL, 1.67 mmol) was added to a stirred solution of tert-butyl N-[trans-4-[[4-amino-7-(3-cyanopyrrolidin-1-yl)-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate (100 mg, 0.17 mmol) in DMSO, followed by the addition of K2CO3(119 mg, 0.8 4 mmol). After stirring for 16 h at 50 °C, the reaction mixture was concentrated and purified using Combiflash to give tert-butyl N-[trans-4-[[4-amino-7-(3-carbamoylpyrrolidin-1-yl)-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate as a white solid (74 mg, 72% yield).

[1138] 1H NMR (400 MHz, DMSO-d6) δ m.d.: 8.22 (s, 1H), 7.84 (d, J=8.8 Hz, 1H), 7.33 (s, 1H), 6.97 (d, J=8.8 Hz, 1H), 6.82 (m, 2H), (2H), 4.34 (m, 1H), 3.21 (m, 2H), 3.13 (m, 2H), 3.01 (m, 2H), 2.83 (m, 2H), 2.08 (m, 4H), 1.83 (m, 2H), 1.38 (m, 13H), , 13H 3H).

[1139] MS m / z (+IER): 551.3 [M+H] + .

[1140] Stage 5: Preparation of tert-butyl N-[4-[[4-amino-7-(3-carbamoylpyrrolidin-1-yl)-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate - 1 and tert-butyl N-[4-[[4-amino-7-(3-carbamoylpyrrolidin-1-yl)-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate is isomer 2:

[1141] tert-butyl butyl N-[4-[[4-amino-7-(3-carbamoylpyrrolidin-1-yl)-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate - isomer 1 and tert-butyl N-[4-[[4-amino-7-(3-carbamoylpyrrolidin-1-yl)-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate - isomer 2 were obtained as a yellow solid (137 mg, yield 43% each) according to Scheme 1 and similarly to Example 15 (step 2).

[1142] MS m / z (+IER): 551.3 [M+H] + .

[1143] Step 6: Preparation of 1-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]pyrrolidine-3-carbonitrile - isomer 1:

[1144] A suspension of tert-butyl N-[4-[[4-amino-7-(3-carbamoylpyrrolidin-1-yl)-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate isomer 1 (135 mg, 0.22 mmol) in POCl3 (8 mL) was stirred at 60°C for 2 h before concentration. The residue was purified by preparative HPLC to give 1-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]pyrrolidine-3-carbonitrile isomer 1 as a white solid (49 mg, yield 51%).

[1145] 1 H NMR (400 MHz, DMSO-d6+D2O) δ ppm: 8.27 (s, 1H), 7.86 (d, J=8.8 Hz, 1H), 7.07 (d, J=8.8 Hz, 1H), 4.41 (m, 1H), 3.41 (overlaps with water peak, 2H), 3.21 (m, 2H), 3.11 (m, 2H), 2.86 (m, 2H), 2.32 (m, 1H), 2.15 (m, 3H), 1.98 (m, 2H), 1.51 (m, 4H), 1.26 (s, 3H), 1.23 (s, 3H).

[1146] MS m / z (+IER): 433.2 [M+H] + .

[1147] [α] D 25 =-20.0° (c=0.07, MeOH).

[1148] Step 7: Preparation of 1-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]pyrrolidine-3-carbonitrile - isomer 2:

[1149] The title compound was obtained as an off-white solid (46 mg, yield 47%) according to Scheme 1 and in analogy to Example 49 (step 6), using tert-butyl N-[4-[[4-amino-7-(3-carbamoylpyrrolidin-1-yl)-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate - isomer 2 (135 mg, 0.22 mmol) as a starting material.

[1150] 1 H NMR (400 MHz, DMSO-d6+D2O) δ ppm: 8.53 (s, 1H), 7.77 (d, J=8.8 Hz, 1H), 7.23 (d, J=8.8 Hz, 1H), 4.48 (m, 1H), 3.41 (overlaps with water peak, 2H), 3.20 (m, 2H), 3.11 (m, 2H), 2.94 (m, 2H), 2.33 (m, 1H), 2.16 (m, 3H), 1.99 (m, 2H), 1.53 (m, 4H), 1.28 (s, 3H), 1.25 (s, 3H).

[1151] MS m / z (+IER): 433.2 [M+H] + .

[1152] [α] D 25 =22.8° (c=0.07, MeOH).

[1153] Preparation of Example 51: 3-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-cyclopropylamino]propanenitrile:

[1154]

[1155] Step 1: Preparation of tert-butyl N-[trans-4-[[4-amino-7-(cyclopropylamino)-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate:

[1156] Cyclopropylboronic acid (444 mg, 4.9 6 mmol) was added to a stirred solution of tert-butyl N-[trans-4-[(4,7-diamino-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl)oxy]cyclohexyl]carbamate (500 mg, 0.99 mmol) in DCM (10 mL), followed by the addition of Cu(OAc)2 (421 mg, 1.98 mmol), 2,2'-bipyridine (316 mg, 1.98 mmol), and TEA (419 μL, 2.98 mmol). After stirring for 3 h at 60 °C, the reaction mixture was filtered. The filtrate was concentrated and purified using Combiflash to give tert-butyl N-[trans-4-[[4-amino-7-(cyclopropylamino)-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate as a light yellow solid (230 mg, 42% yield).

[1157] 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.23 ​​(s, 1H), 7.62 (d, J=8.8 Hz, 1H), 6.90 (d, J=8.8 Hz, 1H), 6.81 (d, J=7.2 Hz, 1H), 6.33 (br, 2H), 4.26 (m, 1H), 4.07 (m, 1H), 3.29 (m, 1H), 2.85 (s, 2H), 2.60 (m, 1H), 2.05 (m, 2H), 1.81 (m, 2H), 1.41 (m, 2H), 1.38 (s, 9H), 1.32 (m, 2H), 1.27 (s, 6H), 0.54 (m, 2H), 0.40 (m, 2H).

[1158] MS m / z (+IER): 494.4 [M+H] + .

[1159] Step 2: Preparation of tert-butyl N-[trans-4-[[4-amino-7-[2-chloroethyl(cyclopropyl)amino]-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate:

[1160] The title compound was obtained as a white solid (182 mg, yield 91%) according to Scheme 1 and in analogy with Example 8 (step 1), using tert-butyl N-[trans-4-[[4-amino-7-(cyclopropylamino)-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate (180 mg, 0.33 mmol) as a starting material.

[1161] MS m / z (+IER): 556.3, 558.3 ​​[M+H] + .

[1162] Step 3: Preparation of tert-butyl N-[trans-4-[[4-amino-7-[2-cyanoethyl(cyclopropyl)amino]-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate:

[1163] KCN (56 mg, 0.85 mmol) was added to a stirred solution of tert-butyl N-[trans-4-[[4-amino-7-[2-chloroethyl(cyclopropyl)amino]-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate (175 mg, 0.28 mmol) in EtOH (1.5 mL) and H2O (0.3 mL), followed by the addition of NaI (43 mg, 0.28 mmol). After stirring for 8 h at 70°C, the reaction mixture was extracted with DCM and H2O. The combined organic layers were dried over Na2SO4, filtered, concentrated and purified with Combiflash to give tert-butyl N-[trans-4-[[4-amino-7-[2-cyanoethyl(cyclopropyl)amino]-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate as a white solid (120 mg, 70% yield).

[1164] MS m / z (+IER): 547.4 [M+H] + .

[1165] Step 4: Preparation of 3-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]cyclopropylamino]propanenitrile:

[1166] The title compound was obtained as a white solid (39 mg, yield 48%) according to Scheme 1 and similarly to Example 9 (step 2) using tert-butyl N-[trans-4-[[4-amino-7-[2-cyanoethyl(cyclopropyl)amino]-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate (110 mg, 0.18 mmol) as a starting material.

[1167] 1 H NMR (400 MHz, DMSO-d6+D2O) δ ppm: 8.22 (s, 1H), 7.91 (d, J=8.8 Hz, 1H), 7.04 (d, J=8.8 Hz, 1H), 4.42 (m, 1H), 3.29 (t, J=6.0 Hz, 2H), 3.01 (m, 1H), 2.88 (m, 2H), 2.66 (m, 2H), 2.40 (m, 1H), 2.16 (m, 2H), 1.95 (m, 2H), 1.48 (m, 4H), 1.23 (s, 3H), 1.21 (s, 3H), 0.56 (m, 2H), 0.26 (m, 1H), 0.14 (m, 1H).

[1168] MS m / z (+IER): 447.3 [M+H] + .

[1169] Preparation of Example 52: 3-[[4-amino-5,5-dimethyl-8-(trans-4-morpholinocyclohexoxy)-6H-benzo[h]quinazolin-7-yl]methylamino]propanenitrile:

[1170]

[1171] Step 1: Preparation of 2-[2-(3-methoxyphenyl)-1,1-dimethylethyl]propane dinitrile:

[1172] 3-Methoxybenzylmagnesium chloride (96 mL, 24 mmol, 0.25 M in THF) was added dropwise at 0 °C to a stirred solution of isopropylidenemalononitrile (2 g, 18.5 mmol) in THF (50 mL). The resulting solution was stirred at room temperature for 3 h. Then, 1 N aqueous HCl solution was added at 0 °C, and the resulting mixture was concentrated. The residue was extracted with EA and H2O. The combined organic layers were dried over Na2SO4, filtered, concentrated, and purified by column chromatography (silica gel; PE:EA; 5:1; v:v) to give 2-[2-(3-methoxyphenyl)-1,1-dimethylethyl]propane dinitrile as a yellow oil (1.69 g, yield 38%).

[1173] 1H NMR (400 MHz, CDCl3) δ ppm: 7.27 (m, 1H), 6.86 (m, 1H), 6.79 (d, J=7.6 Hz, 1H), 6.74 (m, 1H), 3.82 (s, 3H), 3.44 (s, 1H), 2.81 (s, 2H), 1.29 (s, 6H).

[1174] MS m / z (+IER): 229.1 [M+H] + .

[1175] Step 2: Preparation of 1-amino-6-methoxy-3,3-dimethyl-4H-naphthalene-2-carbonitrile:

[1176] TfOH (1.04 g, 6.24 mmol) was added to a stirred solution of 2-[2-(3-methoxyphenyl)-1,1-dimethylethyl]propane dinitrile (300 mg, 1.25 mmol) in DCM (6 mL) at 0 °C, and the resulting mixture was stirred at 0 °C for 2 h. Saturated aqueous NaHCO3 solution was added, and the mixture was extracted with DCM. The combined organic layers were dried over Na2SO4, filtered, and concentrated to give 1-amino-6-methoxy-3,3-dimethyl-4H-naphthalene-2-carbonitrile as a yellow solid (300 mg, 95% yield), which was used in the next step without further purification.

[1177] 1H NMR (400 MHz, CDCl3) δ ppm: 7.31 (d, J=8.8 Hz, 1H), 6.81 (m, 1H), 6.74 (d, J=2.4 Hz, 1H), 4.51 (br., 2H), 3.85 (s, 3H), 2.69 (s, 2H), 1.17 (s, 6H).

[1178] MS m / z (+IER): 229.1 [M+H] + .

[1179] Step 3: Preparation of 8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine:

[1180] A suspension of 1-amino-6-methoxy-3,3-dimethyl-4H-naphthalene-2-carbonitrile (1 g, 3.9 4 mmol) and formamide (19 mL, 473 mmol) was stirred at 180°C for 8 h. After cooling to room temperature, the reaction mixture was diluted with H2O and extracted with EA. The combined organic layers were dried over Na2SO4, filtered, concentrated, and purified by column chromatography (silica gel; PE:EA; 1:1; v:v) to give 8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine as a light yellow solid (700 mg, yield 63%).

[1181] 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.24 (s, 1H), 7.99 (d, J=8.8 Hz, 1H), 6.86 (m, 1H), 6.79 (d, J=2.8 Hz, 1H), 6.37 (br, 2H), 3.79 (s, 3H), 2.75 (s, 2H), 1.28 (s, 6H).

[1182] MS m / z (+IER): 256.1 [M+H] + .

[1183] Step 4: Preparation of 4-amino-5,5-dimethyl-6H-benzo[h]quinazolin-8-ol:

[1184] BBr3 (1 M in DCM, 4.8 mL, 4.80 mmol) was added dropwise at -40°C to a stirred solution of 8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine (450 mg, 1.58 mmol) in DCM (30 mL). The resulting solution was stirred at rt for 18 h. Saturated aqueous NaHCO3 was added, and the resulting green solid was collected by filtration, washed with H2O, and dried under reduced pressure to give 4-amino-5,5-dimethyl-6H-benzo[h]quinazolin-8-ol (350 mg, 82% yield).

[1185] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 8.21 (s, 1H), 7.88 (d, J=8.4 Hz, 1H), 6.67 (m, 1H), 6.59 (s, 1H), 6.29 (b, 2H), 2.67 (s, 2H), 1.26 (s, 6H).

[1186] MS m / z (+IER): 242.2 [M+H] + .

[1187] Step 5: Preparation of 4-amino-5,5-dimethyl-7-nitro-6H-benzo[h]quinazolin-8-ol:

[1188] HNO3 (7.5 mL, 117.2 mmol) was added dropwise at 0 °C to a stirred solution of 4-amino-5,5-dimethyl-6H-benzo[h]quinazolin-8-ol (700 mg, 2.32 mmol) in H2SO4 (7 mL). After stirring for 4-8 h, the reaction mixture was poured into 200 mL of ice water and neutralized with NaHCO3. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by Combifilash to give 4-amino-5,5-dimethyl-7-nitro-6H-benzo[h]quinazolin-8-ol as a yellow solid (260 mg, 35% yield).

[1189] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 12.76 (br, 1H), 8.27 (s, 1H), 8.09 (d, J=8.4 Hz, 1H), 7.01 (d, J=8.4 Hz, 1H), 6.54 (br, 2H), 2.62 (s, 2H), 1.27 (s, 6H).

[1190] MS m / z (+IER): 287.2 [M+H] + .

[1191] Step 6: Preparation of [cis-4-(tert-butoxycarbonylamino)cyclohexyl]4-methylbenzenesulfonate:

[1192] TsCl (139 g, 721 mmol) was added portionwise to a stirred solution of tert-butyl N-(cis-4-hydroxycyclohexyl)carbamate (80 g, 360 mmol) in DCM (300 mL), followed by the addition of TEA (152 mL, 1081 mmol) and DMAP (4.5 g, 36 mmol). After stirring for 24 h, the reaction mixture was filtered. The filtrate was concentrated, and the residue was purified by column chromatography (silica gel; PE:EA; 10:1; v:v) to give [cis-4-(tert-butoxycarbonylamino)cyclohexyl] 4-methylbenzenesulfonate as a white solid (105 g, yield 71%).

[1193] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.78 (d, J=8.0 Hz, 2H), 7.47 (d, J=8.0 Hz, 2H), 6.81 (d, J=7.2 Hz, 1H), 4.58 (m, 1H), 3.24 (m, 1H), 2.41 (s, 3H), 1.66 (m, 2H), 1.51 (m, 4H), 1.41 (m, 2H), 1.36 (s, 9H).

[1194] MS m / z (+IER): 370.1 [M+H] + .

[1195] Step 7: Preparation of tert-butyl N-[trans-4-[(4-amino-5,5-dimethyl-7-nitro-6H-benzo[h]quinazolin-8-yl)oxy]cyclohexyl]carbamate:

[1196] Cs2CO3(820 mg, 2.45 mmol) was added to a stirred solution of 4-amino-5,5-dimethyl-7-nitro-6H-benzo[h]quinazolin-8-ol (260 mg, 0.82 mmol) and [cis-4-(tert-butoxycarbonylamino)cyclohexyl]4-methylbenzenesulfonate (2.0 g, 4.90 mmol) in DMF (8 mL) and ACN (8 mL). After stirring for 40 h at 80°C, the reaction mixture was filtered. The filtrate was concentrated and the residue was purified using Combiflash to give tert-butyl N-[trans-4-[(4-amino-5,5-dimethyl-7-nitro-6H-benzo[h]quinazolin-8-yl)oxy]cyclohexyl]carbamate as a light yellow solid (400 mg, 91% yield).

[1197] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 8.29 (s, 1H), 8.19 (d, J=8.8 Hz, 1H), 7.38 (d, J=8.8 Hz, 1H), 6.84 (d, J=7.2 Hz, 1H), 6.57 (s, 2H), 4.52 (m, 1H), 3.28 (m, 1H), 2.62 (s, 2H), 2.03 (m, 2H), 1.79 (m, 2H), 1.38 (m, 13H), 1.27 (s, 6H).

[1198] MS m / z (+IER): 484.4 [M+H] + .

[1199] Step 8: Preparation of tert-butyl N-[trans-4-[(4,7-diamino-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl)oxy]cyclohexyl]carbamate:

[1200] Pd(OH)2(20% on carbon, 52 mg, 0.07 mmol) was added to a stirred solution of tert-butyl N-[trans-4-[(4-amino-5,5-dimethyl-7-nitro-6H-benzo[h]quinazolin-8-yl)oxy]cyclohexyl]carbamate (400 mg, 0.74 mmol) in MeOH (10 mL) and EA (10 mL). After stirring for 20 h under a stream of hydrogen, the catalyst was removed by filtration and the solution was concentrated to give tert-butyl N-[trans-4-[(4,7-diamino-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl)oxy]cyclohexyl]carbamate as a light yellow solid (340 mg, 96% yield), which was used in the next step without further purification.

[1201] 1H NMR (400 MHz, DMSO-d6) δ MD: 8.21 (s, 1H), 7.41 (d, J=8.4 Hz, 1H), 6.82 (d, J=8.4 Hz, 1H), 6.79 (d, J=7.2 Hz, 1H), 6.79 (d, J=7.2 Hz, 1H), (s, 2H), 4.22 (m, 1H), 3.29 (m, 1H), 2.61 (s, 2H), 2.06 (m, 2H), 1.83 (m, 2H), 1.46 (m, 2H), 1.38 (s, 9H), 1.36 (m, 2H), (s, 68).

[1202] MS m / z (+IER): 454.3 [M+H] + .

[1203] Stage 9: Preparation of tert-butyl N-[trans-4-[[4-amino-5,5-dimethyl-7-[(4-nitrophenyl)sulfonylamino]-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate:

[1204] NsCl (7.8 g, 34.13 mmol) was added to a stirred solution of tert-butyl N-[trans-4-[(4,7-diamino-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl)oxy]cyclohexyl]carbamate (4.3 g, 8.53 mmol) in pyridine (40 mL). After stirring for 30 min, the reaction mixture was poured into H2O. The resulting suspension was filtered, and the filter cake was washed with water and dried under high vacuum to give tert-butyl N-[trans-4-[[4-amino-5,5-dimethyl-7-[(4-nitrophenyl)sulfonylamino]-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate as a light yellow solid (6 g, yield 94%).

[1205] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 9.62 (s, 1H), 8.39 (d, J=8.8 Hz, 2H), 8.25 (s, 1H), 7.94 (m, 3H), 6.91 (d, J=8.8 Hz, 1H), 6.72 (d, J=7.2 Hz, 1H), 6.41 (s, 2H), 4.00 (m, 1H), 3.03 (m, 1H), 2.87 (s, 2H), 1.63 (m, 4H), 1.37 (s, 9H), 1.27 (s, 6H), 1.13 (m, 4H).

[1206] MS m / z (+IER): 639.0 [M+H] + .

[1207] Step 10: Preparation of tert-butyl N-[trans-4-[[4-amino-7-[2-cyanoethyl-(4-nitrophenyl)sulfonylamino]-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate:

[1208] Acrylonitrile (18.97 mL, 285.2 mmol) was added to a stirred solution of tert-butyl N-[trans-4-[[4-amino-5,5-dimethyl-7-[(4-nitrophenyl)sulfonylamino]-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate (5.5 g, 7.32 mmol) in pyridine (33 mL) and H2O (6.6 mL), followed by the addition of DMAP (452 ​​mg, 3.66 mmol). After stirring for 3 h at 100°C, the reaction mixture was cooled to room temperature before adding H2O (500 mL). The resulting suspension was filtered, the filter cake was washed with water and dried under high vacuum to give tert-butyl N-[trans-4-[[4-amino-7-[2-cyanoethyl-(4-nitrophenyl)sulfonylamino]-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate as a light yellow solid (5.5 g, yield 92%).

[1209] 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.41 (d, J=8.8 Hz, 2H), 8.27 (s, 1H), 8.10 (d, J=8.8 Hz, 1H), 8.02 (d, J=8.8 Hz, 2H), 7.03 (d, J=8.8 Hz, 1H), 6.73 (d, J=7.2 Hz, 1H), 6.47 (s, 2H), 4.15 (m, 1H), 4.05 (m, 1H), 3.65 (m, 1H), 2.95 (m, 3H), 2.72 (m, 1H), 2.62 (m, 1H), 1.80 (m, 1H), 1.63 (m, 2H), 1.47 (m, 1H), 1.41 (s, 3H), 1.36 (s, 9H), 1.25 (s, 3H), 1.15 (m, 2H), 0.86 (m, 1H), 0.58 (m, 1H).

[1210] MS m / z (+IER): 692.0 [M+H] + .

[1211] Step 11: Preparation of tert-butyl N-[trans-4-[[4-amino-7-(2-cyanoethylamino)-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate:

[1212] p-Toluenethiol (1.39 g, 11.06 mmol) was added to a stirred solution of tert-butyl N-[trans-4-[[4-amino-7-[2-cyanoethyl-(4-nitrophenyl)sulfonylamino]-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate (5.5 g, 6.76 mmol) in DMF (40 mL), followed by the addition of K2CO3 (2.57 g, 18.43 mmol). After stirring for 1.5 h at 55°C, the solvent was removed and the crude product was extracted with EA and H2O. The combined organic layers were dried over Na2SO4, filtered, concentrated and the residue was purified using Combiflash to give tert-butyl N-[trans-4-[[4-amino-7-(2-cyanoethylamino)-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate as a light yellow solid (2.95 g, 71% yield).

[1213] 1H NMR (400 MHz, DMSO-d6) δ m.d.: 8.23 ​​(s, 1H), 7.67 (d, J=8.8 Hz, 1H), 6.94 (d, J=8.8 Hz, 1H), 6.82 (d, J=7.6 Hz, 1H), 6.82 (d, J=7.6 Hz, 1H), 6.4, 23 Hz, (m, 2H), 3.28 (m, 1H), 3.20 (m, 2H), 2.75 (s, 2H), 2.60 (t, J=6.4 Hz, 2H), 2.07 (m, 2H), 1.83 (m, 2H), 1.48 (m, 2H), (m, 3H), (m, 2H), 1.27 (s, 6H).

[1214] MS m / z (+IER): 507.4 [M+H] + .

[1215] Stage 12: Preparation of tert-butyl N-[trans-4-[[4-amino-7-[2-cyanoethyl(methyl)amino]-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate:

[1216] H2CO (2.13 g, 26.20 mmol) was added to a stirred solution of tert-butyl N-[trans-4-[[4-amino-7-(2-cyanoethylamino)-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate (2.95 g, 5.24 mmol) in MeOH (25 mL) and THF (5 mL), followed by the addition of NaBH3CN (693 mg, 10.48 mmol) and AcOH (304 μL, 5.24 mmol). After stirring for 2 h, the reaction mixture was concentrated and the crude product was extracted with DCM and H2O. The combined organic layers were dried over Na2SO4, filtered, and concentrated to give tert-butyl N-[trans-4-[[4-amino-7-[2-cyanoethyl(methyl)amino]-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate as an off-white solid (2.98 g, 98% yield), which was used in the next step without further purification.

[1217] MS m / z (+IER): 521.4 [M+H] + .

[1218] Step 13: Preparation of 3-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]methylamino]propanenitrile

[1219] A solution of tert-butyl N-[trans-4-[[4-amino-7-[2-cyanoethyl(methyl)amino]-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate (2.98 g, 5.15 mmol) in HCO2H (25 mL) was stirred for 2.5 hours. Then, the solvent was removed and the residue was purified by Combiflash to give 3-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]methylamino]propanenitrile as a white solid (2.15 g, yield 97%).

[1220] 1 H NMR (400 MHz, DMSO-d6+D2O) δ ppm: 8.21 (s, 1H), 7.87 (d, J=8.8 Hz, 1H), 7.02 (d, d=8.8 Hz, 1H), 4.38 (m, 1H), 3.21 (m, 2H), 3.09 (m, 3H), 2.75 (m, 1H), 2.66 (m, 1H), 2.64 (s, 3H), 2.15 (m, 2H), 1.97 (m, 2H), 1.49 (m, 4H), 1.30 (s, 3H), 1.21 (s, 3H)

[1221] MS m / z (+IER): 421.3 [M+H] + .

[1222] Step 14: Preparation of 3-[[4-amino-5,5-dimethyl-8-(trans-4-morpholinocyclohexoxy)-6H-benzo[h]quinazolin-7-yl]methylamino]propanenitrile:

[1223] 2-Bromoethyl ether (288 mg, 1.22 mmol) was added to a stirred solution of 3-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]methylamino]propanenitrile f (265 mg, 0.57 mmol) in ACN (5 mL), followed by the addition of K2CO3 (340 mg, 2.43 mmol). After stirring for 18 h at 70°C, the suspension was extracted with DCM and H2O. The combined organic layers were dried over Na2SO4, filtered, concentrated and purified by preparative HPLC to give 3-[[4-amino-5,5-dimethyl-8-(trans-4-morpholinocyclohexoxy)-6H-benzo[h]quinazolin-7-yl]methylamino]propanenitrile as a white solid (491 mg, 60% yield).

[1224] 1 H NMR (400 MHz, DMSO-d6+D2O) δ ppm: 8.22 (s, 1H), 7.88 (d, J=8.8 Hz, 1H), 6.98 (d, J=8.8 Hz, 1H), 4.37 (m, 1H), 3.56 (m, 4H), 3.23 (t, J=6.4 Hz, 2H), 2.97 (m, 2H), 2.65 (s, 3H), 2.46 (m, 6H), 2.26 (m, 1H), 2.14 (m, 2H), 1.85 (m, 2H), 1.42 (m, 4H), 1.31 (s, 3H), 1.23 (s, 3H).

[1225] MS m / z (+IER): 491.3 [M+H]+ .

[1226] Preparation of Example 54: 8-(trans-4-aminocyclohexoxy)-N7-but-3-ynyl-N7,5,5-trimethyl-6H-benzo[h]quinazoline-4,7-diamine:

[1227]

[1228] Step 1: Preparation of 8-(trans-4-aminocyclohexoxy)-N7,5,5-trimethyl-N7-(4-trimethylsilylbut-3-ynyl)-6H-benzo[h]quinazoline-4,7-diamine:

[1229] The target compound was obtained as a light yellow solid according to Scheme 1 in the same manner as Examples 5, 9, 21, 48, using tert-butyl N-[trans-4-[(4,7-diamino-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl)oxy]cyclohexyl]carbamate, 4-trimethylsilylbut-3-yn-1-ol, 4-nitrobenzenesulfonyl chloride and formaldehyde as starting materials.

[1230] MS m / z (+IER): 492.1 [M+H] + .

[1231] Step 2: Preparation of 8-(trans-4-aminocyclohexoxy)-N7-but-3-ynyl-N7,5,5-trimethyl-6H-benzo[h]quinazoline-4,7-diamine:

[1232] K2CO3 (108 mg, 0.78 mmol) was added to a stirred solution of 8-(trans-4-aminocyclohexoxy)-N7,5,5-trimethyl-N7-(4-trimethylsilylbut-3-ynyl)-6H-benzo[h]quinazoline-4,7-diamine (150 mg, 0.26 mmol) in MeOH (0.5 mL). After stirring for 2 h, the suspension was filtered. The filtrate was concentrated and purified by preparative HPLC to give 8-(trans-4-aminocyclohexoxy)-N7-but-3-ynyl-N7,5,5-trimethyl-6H-benzo[h]quinazoline-4,7-diamine as a white solid (90 mg, yield 80%).

[1233] 1 H NMR (400 MHz, DMSO-d6+D2O) δ ppm: 8.21 (s, 1H), 7.85 (d, J=8.8 Hz, 1H), 6.99 (d, J=8.8 Hz, 1H), 4.37 (m, 1H), 3.15 (m, 1H), 3.06 (m, 3H), 2.78 (m, 1H), 2.71 (t, J=2.4 Hz, 1H), 2.64 (s, 3H), 2.17 (m, 4H), 1.97 (m, 2H), 1.48 (m, 4H), 1.27 (s, 3H), 1.21 (s, 3H).

[1234] MS m / z (+IER): 420.2 [M+H] + .

[1235] Preparation of Example 56: 1-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-2H-pyrrol-5-one:

[1236]

[1237] 2-Hydroxybutanediyal (126 mg, 1.11 mmol) was added to a stirred solution of tert-butyl N-[trans-4-[(4,7-diamino-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl)oxy]cyclohexyl]carbamate (200 mg, 0.37 mmol) in MeOH (6 mL) and 3 N aqueous HCl (3 mL). After stirring for 4 h, the reaction mixture was concentrated and the residue was purified by preparative HPLC to give 1-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-2H-pyrrol-5-one as a light yellow solid (10 mg, 6% yield).

[1238] 1 H NMR (400 MHz, DMSO-d6+D2O) δ ppm: 8.50 (s, 1H), 7.92 (d, J=8.8 Hz, 1H), 7.52 (d, J=6.0 Hz, 1H), 7.29 (d, J=8.8 Hz, 1H), 6.27 (dt, J=6.0 Hz, 1.6 Hz, 1H), 4.39 (m, 2H), 4.13 (d, J=16.0 Hz, 1H), 3.07 (m, 1H), 2.57 (d, J=7.2 Hz, 2H), 2.02 (m, 4H), 1.44 (m, 4H), 1.31 (s, 3H), 1.18 (s, 3H).

[1239] MS m / z (+IER): 420.4 [M+H] + .

[1240] Preparation of Example 57: 8-(trans-4-aminocyclohexoxy)-7-(3-methoxypyrrol-1-yl)-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine:

[1241]

[1242] Step 1: Preparation of tert-butyl N-[trans-4-[[4-amino-7-(3-methoxypyrrol-1-yl)-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate:

[1243] NaOAc (87 mg, 1.03 mmol) was added to a stirred solution of tert-butyl N-[trans-4-[(4,7-diamino-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl)oxy]cyclohexyl]carbamate (93 mg, 0.17 mmol) and 2-methoxybutanedial (25 mg, 0.17 mmol) in CHCl3 (3 mL), followed by the addition of I2 (0.4 mg, 0.02 mmol). After stirring for 8 h at 70°C, the reaction mixture was concentrated and the residue was purified by column chromatography (silica gel; PE:EA; 1:1; v:v) to give tert-butyl N-[trans-4-[[4-amino-7-(3-methoxypyrrol-1-yl)-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate as a yellow solid (50 mg, yield 49%).

[1244] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 8.27 (s, 1H), 8.06 (d, J=8.8 Hz, 1H), 7.15 (d, J=8.8 Hz, 1H), 6.79 (d, J=8.0 Hz, 1H), 6.48 (t, J=2.4 Hz, 1H), 6.43 (s, 2H), 6.32 (t, J=2.0 Hz, 1H), 5.90 (dd, J=2.8 Hz, 2.0 Hz 1H), 4.22 (m, 1H), 3.63 (s, 3H), 3.22 (m, 1H), 2.42 (s, 2H), 1.94 (m, 2H), 1.73 (m, 2H), 1.38 (m, 4H), 1.23 (m, 15H).

[1245] MS m / z (+IER): 534.3 [M+H] + .

[1246] Step 2: Preparation of 8-(trans-4-aminocyclohexoxy)-7-(3-methoxypyrrol-1-yl)-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine:

[1247] The title compound was obtained as a black solid (22 mg, yield 22%) according to Scheme 1 and in analogy with Example 9 (step 2), using tert-butyl N-[trans-4-[[4-amino-7-(3-methoxypyrrol-1-yl)-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate (130 mg, 0.22 mmol) as a starting material.

[1248] 1H NMR (400 MHz, DMSO-d6+D2O) δ ppm: 8.26 (s, 1H), 8.06 (d, J=8.8 Hz, 1H), 7.18 (d, J=8.8 Hz, 1H), 6.48 (t, J=2.4 Hz, 1H), 6.31 (t, J=2.0 Hz, 1H), 5.90 (t, J=2.0 Hz, 1H), 4.23 (m, 1H), 3.62 (s, 3H), 2.96 (m, 1H), 2.41 (s, 2H), 1.99 (m, 2H), 1.87 (m, 2H), 1.38 (m, 4H), 1.18 (s, 6H).

[1249] MS m / z (+IER): 434.3 [M+H] + .

[1250] Preparation of Example 61: 8-methoxy-7-(3-methoxypropyl)-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine:

[1251]

[1252] Step 1: Preparation of 7,9-dibromo-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine:

[1253] NBS (4.26 g, 23.48 mmol) was added to a stirred solution of 8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine (3 g, 11.74 mmol) in TFA (30 mL). After stirring for 16 h, the reaction mixture was concentrated. Saturated aqueous NaHCO3 solution (200 mL) was added to the residue, and the resulting suspension was filtered. The precipitate was washed with H2O and dried under high vacuum to give 7,9-dibromo-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine as a yellow solid (5.2 g, yield 96%).

[1254] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 8.39 (s, 1H), 8.26 (s, 1H), 7.15 (br, 2H), 3.85 (s, 3H), 2.91 (s, 2H), 1.31 (s, 6H).

[1255] MS m / z (+IER): 412.0, 414.0 [M+H] + .

[1256] Step 2: Preparation of 7-bromo-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine:

[1257] 10% Pd / C (300 mg, 0.28 mmol) was added to a stirred solution of 7,9-dibromo-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine (1 g, 1.94 mmol) in EtOH (60 mL) and EA (20 mL). After stirring for 24 h under hydrogen flow, the catalyst was removed by filtration and the solution was concentrated. The residue was purified by column chromatography (silica gel; DCM:MeOH; 8:1; v:v) to give 7-bromo-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine as a white solid (400 mg, yield 52%).

[1258] MS m / z (+IER): 334.1, 336.1 [M+H] + .

[1259] Step 3: Preparation of 8-methoxy-7-[(E)-3-methoxyprop-1-enyl]-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine:

[1260] 2-[(E)-3-methoxyprop-1-enyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (764 mg, 3.66 mmol) was added to a stirred solution of 7-bromo-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine (180 mg, 0.4 6 mmol) in dioxane (10 mL) and H2O (2 mL), followed by the addition of Pd(PPh3)4 (54 mg, 0.04 mmol), Pd(dppf)Cl2 (34 mg, 0.04 mmol), and KOH (131 mg, 2.29 mmol). After stirring for 2 h at 110°C, the reaction mixture was filtered through decalite, concentrated and purified using CombiFlash to give 8-methoxy-7-[(E)-3-methoxyprop-1-enyl]-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine as a white solid (120 mg, 80% yield).

[1261] 1 H NMR (400 MHz, DMSO-d6+D2O) δ ppm: 8.24 (s, 1H), 8.00 (d, J=8.8 Hz, 1H), 6.97 (d, J=8.8 Hz, 1H), 6.61 (d, J=16.4 Hz, 1H), 5.93 (dt, J=16.4 Hz, 5.6 Hz, 1H), 4.07 (d, J=5.6 Hz, 2H), 3.81 (s, 3H), 3.30 (s, 3H), 2.84 (s, 2H), 1.24 (s, 6H).

[1262] MS m / z (+IER): 326.3 [M+H] + .

[1263] Step 4: Preparation of 8-methoxy-7-(3-methoxypropyl)-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine:

[1264] 10% Pd / C (130 mg, 0.13 mmol) was added to a stirred solution of 8-methoxy-7-[(E)-3-methoxyprop-1-enyl]-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine (80 mg, 0.24 mmol) in EtOH (10 mL) and H2O (0.5 mL), followed by the addition of NH4HCO2 (78 mg, 1.22 mmol). After stirring for 2 hours at 80°C under a stream of hydrogen, the catalyst was removed by filtration and the solution was concentrated. -The residue was purified by preparative HPLC to give 8-methoxy-7-(3-methoxypropyl)-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine as a white solid (65 mg, 81% yield).

[1265] 1 H NMR (400 MHz, DMSO-d6+D2O) δ ppm: 8.23 ​​(s, 1H), 7.95 (d, J=8.8 Hz, 1H), 6.92 (d, J=8.8 Hz, 1H), 3.81 (s, 3H), 3.35 (t, J=6.4 Hz, 2H), 3.24 (s, 3H), 2.74 (s, 2H), 2.67 (m, 2H), 1.63 (m, 2H), 1.27 (s, 6H).

[1266] MS m / z (+IER): 328.4 [M+H] + .

[1267] Preparation of Example 89: (5R)-5-[2-[(4-amino-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)amino]ethyl]oxazolidin-2-one:

[1268]

[1269] Step 1: Preparation of (2R)-4-[tert-butyl(diphenyl)silyl]oxy-1-chlorobutan-2-ol:

[1270] The title compound was obtained as a colorless oil (3.3 g, yield 80%) according to Scheme 1 and similarly to Example 28 (step 3) using (3R)-4-chlorobutane-1,3-diol (1.5 g, 10.84 mmol) as a starting material.

[1271] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.65 (m, 4H), 7.45 (m, 6H), 5.06 (d, J=5.2 Hz, 1H), 3.87 (m, 1H), 3.76 (m, 2H), 3.59 (dd, J=10.8 Hz, 4.8 Hz, 1H), 3.52 (dd, J=10.8 Hz, 5.6 Hz, 1H), 1.82 (m, 1H), 1.61 (m, 1H), 0.98 (s, 9H).

[1272] Step 2: Preparation of (2R)-1-azido-4-[tert-butyl(diphenyl)silyl]oxybutan-2-ol:

[1273] NaN3(87 mg, 1.31 mmol) was added to a stirred solution of (2R)-4-[tert-butyl(diphenyl)silyl]oxy-1-chlorobutan-2-ol (100 mg, 0.26 mmol) in DMF (1 mL). After stirring for 16 h at 90 °C, the reaction mixture was extracted with EA and H2O. The combined organic layers were dried over Na2SO4, filtered, concentrated, and purified by column chromatography (silica gel; PE:EA; 10:1; v:v) to give (2R)-1-azido-4-[tert-butyl(diphenyl)silyl]oxybutan-2-ol as a colorless oil (86 mg, yield 80%).

[1274] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.63 (m, 4H), 7.45 (m, 6H), 5.04 (d, J=5.6 Hz, 1H), 3.87 (m, 1H), 3.73 (m, 2H), 3.23 (dd, J=12.4 Hz, 4.0 Hz, 1H), 3.17 (dd, J=12.8 Hz, 6.8 Hz, 1H), 1.64 (m, 2H), 0.98 (s, 9H).

[1275] Step 3: Preparation of (2R)-1-amino-4-[tert-butyl (diphenyl)silyl]oxybutan-2-ol:

[1276] 10% Pd / C (22 mg, 0.02 mmol) was added to a stirred solution of (2R)-1-azido-4-[tert-butyl(diphenyl)silyl]oxybutan-2-ol (86 mg, 0.18 mmol) in MeOH (1 mL). After stirring for 2 h under hydrogen flow, the catalyst was removed by filtration and the solution was concentrated to give (2R)-1-amino-4-[tert-butyl(diphenyl)silyl]oxybutan-2-ol as a colorless oil (75 mg, yield 94%), which was used in the next step without further purification.

[1277] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.62 (m, 4H), 7.44 (m, 6H), 4.43 (br, 1H), 3.74 (m, 2H), 3.50 (m, 1H), 2.52 (overlaps with DMSO peak, 1H), 2.40 (dd, J=12.4 Hz, 6.8 Hz, 1H), 1.68 (m, 1H), 1.52 (m, 1H), 0.98 (s, 9H).

[1278] MS m / z (+IER): 344.3 [M+H] + .

[1279] Step 4: Preparation of (5R)-5-[2-[tert-butyl (diphenyl)silyl]oxyethyl]oxazolidin-2-one:

[1280] DIPEA (250 μL, 1.41 mmol) was added to a stirred solution of {2R)-1-amino-4-[tert-butyl(diphenyl)silyl]oxybutan-2-ol (90 mg, 0.23 mmol) in DCM (2 mL). The reaction mixture was then cooled to 0°C before adding triphosgene (35 mg, 0.12 mmol). After stirring for 1 h at 0°C, the reaction mixture was extracted with DCM and H2O. The combined organic layers were dried over Na2SO4, filtered, concentrated and purified by column chromatography (silica gel; PE:EA; 2:1; v:v) to give (5R)-5-[2-[tert-butyl(diphenyl)silyl]oxyethyl]oxazolidin-2-one as a colorless oil (87 mg, yield 52%).

[1281] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.64 (m, 4H), 7.44 (m, 7H), 4.71 (m, 1H), 3.74 (m, 2H), 3.55 (t, d=8.4 Hz, 1H), 3.15 (t, J=8.0 Hz, 1H), 1.90 (m, 2H), 0.99 (s, 9H).

[1282] Step 5: Preparation of (5R)-5-[2-[tert-butyl(diphenyl)silyl]oxyethyl]-3-[(4-methoxyphenyl)methyl]oxazolidin-2-one:

[1283] To a solution of (5R)-5-[2-[tert-butyl(diphenyl)silyl]oxyethyl]oxazolidin-2-one (820 mg, 2.00 mmol) in DMF (10 mL) were added cesium carbonate (1.99 g, 5.99 mmol) and 1-(chloromethyl)-4-methoxybenzene (484 mg, 2.99 mmol). The reaction mixture was stirred at 15°C for 16 hours. Then, the reaction mixture was diluted with EA and water. After separation, the combined organic layer was dried over Na2SO4, filtered, concentrated and purified by column chromatography (silica gel; PE:EA; 2:1; v:v) to give (R)-5-[2-[tert-butyl(diphenyl)silyl]oxyethyl]-3-[(4-methoxyphenyl)methyl]oxazolidin-2-one as a colorless oil (1.00 g, yield 92%).

[1284] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.57 (m, 4H), 7.43 (m, 6H), 7.17 (d, J=8.8 Hz, 2H), 6.90 (d, J=8.8 Hz, 2H), 4.64 (m, 1H), 4.24 (s, 2H), 3.73 (s, 3H), 3.71 (m, 2H), 3.48 (t, J=8.8 Hz, 1H), 3.06 (dd, J=8.8 Hz, 6.8 Hz, 1H), 1.86 (m, 2H), 0.95 (s, 9H).

[1285] Step 6: (5R)-5-(2-hydroxyethyl)-3-[(4-methoxyphenyl)methyl]oxazolidin-2-one:

[1286] TBAF (1.70 g, 5.51 mmol) was added to a solution of (5R)-5-[2-[tert-butyl(diphenyl)silyl]oxyethyl]-3-[(4-methoxyphenyl)methyl]oxazolidin-2-one (100 g, 1.84 mmol) in THF (15 mL). The reaction mixture was then heated at 70°C for 1 h. The reaction mixture was diluted with EA and water, and the organic phase was separated, dried over Na2SO4, filtered, and evaporated in vacuo to afford the crude material. The residue was purified by column chromatography (silica gel; 100% EA) to give (5R)-5-(2-hydroxyethyl)-3-[(4-methoxyphenyl)methyl]oxazolidin-2-one as a colorless oil (470 mg, 91% yield).

[1287] 1 H NMR (400 MHz, DMSO-d6+D2O) δ ppm: 7.18 (d, J=8.4 Hz, 2H), 6.91 (d, J=8.4 Hz, 2H), 4.56 (m, 1H), 4.24 (s, 2H), 3.73 (s, 3H), 3.47 (overlaps with H2O peak, 3H), 3.05 (dd, J=8.8 Hz, 7.2 Hz, 1H), 1.72 (m, 2H).

[1288] Step 7. Preparation of 2-[(5R)-3-[(4-methoxyphenyl)methyl]-2-oxooxazolidin-5-yl]ethyl 4-methylbenzenesulfonate:

[1289] The title compound was obtained as a colorless oil according to Scheme 1 and similarly to Examples 5, 19 and 21 using (5R)-5-(2-hydroxyethyl)-3-[(4-methoxyphenyl)methyl]oxazolidin-2-one as a starting material.

[1290] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.78 (d, J=8.4 Hz, 2H), 7.47 (d, J=8.4 Hz, 2H), 7.16 (d, J=8.4 Hz, 2H), 6.91 (d, J=8.4 Hz, 2H), 4.49 (m, 1H), 4.22 (m, 2H), 4.07 (t, J=6.4 Hz, 2H), 3.74 (s, 3H), 3.41 (t, J=8.8 Hz, 1H), 2.99 (dd, J=8.8 Hz, 6.8 Hz, 1H), 2.41 (s, 3H), 1.93 (m, 2H).

[1291] MS m / z (+IER): 406.1 [M+H] + .

[1292] Step 8: Preparation of N-(4-amino-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)-2-nitrobenzenesulfonamide:

[1293] The title compound was obtained as an off-white solid (1.2 g, yield 71%) according to Scheme 1 and analogously to Example 48 (step 1), using 8-methoxy-5,5-dimethyl-6H-benzo[h]quinazoline-4,7-diamine (1.0 g, 3.33 mmol) as a starting material.

[1294] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 9.47 (s, 1H), 8.26 (s, 1H), 8.03 (d, J=8.8 Hz, 1H), 7.98 (d, J=7.6 Hz, 1H), 7.82 (m, 3H), 6.88 (d, J=8.8 Hz, 1H), 6.47 (br, 2H), 3.21 (s, 3H), 2.82 (s, 2H), 1.25 (s, 6H).

[1295] MS m / z (+IER): 456.2 [M+H] + .

[1296] Step 9: Preparation of N-(4-amino-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)-N-[2-[(5R)-3-[(4-methoxyphenyl)methyl]-2-ox-ooxazolidin-5-yl]ethyl]-2-nitrobenzenesulfonamide:

[1297] The title compound was obtained as a yellow solid (800 mg, yield 76%) according to Scheme 1 and similarly to Example 5 (step 3) using N-(4-amino-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)-2-nitrobenzenesulfonamide (700 mg, 1.38 mmol) and 2-[(5R)-3-[(4-methoxyphenyl)methyl]-2-oxo-oxazolidin-5-yl]ethyl 4-methylbenzenesulfonate (623 mg, 1.38 mmol) as the starting material.

[1298] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 8.27 (d, J=1.6 Hz, 1H), 8.16 (dd, J=8.8 Hz, 3.6 Hz, 1H), 7.90 (m, 2H), 7.76 (m, 2H), 7.17 (d, J=8.4 Hz, 1H), 7.11 (d, J=8.4 Hz, 1H), 6.96 (dd, J=8.8 Hz, 5.6 Hz, 1H), 6.90 (d, J=8.4 Hz, 1H), 6.85 (d, J=8.8 Hz, 1H), 6.47 (b, 2H), 4.55 (m, 1H), 4.24 (m, 2H), 3.98 (m, 1H), 3.71 (d, J=13, 6 Hz, 3H), 3.50 (m, 2H), 3.19 (d, J=3.2 Hz, 3H), 2.95 (m, 1H), 2.80 (d, J=8.0 Hz, 2H), 1.90 (m, 1H), 1.62 (m, 1H), 1.38 (d, J=12.4 Hz, 3H), 1.13 (d, J=11.2 Hz, 3H).

[1299] MS m / z (+IER): 689.3 [M+H] + .

[1300] Step 10: Preparation of N-(4-amino-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)-2-nitro-N-[2-[(5R)-2-oxooxazolidin-5-yl]ethyl]benzenesulfonamide:

[1301] CAN (1.65 g, 2.98 mmol) was added to a stirred solution of N-(4-amino-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)-N-[2-[(5R)-3-[(4-methoxyphenyl)methyl]-2-oxo oxazolidin-5-yl]ethyl]-2-nitro benzenesulfonamide (760 mg, 0.99 mmol) in ACN (10 mL) and H2O (3 mL). After stirring for 1 h, the reaction mixture was concentrated and purified using Combiflash to give N-(4-amino-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)-2-nitro-N-[2-[(5R)-2-oxooxazolidin-5-yl]ethyl]benzenesulfonamide as a yellow solid (600 mg, 85% yield).

[1302] MS m / z (+IER): 569.2 [M+H] + .

[1303] Step 11: Preparation of (5R)-5-[2-[(4-amino-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)amino]ethyl]oxazolidin-2-one:

[1304] The title compound was obtained as a white solid (61 mg, yield 19%) according to Scheme 1 and similarly to Example 48 (step 3) using N-(4-amino-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)-2-nitro-N-[2-[(5R)-2-oxooxazolidin-5-yl]ethyl]benzenesulfonamide (580 mg, 0.82 mmol) as a starting material.

[1305] 1 H NMR (400 MHz, DMSO-d6+D2O) δ ppm: 8.22 (s, 1H), 7.67 (d, J=8.8 Hz, 1H), 6.90 (d, J=8.8 Hz, 1H), 4.67 (m, 1H), 3.82 (s, 3H), 3.54 (t, J=8.4 Hz, 1H), 3.10 (t, J=8.0 Hz, 1H), 3.00 (m, 2H), 2.72 (s, 2H), 1.78 (m, 2H), 1.26 (s, 3H), 1.25 (s, 3H).

[1306] MS m / z (+IER): 384.1 [M+H] + .

[1307] Preparation of Example 90: 4-amino-8-(trans-4-aminocyclohexoxy)-N-(cyanomethyl)-5,5-dimethyl-6H-benzo[h]quinazoline-7-carboxamide:

[1308]

[1309] Tert-butyl butyl N-[trans-4-[(4-amino-7-bromo-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl)oxy]cyclohexyl]carbamate was prepared as an off-white solid according to Scheme 1 and in analogy with Examples 5 and 61, using 4-amino-5,5-dimethyl-6H-benzo[h]quinazolin-8-ol and CAS 167081-25-6 as starting materials.

[1310] Step 1: Preparation of methyl 4-amino-8-[trans-4-(tert-butoxycarbonylamino)cyclohexoxy]-5,5-dimethyl-6H-benzo[h]quinazoline-7-carboxylate:

[1311] Pd(dppf)Cl2 (110 mg, 0.15 mmol) was added to a stirred solution of tert-butyl N-[trans-4-[(4-amino-7-bromo-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl)oxy]cyclohexyl]carbamate (300 mg, 0.49 mmol) in MeOH (4 mL), followed by the addition of TEA (350 μL, 2.46 mmol). After stirring for 8 h at 120°C under a CO flow (3.5 MPa), the catalyst was removed by filtration. The solution was concentrated and the residue was purified using Combiflash to give methyl 4-amino-8-[trans-4-(tert-butoxycarbonylamino)cyclohexoxy]-5,5-dimethyl-6H-benzo[h]quinazoline-7-carboxylate as a white solid (190 mg, 70% yield).

[1312] MS m / z (+IER): 497.3 [M+H] + .

[1313] Step 2: Preparation of 4-amino-8-[trans-4-(tert-butoxycarbonylamino)cyclohexoxy]-5,5-dimethyl-6H-benzo[h]quinazoline-7-carboxylic acid:

[1314] NaOH (39 mg, 0.98 mmol) was added to a stirred solution of methyl 4-amino-8-[trans-4-(tert-butoxycarbonylamino)cyclohexoxy]-5,5-dimethyl-6H-benzo[h]quinazoline-7-carboxylate (180 mg, 0.33 mmol) in MeOH (4 mL). After stirring for 16 h at 75°C, the reaction mixture was adjusted to pH 3 with 1 M aqueous HCl. The resulting mixture was extracted with EA and H2O. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by Combiflash to give 4-amino-8-[trans-4-(tert-butoxycarbonylamino)cyclohexoxy]-5,5-dimethyl-6H-benzo[h]quinazoline-7-carboxylic acid as a white solid (150 mg, 86% yield).

[1315] MS m / z (+IER): 483.3 [M+H] + .

[1316] Step 3: Preparation of 4-amino-8-(trans-4-aminocyclohexoxy)-N-(cyanomethyl)-5,5-dimethyl-6H-benzo[h]quinazoline-7-carboxamide:

[1317] The title compound was obtained as a white solid according to Scheme 1 and similarly to Examples 6 and 9, using 4-amino-8-[trans-4-(tert-butoxycarbonylamino)cyclohexoxy]-5,5-dimethyl-6H-benzo[h]quinazoline-7-carboxylic acid and CAS 6011-14-9 as starting materials.

[1318] 1 H NMR (400 MHz, DMSO-d6+D2O) δ ppm: 9.03 (t, J=5.6 Hz, 1H), 8.55 (s, 1H), 7.98 (d, J=8.4 Hz, 1H), 7.30 (d, J=8.4 Hz, 1H), 4.46 (m, 1H), 4.31 (d, J=5.6 Hz, 2H), 3.08 (m, 1H), 2.66 (s, 2H), 2.10 (m, 2H), 1.98 (m, 2H), 1.49 (m, 4H), 1.26 (s, 6H).

[1319] MS m / z (+IER): 421.1 [M+H] + .

[1320] Preparation of Example 92: 3-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]butan-1-ol:

[1321]

[1322] Step 1: Preparation of (E)-3-[4-amino-8-[trans-4-(tert-butoxycarbonylamino)cyclohexoxy]-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]but-2-enoic acid:

[1323] The title compound was obtained as an off-white solid (360 mg, yield 71%) according to Scheme 1 and in analogy with Example 61 (step 3), using tert-butyl N-[trans-4-[(4-amino-7-bromo-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl)oxy]cyclohexyl]carbamate (500 mg, 0.87 mmol) and CAS 448212-00-8 (1.0 g, 3.96 mmol) as starting materials.

[1324] MS m / z (+IER): 523.4 [M+H] + .

[1325] Step 2: Preparation of tert-butyl N-[trans-4-[[4-amino-7-[(E)-3-hydroxy-1-methyl-prop-1-enyl]-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate:

[1326] Isobutyl chloroformate (113 μL, 0.8 3 mmol) was added to a stirred solution of (E)-3-[4-amino-8-[trans-4-(tert-butoxycarbonylamino)cyclohexoxy]-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]but-2-enoic acid (240 mg, 0.41 mmol) in THF (15 mL) at 0 °C, followed by the addition of NMM (93 μL, 0.83 mmol). After stirring for 30 min at 0 °C, a solution of NaBH4 (64 mg, 1.65 mmol) in H2O (3 mL) was added, and the resulting suspension was stirred at 0 °C for 1 h. The reaction mixture was quenched with saturated aqueous NH4Cl and extracted with EA. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified with Combiflash to afford tert-butyl N-[trans-4-[[4-amino-7-[(E)-3-hydroxy-1-methyl-prop-1-enyl]-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate as an off-white solid (180 mg, 77% yield).

[1327] MS m / z (+IER): 509.4 [M+H] + .

[1328] Step 3: Preparation of 3-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]butan-1-ol:

[1329] The title compound was obtained as a white solid according to Scheme 1 and analogously to Examples 9 and 61, using tert-butyl N-[trans-4-[[4-amino-7-[(E)-3-hydroxy-1-methyl-prop-1-enyl]-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate as a starting material.

[1330] 1 H NMR (400 MHz, DMSO-d6+D2O) δ ppm: 8.22 (s, 1H), 7.90 (d, J=8.8 Hz, 1H), 6.95 (d, J=8.8 Hz, 1H), 4.37 (m, 1H), 3.24 (m, 3H), 3.02 (m, 1H), 2.83 (m, 1H), 2.71 (m, 1H), 2.13 (m, 3H), 1.95 (m, 2H), 1.76 (m, 1H), 1.45 (m, 4H), 1.25 (m, 9H).

[1331] MS m / z (+IER): 411.2 [M+H] + .

[1332] Preparation of Example 97: 4-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]pentanenitrile:

[1333]

[1334] Step 1: Preparation of 3-[4-amino-8-[trans-4-(tert-butoxycarbonylamino)cyclohexoxy]-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]butyl 4-methylbenzenesulfonate:

[1335] TsCl (58 mg, 0.30 mmol) was added to a stirred solution of tert-butyl N-[trans-4-[[4-amino-7-(3-hydroxy-1-methylpropyl)-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate (120 mg, 0.20 mmol) in DCM (10 mL), followed by the addition of DABCO (68 mg, 0.60 mmol). After stirring for 2 h, the reaction mixture was concentrated and the residue was purified by Combiflash to give 3-[4-amino-8-[trans-4-(tert-butoxycarbonylamino)cyclohexoxy]-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]butyl 4-methylbenzenesulfonate as a white solid (140 mg, 90% yield).

[1336] MS m / z (+IER): 665.3 [M+H] + .

[1337] Step 2: Preparation of tert-butyl N-[trans-4-[[4-amino-7-(3-cyano-1-methyl-propyl)-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate:

[1338] KCN (37 mg, 0.54 mmol) was added to a stirred solution of 3-[4-amino-8-[trans-4-(tert-butoxycarbonylamino)cyclohexoxy]-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]butyl 4-methylbenzenesulfonate (140 mg, 0.18 mmol) in DMF (4 mL). After stirring for 1 h at 80°C, the reaction mixture was diluted with H2O. The resulting suspension was filtered, the filter cake was washed with H2O and dried under high vacuum to give tert-butyl N-[trans-4-[[4-amino-7-(3-cyano-1-methylpropyl)-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate as a white solid (93 mg, 91% yield).

[1339] MS m / z (+IER): 520.3 [M+H] + .

[1340] Step 3: Preparation of 4-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]pentanenitrile:

[1341] The title compound was obtained as a white solid (52 mg, yield 50%) according to Scheme 1 and in analogy with Example 9 (step 2), using tert-butyl N-[trans-4-[[4-amino-7-(3-cyano-1-methylpropyl)-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate (50 mg, 0.08 mmol) as a starting material.

[1342] 1 H NMR (400 MHz, DMSO-d6+D2O) δ ppm: 8.22 (s, 1H), 7.94 (d, J=8.8 Hz, 1H), 6.99 (d, J=8.8 Hz, 1H), 4.39 (m, 1H), 3.30 (m, 1H), 3.04 (m, 1H), 2.79 (m, 2H), 2.28 (m, 3H), 2.15 (m, 2H), 1.96 (m, 3H), 1.48 (m, 4H), 1.26 (m, 9H).

[1343] MS m / z (+IER): 420.2 [M+H] + .

[1344] Preparation of Example 108: 3-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]sulfanyl]propanenitrile:

[1345]

[1346] Step 1: Preparation of tert-butyl N-[trans-4-[(4-amino-7-iodo-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl)oxy]cyclohexyl]carbamate:

[1347] (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (13 mg, 0.09 mmol) was added to a stirred suspension of tert-butyl N-[trans-4-[(4-amino-7-bromo-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl)oxy]cyclohexyl]carbamate (100 mg, 0.147 mmol) in dioxane (3 mL), followed by the addition of NaI (53 mg, 0.35 mmol) and CuI (17 mg, 0.09 mmol). After stirring for 24 hours at 110°C, the reaction mixture was filtered and the filtrate was concentrated. The residue was purified by Combiflash to give tert-butyl N-[trans-4-[(4-amino-7-iodo-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl)oxy]cyclohexyl]carbamate as an off-white solid (80 mg, 73% yield).

[1348] MS m / z (+IER): 564.9 [M+H] + .

[1349] Step 2: Preparation of tert-butyl N-[trans-4-[[4-amino-7-(2-cyanoethylsulfanyl)-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate:

[1350] 3-sulfanylpropanenitrile (510 μL, 5.67 mmol) was added to a stirred solution of tert-butyl N-[trans-4-[(4-amino-7-iodo-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl)oxy]cyclohexyl]carbamate (500 mg, 0.71 mmol) in dioxane (15 mL), followed by the addition of Xant-Phos (167 mg, 0.28 mmol), Pd2(dba)3 (132 mg, 0.14 mmol), and DIPEA (504 μL, 0.37 mmol). After stirring for 16 hours at 110°C, the reaction mixture was filtered and the filtrate was concentrated. The residue was purified by Combiflash to give tert-butyl N-[trans-4-[[4-amino-7-(2-cyanoethylsulfanyl)-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate as a yellow solid (300 mg, 0.51 mmol).

[1351] MS m / z (+IER): 524.1 [M+H] + .

[1352] Step 3: Preparation of 3-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]sulfanyl]propanenitrile:

[1353] The title compound was obtained as a white solid (47 mg, yield 63%) according to Scheme 1 and in analogy with Example 9 (step 2), using tert-butyl N-[trans-4-[[4-amino-7-(2-cyanoethylsulfanyl)-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate (100 mg, 0.17 mmol) as a starting material.

[1354] 1 H NMR (400 MHz, DMSO-d6+D2O) δ ppm: 8.24 (s, 1H), 8.08 (d, J=8.8 Hz, 1H), 7.12 (d, J=8.8 Hz, 1H), 4.46 (m, 1H), 3.09 (s, 2H), 3.06 (m, 1H), 3.02 (t, J=6.4 Hz, 2H), 2.55 (t, J=6.4 Hz, 2H), 2.15 (m, 2H), 1.97 (m, 2H), 1.49 (m, 4H), 1.28 (s, 6H).

[1355] MS m / z (+IER): 424.2 [M+H] + .

[1356] Preparation of Example 109: 3-[(4-amino-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)methylamino]propanenitrile:

[1357]

[1358] Step 1: Preparation of (4-amino-5,5-dimethyl-7-nitro-6H-benzo[h]quinazolin-8-yl) trifluoromethanesulfonate:

[1359] N-phenyl bis(trifluoromethanesulfonimide) (7.73 g, 21.22 mmol) was added to a stirred solution of 4-amino-5,5-dimethyl-7-nitro-6H-benzo[h]quinazolin-8-ol (4.5 g, 14.15 mmol) in THF (45 mL), followed by the addition of K2CO3 (5.98 g, 42.44 mmol). After stirring for 2 h at 50 °C, the reaction mixture was filtered. The filtrate was concentrated, and the residue was purified with Combiflash to give (4-amino-5,5-dimethyl-7-nitro-6H-benzo[h]quinazolin-8-yl) trifluoromethanesulfonate as a light yellow solid (3 g, yield 46%). MS m / z (+IER): 419.0 [M+H] + .

[1360] Step 2: Preparation of 5,5-dimethyl-6H-benzo[h]quinazoline-4,7-diamine:

[1361] Triethylsilane (1.25 mL, 7.74 mmol) was added to a stirred solution of (4-amino-5,5-dimethyl-7-nitro-6H-benzo[h]quinazolin-8-yl) trifluoromethanesulfonate (1.2 g, 2.58 mmol) in DMF (30 mL), followed by the addition of Pd(PPh3)4 (304 mg, 0.26 mmol). After stirring for 2 h at 50°C, the reaction mixture was filtered. The filtrate was concentrated, and the residue was purified with Combiflash to give 5,5-dimethyl-6H-benzo[h]quinazoline-4,7-diamine as a light yellow solid (600 mg, yield 77%).

[1362] MS m / z (+IER): 271.1 [M+H] + .

[1363] Step 3: Preparation of 3-[(4-amino-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)methylamino]propanenitrile:

[1364] The title compound was obtained as a white solid according to Scheme 1 and in analogy with Examples 2, 22 and 48 (step 2) using 5,5-dimethyl-6H-benzo[h]quinazoline-4,7-diamine, CAS 98-74-8, CAS 2417-90-5 and CAS 50-00-0 as starting materials.

[1365] 1H NMR (400 MHz, DMSO-d6+D2O) δ ppm: 8.27 (s, 1H), 7.81 (d, J=6.8 Hz, 1H), 7.26 (m, 2H), 3.12 (t, J=6.4 Hz, 2H), 2.88 (s, 2H), 2.66 (t, J=6.4 Hz, 2H), 2.63 (s, 3H), 1.26 (s, 6H).

[1366] MS m / z (+IER): 308.2 [M+H] + .

[1367] Preparation of Example 113: 4-amino-8-(trans-4-aminocyclohexoxy)-N-(cyanomethyl)-N,5,5-trimethyl-6H-benzo[h]quinazoline-7-sulfonamide:

[1368]

[1369] Step 1: Preparation of tert-butyl N-[trans-4-[(4-amino-7-benzylsulfanyl-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl)oxy]cyclohexyl]carbamate:

[1370] The title compound was obtained as a yellow solid (200 mg, yield 71%) according to Scheme 1 and similarly to Example 108 (step 2) using tert-butyl N-[trans-4-[(4-amino-7-iodo-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl)oxy]cyclohexyl]carbamate (300 mg, 0.43 mmol) and CAS 100-53-8 (252 μL, 2.12 mmol) as starting materials. MS m / z (+ESI): 561.1 [M+H] + .

[1371] Step 2: Preparation of tert-butyl N-[trans-4-[(4-amino-7-chlorosulfonyl-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl)oxy]cyclohexyl]carbamate:

[1372] NCS (170 mg, 1.21 mmol) was added to a stirred solution of tert-butyl N-[trans-4-[(4-amino-7-benzylsulfanyl-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl)oxy]cyclohexyl]carbamate (200 mg, 0.30 mmol) in DCM (4 mL) and H2O (0.1 mL), followed by the addition of AcOH (280 μL, 4.80 mmol). After stirring for 16 h, the reaction mixture was diluted with DCM (20 mL) and NaHCO3 (2 g) was added. The resulting suspension was filtered. The filtrate was concentrated and extracted with DCM and H2O. The combined organic layers were dried over Na2SO4, filtered, and concentrated to give tert-butyl N-[trans-4-[(4-amino-7-chlorosulfonyl-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl)oxy]cyclohexyl]carbamate as a yellow liquid (190 mg, 93% yield), which was used in the next step without further purification.

[1373] MS m / z (+IER): 537.0 [M+H] + .

[1374] Step 3: Preparation of tert-butyl N-[trans-4-[[4-amino-7-[cyanomethyl(methyl)sulfamoyl]-5,5-dimethyl-6L-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate:

[1375] 2-(Dimethylamino)acetonitrile (331 μL, 4.24 mmol) was added to a stirred solution of tert-butyl N-[trans-4-[(4-amino-7-chlorosulfonyl-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl)oxy]cyclohexyl]carbamate (190 mg, 0.28 mmol) in DCM (10 mL) and pyridine (2 mL). After stirring for 30 min, the reaction mixture was concentrated and the residue was purified by preparative HPLC to give tert-butyl N-[trans-4-[[4-amino-7-[cyanomethyl(methyl)sulfamoyl]-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate as an off-white solid (160 mg, 0.25 mmol).

[1376] MC m / z (+IER): 571.0 [M+H] + .

[1377] Step 4: Preparation of 4-amino-8-(trans-4-aminocyclohexoxy)-N-(cyanomethyl)-N, 5,5-trimethyl-6H-benzo[h]quinazoline-7-sulfonamide:

[1378] The title compound was obtained as a white solid (105 mg, yield 88%) according to Scheme 1 and similarly to Example 9 (step 2) using tert-butyl N-[trans-4-[[4-amino-7-[cyanomethyl(methyl)sulfamoyl]-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate (160 mg, 0.25 mmol) as a starting material.

[1379] 1 H NMR (400 MHz, DMSO-d6+D2O) δ ppm: 8.31 (d, J=8.8 Hz, 1H), 8.27 (s, 1H), 7.35 (d, J=8.8 Hz, 1H), 4.56 (m, 1H), 4.43 (s, 2H), 3.30 (s, 2H), 3.00 (m, 1H), 2.87 (s, 3H), 2.12 (m, 2H), 1.97 (m, 2H), 1.60 (m, 2H), 1.47 (m, 2H), 1.26 (s, 6H).

[1380] MC m / z (+IER): 471.1 [M+H] + .

[1381] Preparation of Example 115: 3-[(4-amino-8-bromo-5,5-dimethyl-6H-benZo[h]quinazolin-7-yl)methylamino]propanenitrile:

[1382]

[1383] [4-Amino-7-[2-cyanoethyl(methyl)amino]-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]trifluoromethanesulfonate was obtained as a white solid according to Scheme 1 and similarly to Examples 2, 22 and 48 using 4-amino-5,5-dimethyl-7-nitro-6H-benzo[h]quinazolin-8-ol and CAS 98-74-8, CAS 2417-90-5 and CAS 50-00-0 as starting materials.

[1384] MC m / z (+IER): 456.2 [M+H] + .

[1385] Step 1: Preparation of [4-amino-7-[2-cyanoethyl(methyl)amino]-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]boronic acid:

[1386] Bis(pinacolato)diboron (2.05 g, 7.90 mmol) was added to a stirred solution of [4-amino-7-[2-cyanoethyl(methyl)amino]-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]trifluoromethanesulfonate (300 mg, 0.53 mmol) in DMF (15 mL), followed by the addition of Pd(dppf)Cl2 (78 mg, 0.10 mmol) and K2CO3 (223 mg, 1.58 mmol). After stirring for 8 h at 90°C, the reaction mixture was filtered. The filtrate was concentrated and the residue was purified using Combiflash to give [4-amino-7-[2-cyanoethyl(methyl)amino]-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]boronic acid as a white solid (80 mg, 39% yield).

[1387] 1 H NMR (400 MHz, DMSO-d6+D2O) δ ppm: 8.27 (s, 1H), 7.84 (d, J=8.0 Hz, 1H), 7.33 (d, J=8.0 Hz, 1H), 3.28 (m, 2H), 2.88 (m, 2H), 2.74 (s, 3H), 2.67 (m, 2H), 1.28 (s, 6H).

[1388] MS m / z (+IER): 352.3 [M+H] + .

[1389] Step 2: Preparation of 3-[(4-amino-8-bromo-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)methylamino]propanenitrile:

[1390] CuBr2 (964 mg, 4.30 mmol) was added to a stirred solution of [4-amino-7-[2-cyanoethyl(methyl)amino]-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]boronic acid (500 mg, 0.43 mmol) in MeOH (10 mL) and H2O (10 mL). After stirring for 10 h at 80°C, the reaction mixture was filtered. The filtrate was concentrated, and the residue was extracted with DCM and H2O. The combined organic layers were dried over Na2SO4, filtered, concentrated, and the residue was purified by preparative HPLC to give 3-[(4-amino-8-bromo-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)-methylamino]propanenitrile as a white solid (44 mg, 26% yield).

[1391] 1 H NMR (400 MHz, DMSO-d6+D2O) δ ppm: 8.27 (s, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.55 (d, J=8.4 Hz, 1H), 3.41 (m, 1H), 3.34 (m, 1H), 2.96 (m, 2H), 2.78 (s, 3H), 2.70 (m, 1H), 2.59 (m, 1H), 1.30 (s, 3H), 1.28 (s, 3H).

[1392] MS m / z (+IER): 386, 0, 388, 1 [M+H] + .

[1393] Preparation of Example 118: 3-[[4-amino-5,5-dimethyl-8-(4-methylpiperazin-1-yl)-6H-benzo[h]quinazolin-7-yl]methylamino]propanenitrile:

[1394]

[1395] Step 1: Preparation of 5,5-dimethyl-8-(4-methylpiperazin-1-yl)-7-nitro-6H-benzo[h]quinazolin-4-amine:

[1396] 1-Methylpiperazine (527 mg, 5.16 mmol) was added to a stirred solution of (4-amino-5,5-dimethyl-7-nitro-6H-benzo[h]quinazolin-8-yl) trifluoromethanesulfonate (400 mg, 0.86 mmol) in ACN (40 mL). After stirring for 16 h at 50 °C, the reaction mixture was concentrated and the residue was extracted with EA and H2O. The combined organic layers were dried over Na2SO4, filtered and concentrated to give 5,5-dimethyl-8-(4-methylpiperazin-1-yl)-7-nitro-6H-benzo[h]quinazolin-4-amine as a yellow solid (317 mg, yield 99%), which was used in the next step without further purification.

[1397] 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.30 (s, 1H), 8.20 (d, J=8.4 Hz, 1H), 7.35 (d, J=8.4 Hz, 1H), 6.59 (br, 2H), 2.97 (m, 4H), 2.59 (s, 2H), 2.40 (m, 4H), 2.21 (s, 3H), 1.27 (s, 6H).

[1398] NS m / z (+IER): 369.0 [M+H] + .

[1399] Step 2: Preparation of 3-[[4-amino-5,5-dimethyl-8-(4-methylpiperazin-1-yl)-6H-benzo[h]quinazolin-7-yl]methylamino]propanenitrile:

[1400] The title compound was obtained as a white solid according to Scheme 1 and similarly to Examples 2, 22 and 48, using 5,5-dimethyl-8-(4-methylpiperazin-1-yl)-7-nitro-6H-benzo[h]quinazolin-4-amine, CAS 98-74-8, CAS 2417-90-5 and CAS 50-00-0 as the starting materials.

[1401] 1 H NMR (400 MHz, DMSO-d6+D2O) δ ppm: 8.24 (s, 1H), 7.83 (d, J=8.4 Hz, 1H), 7.06 (d, J=8.4 Hz, 1H), 3.61 (m, 1H), 3.31 (m, 1H), 2.97 (m, 4H), 2.80 (s, 3H), 2.66 (m, 8H), 2.25 (s, 3H), 1.38 (s, 3H), 1.17 (s, 3H).

[1402] MS m / z (+IER): 406.2 [M+H] + .

[1403] Preparation of Example 120: 1-(4-amino-8-bromo-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)pyrrolidine-3-carbonitrile:

[1404]

[1405] Step 1: Preparation of 8-bromo-5,5-dimethyl-7-nitro-6H-

[1406] benzo[h]quinazolin-4-amine:

[1407] HBr (33% in AcOH, 50 mL) was added to a stirred suspension of (4-amino-5,5-dimethyl-7-nitro-6H-benzo[h]quinazolin-8-yl) trifluoromethanesulfonate (1.4 g, 3.01 mmol) in AcOH (25 mL). After stirring for 16 h at 130°C, the reaction mixture was diluted with H2O (150 mL). The resulting suspension was filtered, the precipitate was washed with H2O and dried under high vacuum. The resulting off-white solid was taken up in THF (300 mL) and saturated aqueous NaHCO3 (100 mL). After stirring for 10 min, the organic layer was separated, washed with H2O and brine, dried over Na2SO4, filtered and concentrated to give 8-bromo-5,5-dimethyl-7-nitro-6H-benzo[h]quinazolin-4-amine as a yellow solid (950 mg, 72% yield), which was used in the next step without further purification.

[1408] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 8.33 (s, 1H), 8.18 (d, J=8.8 Hz, 1H), 7.84 (d, d=8.8 Hz, 1H), 6.73 (b, 2H), 2.71 (s, 2H), 1.28 (s, 6H).

[1409] MS m / z (+IER): 348.9, 350.9 [M+H] + .

[1410] Step 2: Preparation of 8-bromo-5,5-dimethyl-6H-benzo[h]quinazoline-4,7-diamine:

[1411] Iron (1.24 g, 21.77 mmol) was added to a stirred suspension of 8-bromo-5,5-dimethyl-7-nitro-6-L-benzo[h]quinazolin-4-amine (950 mg, 2.18 mmol) in EtOH (80 mL) and H2O (8 mL), followed by the addition of NH4Cl (594 mg, 10.88 mmol). After stirring for 1 h at 80°C, the reaction mixture was filtered. The filtrate was concentrated, and the residue was poured into H2O (60 mL). The resulting suspension was sonicated, filtered, the precipitate was washed with H2O and dried under high vacuum to give 8-bromo-5,5-dimethyl-6H-benzo[h]quinazoline-4,7-diamine as an off-white solid (700 mg, 91% yield), which was used in the next step without further purification.

[1412] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 8.61 (s, 1H), 7.54 (d, J=8.4 Hz, 1H), 7.04 (d, J=8.4 Hz, 1H), 2.21 (s, 2H), 1.30 (s, 6H).

[1413] MS m / z (+IER): 319.0, 321.0 [M+H] + .

[1414] Step 3. Preparation of 1-(4-amino-8-bromo-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)pyrrolidine-3-carbonitrile:

[1415] The title compound was obtained as a white solid (50 mg, yield 15%) according to Scheme 1, similarly to Example 9 (step 1), using 8-bromo-5,5-dimethyl-6H-benzo[h]quinazoline-4,7-diamine (270 mg, 0.76 mmol) and CAS 1823050-70-9 (282 mg, 2.28 mmol) as starting materials.

[1416] 1 H NMR (400 MHz, DMSO-d6+D2O) δ ppm: 8.28 (s, 1H), 7.84 (d, J=8.4 Hz, 1H), 7.57 (d, J=8.4 Hz, 1H), 3.57 (m, 2H), 3.32 (m, 3H), 2.86 (m, 2H), 2.41 (m, 1H), 2.31 (m, 1H), 1.29 (s, 3H), 1.26 (s, 3H).

[1417] MS m / z (+IER): 398.1, 400.1 [M+H] + .

[1418] Preparation of Example 121: (5R)-5-[[(4-amino-8-bromo-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)amino]methyl]oxazolidin-2-one:

[1419]

[1420] Step 1: Preparation of (4-amino-5,5-dimethyl-7-nitro-6H-benzo[h]quinazolin-8-yl) trifluoromethanesulfonate:

[1421] N-phenyl bis(trifluoromethanesulfonimide) (7.73 g, 21.22 mmol) was added to a stirred solution of 4-amino-5,5-dimethyl-7-nitro-6H-benzo[h]quinazolin-8-ol (4.5 g, 14.15 mmol) in THF (45 mL), followed by the addition of K2CO3 (5.98 g, 42.44 mmol). After stirring for 2 h at 50 °C, the reaction mixture was filtered. The filtrate was concentrated, and the residue was purified with Combiflash to give (4-amino-5,5-dimethyl-7-nitro-6H-benzo[h]quinazolin-8-yl) trifluoromethanesulfonate as a light yellow solid (3 g, yield 46%).

[1422] MS m / z (+IER): 419.0 [M+H] + .

[1423] Step 2: Preparation of 8-bromo-5,5-dimethyl-7-nitro-6H-benzo[h]quinazolin-4-amine:

[1424] HBr (33% in AcOH, 50 mL) was added to a stirred suspension of (4-amino-5,5-dimethyl-7-nitro-6H-benzo[h]quinazolin-8-yl) trifluoromethanesulfonate (1.4 g, 3.01 mmol) in AcOH (25 mL). After stirring for 16 h at 130°C, the reaction mixture was diluted with H2O (150 mL). The resulting suspension was filtered, the precipitate was washed with H2O and dried under high vacuum. The resulting off-white solid was taken up in THF (300 mL) and saturated aqueous NaHCO3 (100 mL). After stirring for 10 min, the organic layer was separated, washed with H2O and brine, dried over Na2SO4, filtered and concentrated to give 8-bromo-5,5-dimethyl-7-nitro-6H-benzo[h]quinazolin-4-amine as a yellow solid (950 mg, 72% yield), which was used in the next step without further purification.

[1425] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 8.33 (s, 1H), 8.18 (d, J=8.8 Hz, 1H), 7.84 (d, J=8.8 Hz, 1H), 6.73 (br, 2H), 2.71 (s, 2H), 1.28 (s, 6H).

[1426] MS m / z (+IER): 348.9, 350.9 [M+H] + .

[1427] Step 3: Preparation of 8-bromo-5,5-dimethyl-6H-benzo[h]quinazoline-4,7-diamine:

[1428] Iron (1.24 g, 21.77 mmol) was added to a stirred suspension of 8-bromo-5,5-dimethyl-7-nitro-6-L-benzo[h]quinazolin-4-amine (950 mg, 2.18 mmol) in EtOH (80 mL) and H2O (8 mL), followed by the addition of NH4Cl (594 mg, 10.88 mmol). After stirring for 1 h at 80°C, the reaction mixture was filtered. The filtrate was concentrated, and the residue was poured into H2O (60 mL). The resulting suspension was sonicated, filtered, the precipitate was washed with H2O and dried under high vacuum to give 8-bromo-5,5-dimethyl-6H-benzo[h]quinazoline-4,7-diamine as an off-white solid (700 mg, 91% yield), which was used in the next step without further purification.

[1429] 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 8.61 (s, 1H), 7.54 (d, J=8.4 Hz, 1H), 7.04 (d, J=8.4 Hz, 1H), 2.21 (s, 2H), 1.30 (s, 6H).

[1430] MS m / z (+IER): 319.0, 321.0 [M+H] + .

[1431] Step 4: Preparation of N-(4-amino-8-bromo-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)-4-nitrobenzenesulfonamide:

[1432] NsCl (1.06 g, 4.66 mmol) was added to a stirred solution of 8-bromo-5,5-dimethyl-6H-benzo[h]quinazoline-4,7-diamine (700 mg, 1.86 mmol) in pyridine (12 mL). After stirring for 5 h, the reaction mixture was poured into H2O. The resulting mixture was concentrated, and the residue was purified with Combiflash to give N-(4-amino-8-bromo-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)-4-nitrobenzenesulfonamide as a yellow solid (320 mg, 22% yield).

[1433] 1 H NMR (400 MHz, DMSO-d6) δ (ppm): 10.36 (s, 1H), 8.41 (d, J=8.8 Hz, 2H), 8.29 (s, 1H), 8.99 (d, J=8.8 Hz, 2H), 7.94 (d, J=8.8 Hz, 1H), 7.58 (d, J=8.8 Hz, 1H), 6.57 (b, 2H), 2.70 (s, 2H), 1.18 (s, 6H).

[1434] MS m / z (+IER): 504.0, 506.0 [M+H] + .

[1435] Step 5: Preparation of (5S)-5-(iodomethyl)oxazolidin-2-one:

[1436] To a stirred solution of (5S)-5-(chloromethyl)oxazolidin-2-one (200 mg, 1.40 mmol) in acetone (2 mL) in a sealed tube was added NaI (637 mg, 4.20 mmol). After stirring for 16 h at 80°C, the reaction mixture was concentrated and the residue was purified by Combiflash to give {5S)-5-(iodomethyl)oxazolidin-2-one as an off-white solid (120 mg, yield 34%).

[1437] 1 H NMR (400 MHz, DMSO-d6) δ ppm: 7.61 (s, 1H), 4.57 (m, 1H), 3.57 (t, J=8.8 Hz, 1H), 3.46 (m, 2H), 3.09 (m, 1H).

[1438] MS m / z (+IER): 228.0 [M+H] + .

[1439] Step 6: Preparation of N-(4-amino-8-bromo-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)-4-nitro-N-[[(5S)-2-oxooxazolidin-5-yl]methyl]benzenesulfonamide:

[1440] (5S)-5-(iodomethyl)oxazolidin-2-one (4 g, 10.57 mmol) was added to a stirred solution of N-(4-amino-8-bromo-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)-4-nitrobenzenesulfonamide (300 mg, 0.53 mmol) in DMF (15 mL), followed by the addition of Cs2CO3 (1.78 g, 5.35 mmol). After stirring for 16 h at 100°C, the solvent was removed and the residue was extracted with EA and H2O. The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated, and the residue was purified using Combiflash to give N-(4-amino-8-bromo-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)-4-nitro-N-[[(5S)-2-oxooxazolidin-5-yl]methyl]benzenesulfonamide as a yellow solid (290 mg, 81% yield).

[1441] 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.40 (d, J=8.8 Hz, 2H), 8.32 (s, 1H), 8.13 (d, J=8.8 Hz, 2H), 8.06 (d, J=8.8 Hz, 1H), 7.61 (m, 2H), 6.62 (s, 2H), 4.89 (m, 1H), 3.82 (m, 1H), 3.60 (m, 1H), 3.47 (m, 1H), 2.98 (m, 1H), 2.90 (m, 1H), 2.67 (m, 1H), 1.36 (s, 3H), 1.29 (s, 3H).

[1442] MS m / z (+IER): 603.1, 605.1 [M+H] + .

[1443] Step 7: Preparation of (5R)-5-[[(4-amino-8-bromo-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)amino]methyl]oxazolidin-2-one:

[1444] p-Toluenethiol (157 mg, 1.25 mmol) was added to a stirred solution of N-(4-amino-8-bromo-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)-4-nitro-N-[[(5S)-2-oxooxazolidin-5-yl]methyl]benzenesulfonamide (280 mg, 0.42 mmol) in DMF (6 mL), followed by the addition of K2CO3 (177 mg, 1.25 mmol). After stirring for 2 h at 50°C, the solvent was removed and the crude product was purified by preparative HPLC to give (5R)-5-[[(4-amino-8-bromo-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)amino]methyl]oxazolidin-2-one as a white solid (32 mg, 18% yield).

[1445] 1 H NMR (400 MHz, DMSO-d6+D2O) δ ppm: 8.27 (s, 1H), 7.62 (d, J=8.4 Hz, 1H), 7.50 (d, J=8.4 Hz, 1H), 4.67 (m, 1H), 3.50 (m, 2H), 3.18 (m, 2H), 2.83 (s, 2H), 1.28 (s, 3H), 1.26 (s, 3H).

[1446] MS m / z (+IER): 418.2, 420.2 [M+H] + .

[1447] Preparation of Example 122: N7-[[5-(1-fluoroethyl)-1,3,4-oxadiazol-2-yl]methyl]-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazoline-4,7-diamine:

[1448]

[1449] Step 1: Preparation of ethyl 2-[2-(2-fluoropropanoyl)hydrazino]-2-oxoacetate:

[1450] EDCI (10.44 g, 53.93 mmol) was added to a stirred solution of 2-fluoropropanoic acid (3.48 g, 35.95 mmol) and ethyl 2-hydrazino-2-oxoacetate (5 g, 35.95 mmol) in DCM (50 mL). After stirring for 16 h, the reaction mixture was concentrated, and the residue was purified by column chromatography (silica gel; DCM:MeOH; 10:0 to 10:1; v:v) to give ethyl 2-[2-(2-fluoropropanoyl)hydrazino]-2-oxoacetate as a colorless oil (6.5 g, yield 79%).

[1451] 1 H NMR (400 MHz, CDCl3) δ ppm: 9.37 (s, 1H), 8.76 (s, 1H), 5.18 (dk, J=6.8, 48.4 Hz, 1H), 4.41 (k, J=7.2 Hz, 2H), 1.66 (dd, J=6.8, 25.2 Hz, 3H), 1.41 (t, J=7.2 Hz, 3H).

[1452] Step 2: Preparation of ethyl 5-(1-fluoroethyl)-1,3,4-oxadiazole-2-carboxylate:

[1453] TsCl (6.56 g, 34.05 mmol) was added to a stirred solution of ethyl 2-[2-(2-fluoropropanoyl)hydrazino]-2-oxoacetate (6.5 g, 28.38 mmol) in DCM (65 mL), followed by the addition of TEA (4.78 mL, 34.05 mmol). After stirring for 16 h, the reaction mixture was concentrated, and the residue was purified by column chromatography (silica gel; DCM:MeOH; 10:0 to 10:1; v:v) to give ethyl 5-(1-fluoroethyl)-1,3,4-oxadiazole-2-carboxylate as a colorless oil (3.5 g, yield 59%).

[1454] 1 H NMR (400 MHz, CDCl3) δ ppm: 5.84 (m, 1H), 4.55 (k, J=7.2 Hz, 2H), 1.88 (m, 3H), 1.48 (t, J=7.2 Hz, 3H).

[1455] Step 3. Preparation of N7-[[5-(1-fluoroethyl)-1,3,4-oxadiazol-2-yl]methyl]-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazoline-4,7-diamine:

[1456] The title compound was obtained as an off-white solid according to Scheme 1 similarly to Examples 5, 26 and 48, using 8-methoxy-5,5-dimethyl-6H-benzo[h]quinazoline-4, 7-diamine, ethyl 5-(1-fluoroethyl)-1,3,4-oxadiazole-2-carboxylate and CAS 98-74-8 as the starting materials.

[1457] 1 H NMR (400 MHz, DMSO-d6+D2O) δ ppm: 8.21 (s, 1H), 7.69 (d, J=8.4 Hz, 1H), 6.87 (d, J=8.4 Hz, 1H), 5.90 (dk, J=6.4, 47.2 Hz, 1H), 4.43 (s, 2H), 3.73 (s, 3H), 2.72 (s, 2H), 1.63 (dd, J=6.4, 24.0 Hz, 3H), 1.23 (s, 6H).

[1458] MS m / z (+IER): 399.3 [M+H] + .

[1459] BIOLOGICAL EXAMPLES

[1460] CLK3 kinase assay

[1461] CLK3 kinase activity was measured using LANCE® Ultra technology (PerkinElmer), essentially according to the supplier’s recommendations. Briefly, 2.5 µL of the test sample at 4x the final desired concentration in 4% DMSO was pipetted into white, round-bottomed, low-volume 384-well plates (Corning, cat.№ 4512). Then, 5 µL of a mixture containing recombinant human CLK3 (Thermo Fisher Scientific, cat.№PV3826) and the labeled peptide substrate ULight™-CREBtide (PerkinElmer, cat.№TRF0107) prepared in 1.33x kinase buffer (Thermo Fisher Scientific, cat.№PV3189) were added. Finally, reactions were started by adding 2.5 µl of 4× ATP in kinase buffer. The plates were sealed with adhesive film and incubated for 3 hours at 30°C in the dark. The final concentrations of CLK3, ULight™-CREBtide, and ATP were 0.5 nM, 50 nM, and 300 µM, respectively. 5 µl of 40 mM EDTA were then added to stop the reaction. Eu-anti-phospho-CREB antibody (PerkinElmer, cat.(#TRF0200) diluted in LANCE® Detection Buffer (PerkinElmer, cat.#CR97) was added to a final concentration of 2 nM, and reactions were incubated for 1 hour at room temperature in the dark. Signals were measured using a Synergy 4 reader (BioTek) with a 320 / 80 nm filter for excitation and 620 / 10 nm and 665 / 8 nm filters for donor and acceptor emission, respectively. Relative inhibition values.

[1462] was calculated by normalizing the raw data using solvent control wells (0% inhibition) and wells without ATP (100% inhibition). IC values 50 were calculated by fitting the concentration-response data to a sigmoidal 4-parameter logistic model. The results are presented in Table 2 below. IC50 values ​​for CLK3 are determined based on repeated measurements at ten different concentrations (serial dilutions of 1:3).

[1463] MDA-MB-231 and CAL-51 Proliferation Assay

[1464] Cells (MDA-MB-231 (American Type Culture Collection (ATCC), # HTB-26) or CAL-51 (Deutsche Sammlung von Mikroorganismen unci Zellkulturen (DSMZ), # ACC302), as appropriate) were cultured in DMEM high glucose (4.5 g / L) with L-glutamine (BioConcept, Cat. No. 1-26F03-I) supplemented with 1% Na-pyruvate (Sigma, Cat. No. S8636), 1% penicillin-streptomycin (BioConcept, Cat. No. 4-01F00H), and 10% FBS (Sigma, Cat. No. F9665) using standard procedures. Cells were seeded in black, 384-well, clear-bottomed tissue culture plates (Greiner Bio-One, cat. no. 781091) at a density of 750 cells per well in 20 µl of medium, and the plates were incubated overnight at 37°C with 5% CO2 before treatment. Experimental compounds were serially diluted in DMSO to 200-fold the final desired concentrations. The solutions were then diluted 1:40 with culture medium, and 5 µl aliquots were added to wells containing cells. The final DMSO concentration was 0.5%.The plates were incubated for 72 hours, after which cell numbers were measured using Y0-PR0™-1 iodide (ThermoFisher Scientific, cat. #Y3603) according to the manufacturer's recommendations. A solution of 12.5 μM Y0-PR0™-1 iodide in 5x YO-PRO buffer (100 mM Na-citrate, 130 mM NaCl, pH 4) was combined with an equal volume of lysis buffer (0.6% NP-40, 30 mM EDTA, 30 mM EGTA, 0.33x YO-PRO buffer), and 12.5 μl of the mixture was dispensed into each well. The plates were incubated at room temperature in the dark for 30 minutes. Fluorescence intensity was then measured on a Synergy 4 reader (BioTek) using 485 / 20 nm and 530 / 25 nm filters for excitation and emission, respectively. Relative proliferation values ​​were calculated by normalizing the raw data using DMSO-treated cells (100% proliferation) and signals obtained from cells assessed during compound addition (0% proliferation).Concentration-response data were fitted to a sigmoidal 4-parameter logistic model with a maximum limit of 100%. GI50 values ​​were calculated from the curves as the compound concentrations that reduced proliferation by 50%. The results are presented in Table 2 below.

[1465]

[1466]

[1467]

[1468]

[1469]

[1470] Evaluation of the inhibition of phospho-SKSF6 levels in MDA-MB-468 cells

[1471] MDA-MB-468 cells (ATCC, HTB-132) were cultured in DMEM (BioConcept, cat. No. 1-26F03) supplemented with 10% FBS (Sigma, cat. No. F9665), 1% Na-pyruvate (Sigma, cat. No. S8636), 1% penicillin-streptomycin G (BioConcept cat. No. 4-01F00-H). When the cells reached a density of 70% in 6-well plates (TPP cat. No. 92006), they were treated with either the test compound carrier DMSO or experimental compounds at a final concentration of 10 or 100 nM for 2 hours. Afterwards, the culture medium was removed and the cells were collected by scraping in lysis buffer (20 mM Tris-HCl, pH 7.5, 150 mM NaCl, 1 mM EGTA, 1 mM EDTA, 1% Triton, and 1% NP-40) containing protease and phosphatase inhibitors (Halt™ Protease&Phosphatase inhibitor cocktail 100× ThermoScientific cat. no. 1861281) and 1 mM PMSF (Fluka cat. no. 93482). Cleared lysates were stored in Eppendorf tubes at -80°C until use, and the protein concentration of the lysates was determined using Pierce 660 nm Protein Assay Reagent (ThermoScientific cat.№22660). Twenty micrograms of proteins were diluted in 4-fold Laemmli buffer (Biorad cat.№161-0747) containing 10% beta-mercaptoethanol, separated by SDS-PAGE using 10% gels, and then transferred to PVDF membranes (Trans Blot Turbo Transfer Pack BioRad cat.™1704156) using the semi-dry blotting method of the Trans-Blot® Turbo™ system (BioRad). Primary antibodies were incubated in TBS-0.1% Tween-20 buffer containing 3% bovine albumin BSA Fr.V (Millipore cat.№81-053-3) overnight at 4°C. The following primary antibodies were used: Mouse anti-phosphoepitope of SR proteins, clone 1H4 (Millipore cat. No. MABE50), diluted 1:5000, and rabbit anti-GAPDH clone 14C10 (Cell Signaling cat. No. 2118S) as a control for equal protein loading, diluted 1:2000. HRP-conjugated secondary antibodies were incubated for 1 hour at room temperature, diluted 1:5000 in TBS-0.1% Tween-20 buffer containing 5% non-fat bovine milk (Sigma cat. No. M7409).The following secondary antibodies were used: Goat anti-mouse HRP (Jackson cat. No. 115-035-146) and goat anti-rabbit HRP (Jackson cat. No. 111-035-144). Membranes were incubated with ECL Prime Western Blot Detection Reagent (Amersham, cat. No. RPN2236) to detect specific signals using a Fusion SOLO S instrument (Vilber Lourmat). The pixel intensities of phopsho-SRSF6 (MW 55 kDa relative to markers) and GAPDH (MW 37 kDa) signals in Western blots were determined using Evolution-Capt image analysis software (v17.01, Vilber Lourmat). To determine the phospho-SRSF6 signal at the baseline level, a DMSO control was used, the phospho-SRSF6 signals for each sample were normalized to the corresponding GAPDH signals, and the percentage signal intensity of P-SRSF6 at 10 and 100 nM compound was calculated compared to the DMSO control (see Figure 1).

[1472] Several examples of the invention were tested for inhibition of phospho-SRSF6 levels in MDA-MB-468 cells, which showed an inhibition level of more than 50% compared to the DMSO control when tested at a concentration of 100 or 10 nM. The results are shown below in Table 3.

[1473]

[1474] Mouse xenograft models

[1475] The efficacy of the compound from Example 13 was evaluated in a mouse xenograft model. For this purpose, a SW480 colorectal cancer xenograft model was used, in which tumor cells were injected subcutaneously into the flanks of immunodeficient NOD / SCID mice (absence of functional / mature T and B cells, functional immature macrophages, and residual NK cell function). SW480 cells (ATCC, #CCL-228) were cultured in high-glucose RPMI medium supplemented with 10% heat-inactivated fetal bovine serum at 37°C. SW480 cells were harvested when they grew exponentially.

[1476] Female NOD / SCID mice aged 8-9 weeks weighing approximately 23 g (Jiangsu GemPharmatech Co., Ltd) were used for the study. Mice were inoculated subcutaneously in the flank area with 1×10 7 SW480 cells in PBS mixed with Matrigel™ (1:1) in a final injection volume of 0.2 ml / mouse. Once the tumors reached an average size of 100-150 mm 3 , Pair-matched studies were performed to assign mice to the different treatment groups. Mice in the control group were administered vehicle (20% propylene glycol; 79.2% 10 mM citric acid; 0.8% Tween™ 80) twice daily and twice weekly (BID*BW) for 3 weeks at a compound administration volume of 10 mL / kg. A solution of the compound from Example 13 was administered orally at a volume of 10 mL / kg twice daily*BW at a dose of 45 mg / kg on days 1-10 and 50 mg / kg on days 11-22 (doses represent the free base equivalent).

[1477] Tumor volumes (expressed in mm 3) were measured in duplicate with calipers on days 1, 4, 8, 11, 15, 18, 22, and 23 of the treatment period. Figures 2A and 2B depict tumor growth and body weight changes during the treatment period. Results represent mean ± SEM (n=8). Figure 2C shows changes in tumor volume at the end of the study. Changes in tumor volume between the vehicle and compound of Example 13 treatment groups were compared by a two-tailed t-test using GraphPad™ Prism version 9. During the treatment period, tumor volumes in mice treated with compound of Example 13 at 45 mg / kg twice daily and twice weekly (BID*BW) were consistently smaller compared to tumor volumes in vehicle-treated animals (Figures 2A and 2B).At the study endpoint (day 23), tumor volumes in the group treated with Example 13 were 61% of those in the vehicle group (Figure 2C); p=0.06. Treatment with Example 13 was tolerated with a maximum body weight loss of 5% on day 17 (Figure 2B).

Claims

1. Compound of formula (I) or its pharmaceutically acceptable salt, where R a and R b both are -CH3; A is -CH2-; T represents -N(R 11 )-; R 11 represents hydrogen, C1-C4 alkylene-R 11a or C3-C6cycloalkyl; R 11a is hydrogen; R 1 represents -YR 3 ; Y is C1-C6 alkylene, wherein the alkylene moiety may include a 3-5 membered saturated carbocyclic ring as part of the moiety; R 3 represents -CN or the P cycle; the P ring is a 3-6 membered saturated heterocyclic ring containing one N and one O and substituted with oxo; X is -O- or X is a bond when R 2 is a halogen; R2 is a halogen, C1-C4 alkyl, substituted by one R 7 , or is a 4-7-membered saturated carbocyclic ring substituted with one R 8 ; R 7 represents -N(R 7a )R 7b ; each R 7a and R 7b independently represents hydrogen or C1-C4alkylene-R 7с ; each R 7c independently represents hydrogen; R 8 represents -N(R 8a )R 8b ; R 8a and R 8b , if they do not together form a ring, independently represent hydrogen or C1-C4 alkylene-R 8c or R 8a and R 8b together can form a 4-7-membered saturated heterocyclic ring containing one O; and R 8c is hydrogen.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the structure 3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the structure 4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the structure 5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the structure 6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the structure

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