Benzo[h]quinazolin-4-amine derivatives for cancer treatment

Abstract

The present invention relates to a compound of formula (I) [Formula 1] TIFF2024541948000090.tif50133 and pharma- ceutical acceptable salts thereof, wherein Ra and Rb are both -CH3, or Ra and Rb together form a -CH2-CH2-CH2- or -CH2-CH2-CH2-CH2- bridging moiety, A is -CH2- or -C(=O)-, T is -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)-, wherein R1, R2, R11, R12, R13 and R14 are as defined in the claims, and the present invention also provides a method of using the compound for the treatment of a neoplastic disease, e.g., cancer.

Description

[Technical Field]

[0001] The present invention relates to compounds that target the CDC2-like kinase (CLK) family and their use in the treatment of neoplastic 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 group of kinases and include four family members: CLK1, 2, 3, and 4. CLKs are known to play an important role in regulating alternative splicing (AS) by phosphorylating the serine-arginine-rich (SR) family of splicing factors. In eukaryotes, alternative splicing of transcripts is an important regulatory mechanism, allowing 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):265-75). SR protein phosphorylation must be tightly regulated for nuclear import, spliceosome assembly, and ultimately correct splicing, particularly to promote exon inclusion. Small molecule inhibitors of CLK have been shown to be effective in preclinical animal cancer models (Yoshida T et al., Cancer Res. 2015, 75(7):1516-26; Iwai K et al., EMBO Mol Med. 2018, 10(6):e8289; Zhu D et al., Mol Cancer Ther. 2018, 17(8):1727-1738). Thus, targeting CLK offers potential for anticancer therapy, for example, in splicing factor-mutated cancers, providing a compelling rationale for exploiting aberrant splicing as a vulnerability and therapeutic opportunity.

[0003] In a first aspect, the present invention provides a compound of formula (I)

[0004] [ka]

[0005] and pharmaceutically acceptable salts thereof, wherein: Ra and Rb are both -CH3, or Ra and Rb together form a -CH2-CH2-CH2- or a -CH2-CH2-CH2-CH2- bridging moiety; A is -CH2- or -C(=O)-; T is -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)-; When R does not form a ring with R or R, it is hydrogen, C-C alkylene-R, C-C haloalkylene-R, or C-C cycloalkyl, wherein the cycloalkyl is optionally substituted with one or two R; each R, when not forming a ring with R, is independently hydrogen, C-C alkylene-R, C-C haloalkylene-R, or C-C cycloalkyl, wherein the cycloalkyl is optionally substituted with one or two R; When R14 does not form a ring with R1 or R2, it is hydrogen, C1-C4 alkylene-R14a, C1-C4 haloalkylene-R14a or C3-C6 cycloalkyl, wherein the cycloalkyl is optionally substituted with one or two R14b; each R, R, and R is independently hydrogen, halogen, —OH, —CN, —NH, —O—C-C alkyl, —O—C-C haloalkyl, —NH(C-C alkyl), or —N(C-C alkyl); each R, R, and R is independently halogen, —OH, —CN, —NH, —O—C-C alkyl, —O—C-C haloalkyl, —NH(C-C alkyl), or —N(C-C alkyl); R13 is hydrogen, C1-C4 alkyl or C1-C4 haloalkyl; R2 and R11, R2 and R12, or R2 and R14 may together form a partially unsaturated 6- to 7-membered heterocyclic ring containing no additional heteroatoms as ring members, the heterocyclic ring optionally being substituted with one or two R2a; each R2a is independently halogen, —OH, —CN, —NH2, —O—C1-C2 alkyl, —O—C1-C2 haloalkyl, —NH(C1-C2 alkyl), or —N(C1-C2 alkyl)2; 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 selected from N, O and S as ring members, the heterocyclic ring being 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 selected from N and O as ring members, the heteroaryl ring being optionally substituted with one to three R1b; each R is independently halogen, —OH, —CN, —NH, C-C alkylene-R, C-C haloalkylene-R, —O—C-C alkyl, —O—C-C haloalkyl, —NH(C-C alkyl), —N(C-C alkyl), —C(═O)NH, —C(═O)NH(C-C alkyl), —C(═O)N(C-C alkyl) or oxo; each R is independently halogen, —OH, —CN, —NH, C-C alkylene-R, C-C haloalkylene-R, —O—C-C alkyl, —O—C-C haloalkyl, —NH(C-C alkyl) or —N(C-C alkyl), —C(═O)NH, —C(═O)NH(C-C alkyl) or —C(═O)N(C-C alkyl); each R is independently hydrogen, halogen, —OH, —CN, —NH, —O—C-C alkyl, —O—C-C haloalkyl, —NH(C-C alkyl), or —N(C-C alkyl); R1 is hydrogen or -Y-R3 when it does not form a ring with R11 or R14; Y is a bond or C1-C6 alkylene, in which one non-terminal -CH2- moiety may be replaced by -O-, and 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 the alkylene moiety may contain a 3-5 membered saturated or partially unsaturated carbocyclic ring as part of the moiety; R3 is hydrogen, -CN, -OH, C1-C4 haloalkyl, C2-C4 alkenylene-R4, C2-C4 alkynylene-R4, -O-C1-C4 alkylene-R4, -O-C1-C4 haloalkyl, -NH2, -NH(C1-C4 alkylene-R4), -N(C1-C4 alkylene-R4)2, -C(=O)-OH, -C(=O)-O-C1-C4 alkylene-R4, -C(=O)-NH2, -C(=O)-NH(C1-C4 alkylene-R4), -C(=O)-N(C1-C4 alkylene-R4)2, -NH-C(=O)-C1-C4 alkylene and (ii) when T is not -N(R11)-, -C(R12)(R13)-, or -C=C(R12)2, the atom of R3 connected to Y is not a heteroatom; R4 is hydrogen, halogen, -NH2, -NH(C1-C2 alkyl) or -N(C1-C2 alkyl)2; Ring P is a 3- to 6-membered saturated or partially unsaturated carbocyclic ring optionally substituted with 1 to 3 R5, or a 3- to 6-membered saturated or partially unsaturated heterocyclic ring containing 1 or 2 heteroatoms selected from N and O, optionally substituted with 1 to 3 R5; each R5 is independently halogen, -NH2, -OH, -CN, C1-C4 alkylene-R5a, -O-C1-C4 alkylene-R5a, or oxo; each R5a is independently hydrogen, halogen, —NH2, —OH, —CN, or —O—C1-C2 alkyl; Ring Q is phenyl optionally substituted with 1 to 3 R6, or a 5- to 6-membered heteroaryl ring containing 1 or 2 heteroatoms selected from N, S, and O, optionally substituted with 1 to 3 R6; each R6 is independently halogen, -NH2, -OH, -CN, C1-C4 alkylene-R6a, or -O-C1-C4 alkylene-R6a; each R6a is independently hydrogen, halogen, —NH2, —OH, —CN, or —O—C1-C2 alkyl; X is -O-, -C(=O)-, -C(=CH2)-, -N(R10a)-, or -CH(R10b)-; and when R2 is halogen or -CN, X is a bond; and when X is -C(=O)-, R2 is not hydrogen or X-R2 is hydrogen; R10a is hydrogen or C1-C4 alkyl when it does not form a ring with R2; R10b is hydrogen or C1-C4 alkyl; 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 of X and otherwise containing only carbon atoms as ring members, and optionally substituted by one or two R8; R2 and R10b may together 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 an -N(R9)- moiety as a ring member and otherwise containing only carbon atoms as ring members, and optionally substituted by one or two R8; R2, when not forming a ring with R10a, R10b, R11, R12 or R14, is hydrogen, halogen, -CN, C1-C4 alkyl optionally substituted with one or two R7, or a 4- to 7-membered saturated or partially unsaturated carbocyclic ring optionally substituted with one or two R8, or 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; each R7 is independently -CN, -OH, halogen, -N(R7a)R7b, or -NH(-C(=O)-C1-C4 alkyl); each R7a and R7b, when not taken together to form a ring, is independently hydrogen, C1-C4 alkylene-R7c, or C1-C4 haloalkylene-R7c; each R7c is independently hydrogen, halogen, —O—C1-C2 alkyl, or —O—C1-C2 haloalkyl; R7a and R7b may together form a 4-7 membered saturated or partially unsaturated heterocyclic ring optionally containing one or two additional heteroatoms selected from N, O and S as ring members, the heterocyclic ring being optionally substituted with one or two R7d; each R7d is independently halogen, -OH, -CN, -NH2, C1-C2 alkyl, C1-C2 haloalkyl, -O-C1-C2 alkyl, -O-C1-C2 haloalkyl, -NH(C1-C2 alkyl) or -N(C1-C2 alkyl)2; each R is independently -CN, -OH, halogen, -N(R)R, -NH(-C(=O)-C-C alkyl), C-C alkyl, or C-C haloalkyl; each R8a and R8b, when not taken together to form a ring, is independently hydrogen, C1-C4 alkylene-R8c, or C1-C4 haloalkylene-R8c; R8c is hydrogen, halogen, —O—C1-C2 alkyl, or —O—C1-C2 haloalkyl; R8a and R8b may together form a 4-7 membered saturated or partially unsaturated heterocyclic ring optionally containing one or two additional heteroatoms selected from N, O and S as ring members, the heterocyclic ring being optionally substituted with one or two R8d; each R is independently halogen, —OH, —CN, —NH, C-C alkyl, C-C haloalkyl, —O—C-C alkyl, —O—C-C haloalkyl, —NH(C-C alkyl), or —N(C-C alkyl); R9 is hydrogen, C1-C4 alkylene-R9a, C1-C4 haloalkylene-R9a or —C(═O)—C1-C4 alkyl; R9a is hydrogen, halogen, -OC1-C2 alkyl or -OC1-C2 haloalkyl.

[0006] In a further 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 mammals, particularly humans.

[0007] In a further 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 a neoplastic disease in a subject selected from mammals, particularly a human.

[0008] In a further aspect, the present invention provides a method for treating a neoplastic disease in a subject selected from mammals, particularly a human, the method comprising administering to the subject a compound of formula (I) or a pharmaceutically acceptable salt thereof, e.g., in a therapeutically effective amount.

[0009] In a further aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and optionally one or more pharmaceutically acceptable excipients.

[0010] Each alkyl moiety, alone or as part of a larger group such as alkoxy, is straight or branched. Examples include methyl, ethyl, n-propyl, prop-2-yl, n-butyl, but-2-yl, 2-methyl-prop-1-yl, or 2-methyl-prop-2-yl.

[0011] Each alkylene moiety, alone or as part of a larger group, is straight or branched, for example, -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -CH(CH3)-CH2-, -CH(CH2CH3)- or -CH2CH(CH3)CH2-.

[0012] Each alkenyl moiety, alone or as part of a larger group such as alkenyloxy, is straight or branched. Each moiety may be in either the (E) or (Z) configuration. Examples include vinyl and allyl.

[0013] Each alkenylene moiety, alone or as part of a larger group such as alkenyloxy, is straight or branched, e.g., -CH-CH=CH-. Each moiety may be in either the (E) or (Z) configuration.

[0014] Each alkynyl moiety, alone or as part of a larger group such as alkynyloxy, is straight or branched, for example, ethynyl or propargyl.

[0015] Each alkynylene moiety, alone or as part of a larger group, is straight or branched, for example, -CH2-C≡C-.

[0016] Each haloalkyl moiety, alone or as part of a larger group such as haloalkoxy, is an alkyl group substituted with one or more of the same or different halogen atoms. Examples include difluoromethyl, trifluoromethyl, chlorodifluoromethyl, and 2,2,2-trifluoro-ethyl. A haloalkyl moiety may contain, for example, 1 to 5 halo substituents, or 1 to 3 halo substituents.

[0017] Each cycloalkyl moiety (also referred to as a carbocyclic ring moiety) may be saturated or partially unsaturated (unless otherwise specified) and may be monocyclic or bicyclic, preferably monocyclic. Examples of monocyclic cycloalkyl groups include cyclobutyl, cyclopentyl, and cyclohexyl. An example of a bicyclic cycloalkyl group is bicyclo[2.2.1]heptan-2-yl.

[0018] Halogen is fluorine, chlorine, bromine or iodine.

[0019] The term "heteroaryl ring" refers to an aromatic ring system containing as ring members a specified number of heteroatoms selected from nitrogen, oxygen, and sulfur. A heteroaryl ring does not contain adjacent oxygen atoms, adjacent sulfur atoms, or adjacent oxygen and sulfur atoms, either within the ring or together with atoms outside the ring that connect the ring to the remainder of the molecule.

[0020] The term "heterocyclic ring" refers to a saturated or partially unsaturated carbocyclic ring (unless otherwise indicated) that further contains, as ring members, a specified number of heteroatoms selected from nitrogen, oxygen, and sulfur. A nitrogen ring member is present as an -NH- moiety unless otherwise substituted. Such a ring does not contain adjacent oxygen atoms, adjacent sulfur atoms, or adjacent oxygen and sulfur atoms, either within the ring or together with atoms outside the ring that connect the ring to the remainder of the molecule.

[0021] Oxo is a =O group. When a moiety is said to be "substituted with oxo," that counts as substitution with one substituent; for example, if ring P may be substituted with 1-3 R5, and R5 may be oxo, then ring P may be substituted with oxo and two additional R5 groups. Typically, a ring will not be substituted with more than one oxo group.

[0022] When a group is said to be optionally substituted, it may be unsubstituted or substituted with a specified number of substituents.

[0023] When giving a ring name to a specific moiety, the name is applied assuming that 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 the 4-position of the cyclohexyl relative to the point of attachment, regardless of the identity of any additional substituents that may be present on the cyclohexyl moiety.

[0024] When (E) and (Z) isomers are possible, for example, when R3 is alkenylene, the compounds of the present invention include all (E) and (Z) isomers and 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 included within the scope of Formula (I). Whenever compounds of Formula (I) contain one or more chiral centers, for example, when Y is branched alkylene, such compounds may be provided as pure enantiomers or pure diastereomers, and mixtures thereof in any ratio, and all such isomers are included within the scope of the compounds of Formula (I). The compounds of the present invention also include all tautomeric forms of compounds of Formula (I) where such possibilities exist, for example, when a saturated ring is substituted with oxo. Isotopically labeled compounds, including deuterium substitution and carbon-13 and / or carbon-14 labeling, are also included within the scope of the compounds of Formula (I).

[0025] The compounds of formula (I) may also be solvated, particularly hydrated, and are included within the scope of the compounds of formula (I). Solvation and hydration may occur during the preparation process. Reference to the compounds of the present invention includes pharmaceutically acceptable salts of the compounds. Such salts may also exist as hydrates and solvates. Examples of pharmacologically acceptable salts of 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 compounds of formula (I) are alkali metal and alkaline earth metal salts, such as sodium, potassium, lithium, calcium or magnesium salts, ammonium salts or salts of organic bases, such as methylamine, dimethylamine, triethylamine, piperidine, ethylenediamine, lysine, choline hydroxide, meglumine, morpholine or arginine salts.

[0026] The following examples of substituent definitions and embodiments may be combined in any combination where possible.

[0027] Ra and Rb are both -CH3, or Ra and Rb together form a -CH2-CH2-CH2- or -CH2-CH2-CH2-CH2- bridging moiety.

[0028] Preferably, Ra and Rb are both -CH3 or together form a -CH2-CH2-CH2-CH2- bridging moiety, for example, as shown in Example 37.

[0029] A is -CH2- or -C(=O)-. Preferably, A is -CH2-.

[0030] T is -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)-.

[0031] 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)-.

[0032] More preferably, T is -N(R11)-, -N(R11)-S(O2)-, -O-, -C(R12)(R13)-, -C=C(R12)2, -S- or -C(=O)-N(R14)-.

[0033] Even more preferably, T is —N(R11)— or —N(R11)—S(O2)—.

[0034] In the -C=C(R12)2 moiety, R1 is attached to the first carbon atom as shown here:

[0035] [ka]

[0036] Specific examples of T (when R does not form a ring with R or R, and R does not form a ring with R, R, or R) include -CH-, -CH(CH)-, -C(CH)=CH-, -N(CH)-C(=O)-, -N(CH)-S(O)-, -N-(cyclopropyl)-, -N(CHCHCN)-, -N(CHCHCH)-, -N(CHCHOH)-, -N(CHCH)-, -N(CH)-, -NH-, -NH-C(=O)-, -NH-S(O)-, -O-, -S-, -S(O)-N(CH)-, -S(O)-NH-, -S(O)- and -C(=O)-NH-.

[0037] R11 is hydrogen, C1-C4 alkylene-R11a, C1-C4 haloalkylene-R11a or C3-C6 cycloalkyl, wherein the cycloalkyl is optionally substituted with one or two R11b (when R11 does not form a ring with R1 or R2).

[0038] 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-C6 cycloalkyl.

[0039] 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.

[0040] Specific examples of R11 (when R11 does not form a ring with R1 or R2) include -CH3, cyclopropyl, -CH2CH2CH3, -CH2CH2CN, -CH2CH2OH, -CH2CH3 and hydrogen.

[0041] R11a is hydrogen, halogen, -OH, -CN, -NH2, -O-C1-C2 alkyl, -O-C1-C2 haloalkyl, -NH(C1-C2 alkyl) or -N(C1-C2 alkyl)2.

[0042] Preferably, R11a is hydrogen, halogen, -CN or -OH.

[0043] Specific examples of R11a include hydrogen, -CN and -OH.

[0044] Each R11b is independently halogen, —OH, —CN, —NH2, —O—C1-C2 alkyl, —O—C1-C2 haloalkyl, —NH(C1-C2 alkyl), or —N(C1-C2 alkyl)2.

[0045] Each R12 is independently hydrogen, C1-C4 alkylene-R12a, C1-C4 haloalkylene-R12a, or C3-C6 cycloalkyl, wherein the cycloalkyl is optionally substituted with one or two R12b (when R12 does not form a ring with R2).

[0046] Preferably, each R12 (when R12 does not form a ring with R2) is independently hydrogen or C1-C4 alkylene-R12a.

[0047] Specific examples of R12 include hydrogen, -CH3 and -CH2OH.

[0048] Each R12a is independently hydrogen, halogen, -OH, -CN, -NH2, -O-C1-C2 alkyl, -O-C1-C2 haloalkyl, -NH(C1-C2 alkyl), or -N(C1-C2 alkyl)2.

[0049] Preferably, each R12a is independently hydrogen, halogen, -CN or -OH.

[0050] Specific examples of R12a include hydrogen and -OH.

[0051] Each R12b is independently halogen, -OH, -CN, -NH2, -O-C1-C2 alkyl, -O-C1-C2 haloalkyl, -NH(C1-C2 alkyl), or -N(C1-C2 alkyl)2.

[0052] R13 is hydrogen, C1-C4 alkyl, or C1-C4 haloalkyl.

[0053] Specific examples of R13 include hydrogen.

[0054] R14 is hydrogen, C1-C4 alkylene-R14a, C1-C4 haloalkylene-R14a or C3-C6 cycloalkyl, wherein the cycloalkyl is optionally substituted with one or two R14b (when R14 does not form a ring with R1 or R2).

[0055] Preferably, R14 (when R14 does not form a ring with R1 or R2) is hydrogen or C1-C4 alkyl.

[0056] Specific examples of R14 include hydrogen and -CH3.

[0057] R14a is hydrogen, halogen, -OH, -CN, -NH2, -O-C1-C2 alkyl, -O-C1-C2 haloalkyl, -NH(C1-C2 alkyl) or -N(C1-C2 alkyl)2.

[0058] Each R14b is independently halogen, -OH, -CN, -NH2, -O-C1-C2 alkyl, -O-C1-C2 haloalkyl, -NH(C1-C2 alkyl), or -N(C1-C2 alkyl)2.

[0059] R2 and R11 may together form a partially unsaturated 6- to 7-membered heterocyclic ring containing no additional heteroatoms as ring members, the heterocyclic ring being optionally substituted with one or two R2a.

[0060] Preferably, R2 and R11 may together form a partially unsaturated 6-membered heterocyclic ring that does not contain additional heteroatoms when T is -N(R11)- and X is -O-, but does not otherwise form a heterocyclic ring.

[0061] Specific examples of the bridging moiety formed by R2 and R11 include, when T is -N(R11)- and X is -O-, -CH2CH2-, i.e., -N(R1)CH2CH2O-, including the T and X substituents, e.g., -N(H)CH2CHO-, -N(CH2CH2CN)CH2CHO-, and -N(CH3)CH2CHO- (T is on the left side of the bridging moiety and X is on the right side as shown).

[0062] R2 and R12 may together form a partially unsaturated 6- to 7-membered heterocyclic ring containing no additional heteroatoms as ring members, and the heterocyclic ring is optionally substituted with one or two R2a.

[0063] R2 and R14 may together form a partially unsaturated 6- to 7-membered heterocyclic ring containing no additional heteroatoms as ring members, the heterocyclic ring being optionally substituted with one or two R2a.

[0064] Each R2a is independently halogen, -OH, -CN, -NH2, -O-C1-C2 alkyl, -O-C1-C2 haloalkyl, -NH(C1-C2 alkyl), or -N(C1-C2 alkyl)2.

[0065] R1 and R11 may together form a saturated or partially unsaturated 4- to 7-membered heterocyclic ring optionally containing one or two additional heteroatoms selected from N, O, and S as ring members, the heterocyclic ring being optionally substituted with one to three R1a, or R1 and R11 may together form a 5- to 6-membered heteroaryl ring optionally containing one to three additional heteroatoms selected from N and O as ring members, the heteroaryl ring being optionally substituted with one to three R1b.

[0066] Preferably, R1 and R11 may together form a 4- to 6-membered saturated or partially unsaturated heterocyclic ring optionally containing one further heteroatom selected from N and O as a ring member, for example, a ring selected from piperidinyl, morpholinyl, pyrrolidinyl, azetidinyl, 2,5-dihydropyrrolyl, and 1,1-dioxide-1,2-thiazolidin-2-yl, the heterocyclic ring optionally being substituted with one or two R1a, or R1 and R11 may together form a 5-membered heteroaryl ring optionally containing one further heteroatom selected from N, for example, pyrrolyl, the heteroaryl ring optionally being substituted with one or two R1b.

[0067] More preferably, R1 and R11 may together form a 5- to 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, which 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, which heteroaryl ring is optionally substituted with one R1b.

[0068] Specific examples of the heterocyclic ring formed by R1 and R11 when T is -N(R11)- include piperidinyl (including, for example, 4-hydroxypiperidinyl), morpholinyl, pyrrolidinyl (including, for example, 3-hydroxy-pyrrolidinyl, 3-methoxy-pyrrolidinyl, 3-cyano-pyrrolidinyl, 3-carboxamido-pyrrolidinyl), azetidinyl (including, for example, 3-hydroxy-azetidinyl, 3-hydroxymethyl-azetidinyl), 2,5-dihydropyrrolyl (including, for example, 2H-pyrrolyl-5-one), and 1,1-dioxide-1,2-thiazolidinyl.

[0069] Illustrative 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).

[0070] R1 and R14 may together form a saturated or partially unsaturated 4- to 7-membered heterocyclic ring optionally containing one or two additional heteroatoms selected from N, O and S as ring members, the heterocyclic ring being optionally substituted with one to three R1a, or R1 and R14 may together form a 5- to 6-membered heteroaryl ring optionally containing one to three additional heteroatoms selected from N and O as ring members, the heteroaryl ring being optionally substituted with one to three R1b.

[0071] Each R1a is independently 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.

[0072] Preferably, each R1a is independently halogen, -OH, -CN, C1-C4 alkylene-R1c, -O-C1-C4 haloalkyl, -C(=O)NH2, or oxo.

[0073] More preferably, each R1a is independently halogen, -OH, -CN or -C(=O)NH2.

[0074] Specific examples of R1a include -OH, -CN, -OCH3, -CH2OH, -C(=O)NH2 and oxo.

[0075] Each R is independently halogen, —OH, —CN, —NH, C-C alkylene-R, C-C haloalkylene-R, —O—C-C alkyl, —O—C-C haloalkyl, —NH(C-C alkyl) or —N(C-C alkyl), —C(═O)NH, —C(═O)NH(C-C alkyl) or —C(═O)N(C-C alkyl).

[0076] Preferably, each R1b is independently halogen, -OH, -CN, C1-C4 alkylene-R1c, or -O-C1-C4 haloalkyl.

[0077] More preferably, each R1b is halogen, -OH or -CN.

[0078] Specific examples of R1b include -OH, -CN, -OCH3 and -CH2OH.

[0079] Each R1c is independently hydrogen, halogen, -OH, -CN, -NH2, -O-C1-C2 alkyl, -O-C1-C2 haloalkyl, -NH(C1-C2 alkyl), or -N(C1-C2 alkyl)2.

[0080] Preferably, each R1c is independently hydrogen or -OH.

[0081] Specific examples of R1c include hydrogen and -OH.

[0082] R1 is hydrogen or -Y-R3 (when R1 does not form a ring with R11 or R14).

[0083] Preferably, R1 (when R1 does not form a ring with R11 or R14) is hydrogen, C1-C6 alkylene-R3, the alkylene moiety may be substituted with one -OH, the alkylene moiety may include a 3-membered saturated carbocyclic ring as part of the moiety, and there is a spacer of 3 or less carbon atoms between the connection to T and the connection to R3, or R1 is ring P or ring Q.

[0084] More preferably, R1 (when R1 does not form a ring with R11 or R14) is hydrogen, C1-C3 alkylene-R3, ring P or ring Q.

[0085] Specific examples of R1, when not forming 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, -CH 2CH2CH3, 4-fluorophenyl, -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, - These include 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.

[0086] Y is a bond or C1-C6 alkylene, in which one non-terminal -CH2- moiety may be replaced with -O-, 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 the alkylene moiety may include a 3- to 5-membered saturated or partially unsaturated carbocyclic ring as part of it. 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 the terminal -CH2- moiety proximal to the connection to T, nor the terminal -CH2- moiety distal to the connection to T).

[0087] Preferably, Y is a bond or C1-C6 alkylene, the alkylene moiety may be optionally substituted with one -OH, the alkylene moiety may include a 3-membered saturated carbocyclic ring as part of the moiety, and there is a spacer of no more than 3 carbon atoms between the connection to T and the connection to R3.

[0088] More preferably, Y is C1-C6 alkylene, there is a spacer of no more than 3 carbon atoms between the connection to T and the connection to R3, and one CH2 moiety is replaced with C(-CH2CH2-).

[0089] In some embodiments, Y is C1-C3 alkylene.

[0090] Specific examples of Y include a 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-.

[0091] The unit -C(-CH2CH2-)- corresponds to the following moiety:

[0092] [ka]

[0093] R3 is hydrogen, -CN, -OH, C1-C4 haloalkyl, C2-C4 alkenylene-R4, C2-C4 alkynylene-R4, -O-C1-C4 alkylene-R4, -O-C1-C4 haloalkyl, -NH2, -NH(C1-C4 alkylene-R4), -N(C1-C4 alkylene-R4)2, -C(=O)-OH, -C(=O)-O-C1-C4 alkylene-R4, -C(=O)-NH2, -C(=O)-NH(C1-C4 alkylene-R4), -C(=O)-N(C1-C4 alkylene-R4)2, -NH-C(=O)-C1-C4 alkylene and -R4, -N(C1-C4 alkyl)-C(=O)-C1-C4 alkylene-R4, Ring P, Ring Q, -O-Ring P, -O-Ring Q, -NH-S(O2)-C1-C4 alkylene-R4, -N(C1-C4 alkyl)-S(O2)-C1-C4 alkylene-R4, -S-C1-C4 alkylene-R4 or -S(O2)-C1-C4 alkyl-R4, with the proviso that (i) Y is a bond, and (ii) T is not -N(R11)-, -C(R12)(R13)- or -C=C(R12)2, then the atom of R3 connected to Y is not a heteroatom.

[0094] Preferably, R3 is hydrogen, —CN, —OH, C1-C4 haloalkyl, —O—C1-C4 alkylene-R4, —O—C1-C4 haloalkyl, —NH2, —NH(C1-C4 alkylene-R4), —N(C1-C4 alkylene-R4), —C(═O)—OH, —C(═O)—O—C1-C4 alkylene-R4, —C(═O)—NH2, —C(═O)—NH(C1-C4 alkylene-R4), —C(═O) -N(C1-C4 alkylene-R4)2, -NH-C(=O)-C1-C4 alkylene-R4, -N(C1-C4 alkyl)-C(=O)-C1-C4 alkylene-R4, ring P, ring Q, -NH-S(O2)-C1-C4 alkylene-R4, -N(C1-C4 alkyl)-S(O2)-C1-C4 alkylene-R4, -S-C1-C4 alkylene-R4 or -S(O2)-C1-C4 alkyl-R4.

[0095] More preferably, R3 is hydrogen, -CN, -OH, C1-C4 haloalkyl, -O-C1-C4 alkylene-R4, -O-C1-C4 haloalkyl, -NH2, -NH(C1-C4 alkylene-R4), -N(C1-C4 alkylene-R4)2, -C(=O)-OH, -C(=O)-NH2, ring P or ring Q.

[0096] 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.

[0097] R4 is hydrogen, halogen, -NH2, -NH(C1-C2 alkyl) or -N(C1-C2 alkyl)2.

[0098] Preferably, R4 is hydrogen.

[0099] Specific examples of R4 include hydrogen.

[0100] Ring P is a 3- to 6-membered (e.g., 5- to 6-membered) saturated or partially unsaturated carbocyclic ring optionally substituted with 1 to 3 R5, or a 3- to 6-membered (e.g., 5- to 6-membered) saturated or partially unsaturated heterocyclic ring containing 1 or 2 heteroatoms selected from N and O, optionally substituted with 1 to 3 R5.

[0101] Preferably, ring P is a 3- to 6-membered (e.g., 6-membered) saturated carbocyclic ring optionally substituted with 1 to 2 R5, or a 5- or 6-membered saturated heterocyclic ring containing one heteroatom selected from N and O, optionally substituted with 1 to 2 R5.

[0102] More preferably, ring P is oxazolidinyl optionally substituted with one or two R5, in particular oxazolidinyl-2-one optionally substituted with one R5, where R5 is not oxo.

[0103] Specific examples of ring P include cyclopropyl, tetrahydropyranyl (eg, tetrahydropyran-4-yl), and oxazolidinyl (eg, oxazolidin-5-yl-2-one).

[0104] Each R5 is independently halogen, -NH2, -OH, -CN, C1-C4 alkylene-R5a, -O-C1-C4 alkylene-R5a, or oxo.

[0105] Preferably, each R5 is independently -NH2, C1-C2 alkyl, -C1-C2 alkyl-R5a, or oxo.

[0106] More preferably, each R5 is independently C1-C2 alkyl, -C1-C2 alkyl-R5a, or oxo. Preferably, when a moiety is substituted with R5, no more than one R5 is oxo. In particular, preferably, the oxazolidinyl-2-one moiety is not further substituted with oxo.

[0107] Each R5a is independently hydrogen, halogen, -NH2, -OH, -CN, or -O-C1-C2 alkyl.

[0108] Ring Q is phenyl optionally substituted with 1 to 3 R6, or a 5- to 6-membered heteroaryl ring containing 1 or 2 heteroatoms selected from N, S, and O, optionally substituted with 1 to 3 R6.

[0109] Preferably, ring Q is phenyl optionally substituted with one or two R6, or a 5- to 6-membered heteroaryl ring containing 1 to 2 heteroatoms selected from N, S, and O, optionally substituted with one or two R6.

[0110] More preferably, ring Q is phenyl optionally substituted with one R6, or a 5- to 6-membered heteroaryl ring containing 1 to 2 heteroatoms selected from N and O, optionally substituted with one R6.

[0111] Specific examples of ring Q 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).

[0112] Each R6 is independently halogen, -NH2, -OH, -CN, C1-C4 alkylene-R6a, or -O-C1-C4 alkylene-R6a.

[0113] Preferably, each R6 is independently -NH2, -OH, -CN, C1-C2 alkylene-R6a (e.g., -CH3), or -O-C1-C2 alkyl (e.g., -O-CH3).

[0114] Specific examples of R6 include fluoro and 1-fluoro-eth-1-yl.

[0115] Each R6a is independently hydrogen, halogen, -NH2, -OH, -CN, or -O-C1-C2 alkyl.

[0116] Preferably, each R6a is independently hydrogen, halogen or -CN.

[0117] Specific examples of R6a include hydrogen and fluoro.

[0118] X is -O-, -C(=O)-, -C(=CH2)-, -N(R10a)-, or -CH(R10b)-; and when R2 is halogen or -CN, X is a bond; and when X is -C(=O)-, R2 is not hydrogen or X-R2 is hydrogen.

[0119] Preferably, X is -O- or -N(R10a)-, or X-R2 is halogen or hydrogen.

[0120] More preferably, X is -O- or -N(R10a)-, or X-R2 is halogen.

[0121] Specific examples of X include -O- and -N(R10a)-, where R10a and R2 may be taken together to form a piperazine ring, for example, 4-methylpiperazinyl, and X-R2 may be bromine or hydrogen.

[0122] R10a is hydrogen or C1-C4 alkyl, or R2 and R10a together may 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 of X and otherwise containing only carbon atoms as ring members, and optionally substituted with one or two R8.

[0123] Preferably, R10a is hydrogen or -CH3, or R2 and R10a together may form a 4- to 7-membered saturated heterocyclic ring optionally substituted with one R8 when the ring contains only carbon atoms and optionally contains an -N(R9)- moiety as a ring member in addition to the nitrogen atom of X, and does not contain an -N(R9)- moiety. More preferably, R10a is hydrogen or -CH3, or R2 and R10a together may form a 6- to 7-membered saturated heterocyclic ring optionally substituted with one R8 at the 3-position relative to the nitrogen atom of X (the nitrogen atom of X is at position 0) when the ring contains only carbon atoms and does not contain an -N(R9)- moiety.

[0124] In some embodiments, R10a is hydrogen or -CH3, or R2 and R10a together may form a 6-membered saturated heterocyclic ring containing one -N(R9)- moiety as a ring member at the 3-position ("para") to the nitrogen atom of X, or substituted with one R8 at the 3-position ("para") to the nitrogen atom of X. Specific examples of rings formed by R2 and R10a include piperazinyl, e.g., 1-methylpiperazin-4-yl.

[0125] 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 an -N(R9)- moiety as a ring member and otherwise containing only carbon atoms as ring members, and optionally substituted with one or two R8.

[0126] Preferably, R10b is hydrogen.

[0127] R2 is hydrogen, halogen, -CN, C1-C4 alkyl optionally substituted with one or two R7, or a 4- to 7-membered saturated or partially unsaturated carbocyclic ring optionally substituted with one or two R8, or 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).

[0128] 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 a 4- to 7-membered saturated carbocyclic ring (e.g., a 6- to 7-membered saturated carbocyclic ring) optionally substituted with one R8, or 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 X-R2 is halogen or hydrogen.

[0129] 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 a 6- to 7-membered saturated carbocyclic ring substituted with one R8 at the 3-position relative to X (the atom of the carbocyclic ring connected 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 the 3-position relative to X and otherwise containing only carbon atoms as ring members, or X-R2 is halogen or hydrogen.

[0130] 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 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 X-R2 is bromine.

[0131] Specific examples of R2 when not forming a ring with R10a, B10b, R11, R12, or R14 include azepan-4-yl, -CH3, -CH2CH2N(CH3)2, 4-amino-cyclohexyl (e.g., cis-4-amino-cyclohexyl and trans-4-amino-cyclohexyl), 4-morpholin-4-yl-cyclohexyl (e.g., trans-4-morpholin-4-yl-cyclohexyl), 4-NH(CH2CHOCH3)-cyclohexyl (e.g., trans-4-N(CH2CHOCH3)-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.

[0132] Specific examples of -X-R2 (when R2 does not form a ring with R10a, R10b, R11, R12 or R14) include hydrogen, bromo, -O-CH3, -O-azepan-4-yl, -O-CH3, -O-(4-amino-cyclohexyl) (e.g., -O-(cis-4-amino-cyclohexyl), -O-(trans-4-amino-cyclohexyl)), -O-CH2CH2N(CH3)2, -O-(4-(morpholin-4-yl)-cyclohexyl) (e.g., -O-(trans-4-morpholin-4-yl)-cyclohexyl). trans-4-NH(CHCHOCH)-cyclohexyl), -O-(4-NH(CHCHOCH)-cyclohexyl) (e.g., -O-(trans-4-NH(CHCHOCH)-cyclohexyl)), -O-(4-N(CH)-cyclohexyl) (e.g., -O-(trans-4-N(CH)-cyclohexyl)), -O-(4-NH(CH)-cyclohexyl) (e.g., -O-(trans-4-NH(CH)-cyclohexyl)), and -O-piperidin-4-yl.

[0133] Each R7 is independently -CN, -OH, halogen, -N(R7a)R7b, or -NH(-C(=O)-C1-C4 alkyl).

[0134] In some embodiments, R7 is -N(R7a)R7b.

[0135] A specific example of R7 is -N(CH3)2.

[0136] Each R7a is independently hydrogen, C1-C4 alkylene-R7c, or C1-C4 haloalkylene-R7c (when R7a does not form a ring with R7b).

[0137] In some embodiments, each R7a, when not forming a ring with R7b, is independently hydrogen or C1-C4 alkyl-R7c.

[0138] A specific example of R7a is -CH3.

[0139] Each R7b is independently hydrogen, C1-C4 alkylene-R7c, or C1-C4 haloalkylene-R7c (when R7b does not form a ring with R7a).

[0140] In some embodiments, each R7b, when not forming a ring with R7a, is independently hydrogen or C1-C4 alkyl.

[0141] Specific examples of R7b include -CH3.

[0142] Each R7c is independently hydrogen, halogen, -OC1-C2 alkyl, or -OC1-C2 haloalkyl.

[0143] R7a and R7b may together form a 4- to 7-membered saturated or partially unsaturated heterocyclic ring optionally containing one or two additional heteroatoms selected from N, O and S as ring members, and the heterocyclic ring is optionally substituted with one or two R7d.

[0144] Each R7d is independently halogen, -OH, -CN, -NH2, C1-C2 alkyl, C1-C2 haloalkyl, -O-C1-C2 alkyl, -O-C1-C2 haloalkyl, -NH(C1-C2 alkyl), or -N(C1-C2 alkyl)2.

[0145] Each R8 is independently -CN, -OH, halogen, -N(R8a)R8b, -NH(-C(=O)-C1-C4 alkyl), C1-C4 alkyl, or C1-C4 haloalkyl.

[0146] Preferably, each R8 is -N(R8a)R8b.

[0147] Specific examples of R8 include -NH2, -NH(CH3), -N(CH3)2, NH(CH2CH2OCH3) and morpholin-4-yl.

[0148] Each R8a is independently hydrogen, C1-C4 alkylene-R8c, or C1-C4 haloalkylene-R8c (when R8a does not form a ring with R8b).

[0149] Preferably, each R8a, when not forming a ring with R8b, is independently hydrogen or C1-C4 alkyl-R8c.

[0150] Specific examples of R8a include hydrogen, -CH3 and -CH2CH2OCH3.

[0151] Each R8b is independently hydrogen, C1-C4 alkylene-R8c, or C1-C4 haloalkylene-R8c (when R8b does not form a ring with R8a).

[0152] Preferably, each R8b, when not forming a ring with R8a, is independently hydrogen or C1-C4 alkyl.

[0153] Specific examples of R8b include hydrogen and -CH3.

[0154] Each R8c is independently hydrogen, halogen, -OC1-C2 alkyl, or -OC1-C2 haloalkyl.

[0155] Specific examples of R8c include hydrogen.

[0156] R8a and R8b may together form a 4- to 7-membered saturated or partially unsaturated heterocyclic ring optionally containing one or two additional heteroatoms selected from N, O and S as ring members, and the heterocyclic ring is optionally substituted with one or two R8d.

[0157] Preferably, R8a and R8b may be joined together to form a 6-membered saturated heterocyclic ring optionally containing one or two further heteroatoms selected from N and O as ring members.

[0158] A specific example of the ring formed by R8a and R8b is morpholin-4-yl.

[0159] Each R8d is independently halogen, -OH, -CN, -NH2, C1-C2 alkyl, C1-C2 haloalkyl, -O-C1-C2 alkyl, -O-C1-C2 haloalkyl, -NH(C1-C2 alkyl), or -N(C1-C2 alkyl)2.

[0160] R9 is hydrogen, C1-C4 alkylene-R9a, C1-C4 haloalkylene-R9a, or -C(=O)-C1-C4 alkyl.

[0161] Preferably, R9 is hydrogen or C1-C4 alkyl.

[0162] A specific example of R9 is -CH3.

[0163] R9a is hydrogen, halogen, -OC1-C2 alkyl or -OC1-C2 haloalkyl.

[0164] In some embodiments, Ra and Rb are both -CH3.

[0165] In some embodiments, Ra and Rb together form a -CH2-CH2-CH2-CH2- bridging moiety.

[0166] In some embodiments, A is —CH 2 —.

[0167] In some embodiments, A is —C(═O)—.

[0168] In some embodiments, T is —N(R11)—.

[0169] In some embodiments, T is —N(R 11 )—C(═O)—.

[0170] In some embodiments, T is —N(R11)—S(O2)—.

[0171] In some embodiments, T is —O—.

[0172] In some embodiments, T is —C(R 12 )(R 13 )—.

[0173] In some embodiments, T is —C═C(R 12 ) 2 .

[0174] In some embodiments, T is —C(═O)—N(R 14 )—.

[0175] In some embodiments, T is -S-.

[0176] In some embodiments, T is —S(O 2 )—.

[0177] In some embodiments, T is —S(O 2 )—N(R 14 )—.

[0178] In some embodiments, X is —O—.

[0179] In some embodiments, X is —N(R10a)—.

[0180] In some embodiments, X-R2 is hydrogen.

[0181] In some embodiments, X-R2 is halogen.

[0182] In some embodiments, T is —N(R11)— and X is —O—.

[0183] In some embodiments, T is —N(R 11 )—C(═O)— and X is —O—.

[0184] In some embodiments, T is —N(R 11 )—S(O 2 )— and X is —O—.

[0185] In some embodiments, T is —N(R11)— and X is —NH(R10a)—.

[0186] In some embodiments, T is —N(R 11 )— and X—R 2 is hydrogen.

[0187] In some embodiments, T is —N(R 11 )— and X—R 2 is a halogen.

[0188] In some embodiments, T is —O— and X is —O—.

[0189] In some embodiments, T is —C(R 12 )(R 13 )— and X is —O—.

[0190] In some embodiments, T is —C═C(R 12 ) 2 and X is —O—.

[0191] In some embodiments, T is —C(═O)—N(R14)— and X is —O—.

[0192] In some embodiments, T is —O— and X is —O—.

[0193] In some embodiments, T is -S- and X is -O-.

[0194] In some embodiments, T is —S(O 2 )— and X is —O—.

[0195] In some embodiments, T is —S(O 2 )—N(R 14 )— and X is —O—.

[0196] In some embodiments, T is —N(R11)— and X is —N(R10a)—.

[0197] In some embodiments, A is —CH 2 — and T is —N(R 11 )—.

[0198] In some embodiments, A is —CH 2 — and T is —N(R 11 )—C(═O)—.

[0199] In some embodiments, A is —CH 2 — and T is —N(R 11 )—S(O 2 )—.

[0200] In some embodiments, A is -CH2- and T is -O-.

[0201] In some embodiments, A is —CH 2 — and T is —C(R 12 )(R 13 )—.

[0202] In some embodiments, A is —CH 2 — and T is —C═C(R 12 ) 2 .

[0203] In some embodiments, A is —CH 2 — and T is —C(═O)—N(R 14 )—.

[0204] In some embodiments, A is -CH2- and T is -S-.

[0205] In some embodiments, A is —CH 2 — and T is —S(O 2 )—.

[0206] In some embodiments, A is —CH 2 — and T is —S(O 2 )—N(R 14 )—.

[0207] In some embodiments, A is —C(═O)— and T is —N(R11)—.

[0208] In some embodiments, A is -CH2- and X is -O-.

[0209] In some embodiments, A is -CH2- and X is -N(R10a)-.

[0210] In some embodiments, A is -CH2- and X-R2 is hydrogen.

[0211] In some embodiments, A is —CH 2 — and X—R 2 is halogen.

[0212] In some embodiments, A is -C(=O)- and X is -O-.

[0213] In some embodiments, A is -CH2-, T is -N(R11)-, and X is -O-.

[0214] In some embodiments, A is —CH 2 —, T is —N(R 11 )—C(═O)—, and X is —O—.

[0215] In some embodiments, A is —CH 2 —, T is —N(R 11 )—S(O 2 )—, and X is —O—.

[0216] In some embodiments, A is -CH2-, T is -O-, and X is -O-.

[0217] In some embodiments, A is —CH 2 —, T is —C(R 12 )(R 13 )—, and X is —O—.

[0218] In some embodiments, A is -CH2-, T is -N(R11)-, and X is -N(R10a)-.

[0219] In some embodiments, A is —CH 2 —, T is —C═C(R 12 ) 2 , and X is —O—.

[0220] In some embodiments, A is -CH2-, T is -C(=O)-N(R14)-, and X is -O-.

[0221] In some embodiments, A is -CH2-, T is -O-, and X is -O-.

[0222] In some embodiments, A is -CH2-, T is -S-, and X is -O-.

[0223] In some embodiments, A is —CH 2 —, T is —S(O 2 )—, and X is —O—.

[0224] In some embodiments, A is —CH 2 —, T is —S(O 2 )—N(R 14 )—, and X is —O—.

[0225] In some embodiments, A is —C(═O)—, T is —N(R11)—, and X is —NHR10a)—.

[0226] In some embodiments, Ra and Rb are both -CH3 and A is -CH2-.

[0227] In some embodiments, Ra and Rb together form a -CH2-CH2-CH2-CH2- bridging moiety and A is -CH2-.

[0228] In some embodiments, Ra and Rb are both -CH3 and A is -C(=O)-.

[0229] In some embodiments, Ra and Rb are both -CH3 and T is -N(R11)-.

[0230] In some embodiments, Ra and Rb are both -CH3 and T is -N(R11)-C(=O)-.

[0231] In some embodiments, Ra and Rb are both -CH3 and T is -N(R11)-S(O2)-.

[0232] In some embodiments, Ra and Rb are both -CH3 and T is -O-.

[0233] In some embodiments, Ra and Rb are both -CH3 and T is -C(R12)(R13)-.

[0234] In some embodiments, Ra and Rb are both -CH3 and T is -C=C(R12)2.

[0235] In some embodiments, Ra and Rb are both -CH3 and T is -C(=O)-N(R14)-.

[0236] In some embodiments, Ra and Rb are both -CH3 and T is -S-.

[0237] In some embodiments, Ra and Rb are both -CH3 and T is -S(O2)-.

[0238] In some embodiments, Ra and Rb are both -CH3 and T is -S(O2)-N(R14)-.

[0239] In some embodiments, Ra and Rb together form a -CH2-CH2-CH2-CH2- bridging moiety and T is -N(R11)-.

[0240] In some embodiments, Ra and Rb are both -CH3, A is -CH2-, and T is -N(R11)-.

[0241] In some embodiments, Ra and Rb are both -CH3, A is -CH2-, and T is -N(R11)-C(=O)-.

[0242] In some embodiments, Ra and Rb are both -CH3, A is -CH2-, and T is -N(R11)-S(O2)-.

[0243] In some embodiments, Ra and Rb are both -CH3, A is -CH2-, and T is -O-.

[0244] In some embodiments, Ra and Rb are both -CH3, A is -CH2-, and T is -C(R12)(R13)-.

[0245] In some embodiments, Ra and Rb are both -CH3, A is -CH2-, and T is -C=C(R12)2.

[0246] In some embodiments, Ra and Rb are both -CH3, A is -CH2-, and T is -C(=O)-N(R14)-.

[0247] In some embodiments, Ra and Rb are both -CH3, A is -CH2-, and T is -S-.

[0248] In some embodiments, Ra and Rb are both -CH3, A is -CH2-, and T is -S(O2)-.

[0249] In some embodiments, Ra and Rb are both -CH3, A is -CH2-, and T is -S(O2)-N(R14)-.

[0250] In some embodiments, Ra and Rb together form a -CH2-CH2-CH2-CH2- bridging moiety, A is -CH2-, and T is -N(R11)-.

[0251] In some embodiments, Ra and Rb are both -CH3, A is -C(=O)-, and T is -N(R11)-.

[0252] In some embodiments, when T is —N(R), —O—, —C(R)(R)—, —S—, —S(O)—, or —S(O)—, the substituent R is not hydrogen (i.e., in this case, for the avoidance of doubt, this means that neither R nor the Y-R moiety can be hydrogen).

[0253] In some embodiments, the substituent R1 is not hydrogen.

[0254] In some embodiments, the substituent R1 contains at least one atom other than hydrogen.

[0255] In some embodiments, the substituent R1 contains at least two non-hydrogen atoms.

[0256] In some embodiments, the substituent R1 comprises at least three non-hydrogen atoms.

[0257] In some embodiments, the substituent R1 comprises at least four non-hydrogen atoms.

[0258] In some embodiments, the substituent R1 contains at least five non-hydrogen atoms.

[0259] In some embodiments, R1, when not forming a ring with R11 or R14, is -Y-R3, provided that Y is not a bond when R3 is hydrogen.

[0260] In some embodiments, when R1 does not form a ring with R11 or R14, it is -Y-R3, and Y is C1-C6 alkylene, in which case one non-terminal -CH2- moiety may be replaced with -O-, the alkylene moiety may be substituted with one or two moieties independently selected from -OH, -O-C1-C4 alkyl and -O-C1-C4 haloalkyl, the alkylene moiety may contain a 3- to 5-membered saturated or partially unsaturated carbocyclic ring as part of the moiety, or R1 is ring P or ring Q.

[0261] In some embodiments, when R1 does not form a ring with R11 or R14, it is C1-C6 alkylene-R3, the alkylene moiety may be substituted with one -OH, the alkylene moiety may include a 3-membered saturated carbocyclic ring as part of the moiety, there is a spacer of 3 or less carbon atoms between the connection to T and the connection to R3, or R1 is ring P or ring Q.

[0262] In some embodiments, R1 is C1-C3 alkylene-R3, ring P, or ring Q when it does not form a ring with R11 or R14.

[0263] In some embodiments, R1 is C1-C3 alkylene-R3; R3 is hydrogen, -CN, -OH, C1-C4 haloalkyl, -O-C1-C4 alkylene-R4, -O-C1-C4 haloalkyl, -NH2, -NH(C1-C4 alkylene-R4) or -N(C1-C4 alkylene-R4)2, -C(=O)-OH, -C(=O)-NH2, ring P or ring Q; R11 is hydrogen, C1-C4 alkylene-R11a, C1-C4 haloalkylene-R11a or C3-C4 cycloalkyl; Ring P is oxazolidinyl optionally substituted with one or two R5; each R5 is independently C1-C2 alkyl, -C1-C2 alkyl-R5a or oxo, and ring P is not substituted with two oxo; Each R5a is independently hydrogen, halogen, -NH2, -OH, -CN, or -O-C1-C2 alkyl.

[0264] In some embodiments, X is -O-, -C(=O)-, -N(R10a)-, or -CH(R10b)-; and when R2 is halogen or -CN, X is a bond; and when X is -C(=O)-, R2 is not hydrogen, or X-R2 is hydrogen.

[0265] In some embodiments, R2 and R10a together form a 4-7 membered saturated or partially unsaturated heterocyclic ring that optionally includes an -N(R9)- moiety as a ring member in addition to the nitrogen atom of X, and otherwise contains only carbon atoms as ring members, and is optionally substituted with one or two R8.

[0266] In some embodiments, R2 and R10a together do not form a heterocyclic ring.

[0267] 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, and optionally substituted with one or two R8.

[0268] In some embodiments, R2 and R10b together do not form a heterocyclic ring.

[0269] In some embodiments, R2 and R11 together form a partially unsaturated 6- to 7-membered heterocyclic ring that does not contain additional heteroatoms as ring members, and the heterocyclic ring is optionally substituted with one or two R2a.

[0270] In some embodiments, R2 and R11 together do not form a heterocyclic ring.

[0271] In some embodiments, R2 and R12 together form a partially unsaturated 6- to 7-membered heterocyclic ring that does not contain additional heteroatoms as ring members, and the heterocyclic ring is optionally substituted with one or two R2a.

[0272] In some embodiments, R2 and R12 together do not form a heterocyclic ring.

[0273] In some embodiments, R2 and R14 together form a partially unsaturated 6- to 7-membered heterocyclic ring that does not contain additional heteroatoms as ring members, and the heterocyclic ring is optionally substituted with one or two R2a.

[0274] In some embodiments, R2 and R14 together do not form a heterocyclic ring.

[0275] In some embodiments, R2 and R11, R2 and R12, and R2 and R14 together do not form a heterocyclic ring.

[0276] In some embodiments, R1 and R11 together form a saturated or partially unsaturated 4-7 membered heterocyclic ring optionally containing 1 to 2 additional heteroatoms selected from N, O, and S as ring members, and the heterocyclic ring is optionally substituted with 1 to 3 R1a; or R1 and R11 together form a 5-6 membered heteroaryl ring optionally containing 1 to 3 additional heteroatoms selected from N and O as ring members, and the heteroaryl ring is optionally substituted with 1 to 3 R1b.

[0277] In some embodiments, R1 and R11 together do not form a heterocyclic or heteroaryl ring.

[0278] 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 selected from N, O, and S as ring members, and 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 selected from N and O as ring members, and the heteroaryl ring is optionally substituted with one to three R1b.

[0279] In some embodiments, R1 and R14 together do not form a heterocyclic or heteroaryl ring.

[0280] 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 do not combine to form a heterocyclic or heteroaryl ring.

[0281] In some embodiments, R1 and R11 may together form a heterocyclic or 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 do not together form a heterocyclic ring.

[0282] In some embodiments, R2 is C1-C4 alkyl or a 6-membered saturated carbocyclic ring substituted with one R8 at the 3-position (“para”) to X, and R8 is —N(R8a)R8b.

[0283] In some embodiments, X is -O- or -NH(R10a)-, or X-R2 is halogen or hydrogen; R10a is hydrogen or -CH3; R2 is C1-C4 alkyl or a 6-membered saturated carbocyclic ring substituted with one R8 at the 3-position ("para") to X; R8 is -N(R8a)R8b; When R8a does not form a ring with R8b, R8a is hydrogen or C1-C4 alkyl-R8c; R8b is hydrogen or C1-C4 alkyl when it does not form a ring with R8a; R8a and R8b may together form a 6-membered saturated heterocyclic ring optionally containing one or two further heteroatoms selected from N and O as ring members; R8c is hydrogen, halogen, -OC1-C2 alkyl or -OC1-C2 haloalkyl.

[0284] In some embodiments, T is —N(R11)—, —N(R11)—C(═O)—, or —N(R11)—S(O2)—; When R1 does not form a ring with R11, it is -Y-R3; or or R1 and R11 may together form a saturated or partially unsaturated 4- to 7-membered heterocyclic ring optionally containing one or two additional heteroatoms selected from N, O and S as ring members, which heterocyclic ring is optionally substituted with one to three R1a; or R1 and R11 may together form a 5- to 6-membered heteroaryl ring optionally containing one to three additional heteroatoms selected from N and O as ring members, which heteroaryl ring is optionally substituted with one to three R1b; R11 is C1-C4 alkylene-R11a, C1-C4 haloalkylene-R11a or C3-C6 cycloalkyl, wherein the cycloalkyl is optionally substituted with one or two R11b.

[0285] In some embodiments, T is —N(R11)—, —N(R11)—C(═O)—, or —N(R11)—S(O2)—; When R1 does not form a ring with R11, it is -Y-R3; or Y is C1-C6 alkylene, in which one non-terminal -CH2- moiety may be replaced by -O-, and 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 the alkylene moiety may contain a 3-5 membered saturated or partially unsaturated carbocyclic ring as part of the moiety; or R1 and R11 may together form a saturated or partially unsaturated 4- to 7-membered heterocyclic ring optionally containing one or two additional heteroatoms selected from N, O and S as ring members, which heterocyclic ring is optionally substituted with one to three R1a; or R1 and R11 may together form a 5- to 6-membered heteroaryl ring optionally containing one to three additional heteroatoms selected from N and O as ring members, which heteroaryl ring is optionally substituted with one to three R1b; R11 is C1-C4 alkylene-R11a, C1-C4 haloalkylene-R11a or C3-C6 cycloalkyl, wherein the cycloalkyl is optionally substituted with one or two R11b.

[0286] In some embodiments, T is —N(R11)— or —N(R11)—S(O2)—; When R11 does not form a ring with R1, it is hydrogen, C1-C4 alkylene-R11a, C1-C4 haloalkylene-R11a or C3-C6 cycloalkyl; R11a is hydrogen, halogen, —CN or —OH; R1 and R11 may together form a 4-6 membered saturated or partially unsaturated heterocyclic ring optionally containing one further heteroatom selected from N and O as a ring member, which heterocyclic ring is optionally substituted with one or two R1a, or R1 and R11 may together form a 5 membered heteroaryl ring optionally containing one further heteroatom selected from N as a ring member, which heteroaryl ring is optionally substituted with one or two R1b; each R1a is independently halogen, —OH, —CN, C1-C4 alkylene-R1c, —O—C1-C4 haloalkyl, —C(═O)NH2, or oxo; each R is independently halogen, —OH, —CN, C-C alkylene-R, or —O—C-C haloalkyl; each R is independently hydrogen or -OH; When R1 does not form a ring with R11, it is -Y-R3; Y is a C1-C6 alkylene, the alkylene moiety may be optionally substituted with one -OH, the alkylene moiety may include a 3-membered saturated carbocyclic ring as part of the moiety, and there is a spacer of not more than 3 carbon atoms between the connection to T and the connection to R3; R3 is hydrogen, -CN, -OH, C1-C4 haloalkyl, -O-C1-C4 alkylene-R4, -O-C1-C4 haloalkyl, -NH2, -NH(C1-C4 alkylene-R4), -N(C1-C4 alkylene-R4)2, -C(=O)-NH2, -C(=O)-NH(C1-C4 alkylene-R4), -C(=O)-OH, -C(=O)-O-C1-C4 alkylene-R4, -C(=O)-N( C1-C4 alkylene-R4), -NH-C(=O)-C1-C4 alkylene-R4, -N(C1-C4 alkyl)-C(=O)-C1-C4 alkylene-R4, ring P, ring Q, -NH-S(O2)-C1-C4 alkylene-R4, -N(C1-C4 alkyl)-S(O2)-C1-C4 alkylene-R4, -S-C1-C4 alkylene-R4 or -S(O2)-C1-C4 alkyl-R4; R4 is hydrogen; Ring P is a 3- to 6-membered saturated carbocyclic ring optionally substituted with 1 to 2 R5, or a 5- to 6-membered saturated heterocyclic ring containing one heteroatom selected from N and O and optionally substituted with 1 to 2 R5; each R5 is independently -NH2, C1-C2 alkyl, -C1-C2 alkyl-R5a, or oxo; each R5a is independently hydrogen, halogen, —NH2, —OH, —CN, or —O—C1-C2 alkyl; Ring Q is phenyl optionally substituted with one or two R6, or a 5-6 membered heteroaryl ring containing 1-2 heteroatoms selected from N, S and O, optionally substituted with one or two R6; each R6 is independently -NH2, -OH, -CN, C1-C2 alkylene-R6a, or -O-C1-C2 alkyl; Each R6a is independently hydrogen, halogen, or -CN.

[0287] In some embodiments, T is —N(R11)— or —N(R11)—S(O2)—; When R11 does not form a ring with R1, it is C1-C4 alkylene-R11a, C1-C4 haloalkylene-R11a or C3-C4 cycloalkyl; R11a is hydrogen, halogen, —CN or —OH; R1 and R11 may together form a 5- to 6-membered saturated heterocyclic ring containing no additional heteroatoms as ring members, which heterocyclic ring is optionally substituted with one R1a, or R1 and R11 may together form a 5-membered heteroaryl ring containing no additional heteroatoms as ring members, which heteroaryl ring is optionally substituted with one R1b; R1a is halogen, —OH or —CN; R1b is halogen, —OH or —CN; When R1 does not form a ring with R11, it is C1-C3 alkylene-R3, ring P or ring Q; R3 is hydrogen, -CN, -OH, C1-C4 haloalkyl, -O-C1-C4 alkylene-R4, -O-C1-C4 haloalkyl, -NH2, -NH(C1-C4 alkylene-R4) or -N(C1-C4 alkylene-R4)2, -C(=O)-OH, -C(=O)-NH2, ring P or ring Q; Ring P is oxazolidinyl optionally substituted with one or two R5; each R5 is independently C1-C2 alkyl, -C1-C2 alkyl-R5a, or oxo, and ring P is not substituted with two oxo (e.g., ring P is optionally substituted with only one R5 when R5 is oxo); Ring Q is phenyl optionally substituted with one R6, or a 5-6 membered heteroaryl ring containing 1-2 heteroatoms selected from N and O, optionally substituted with one R6; R6 is independently -NH2, -OH, -CN, C1-C2 alkylene-R6a, or -O-C1-C2 alkyl; R6a is independently hydrogen, halogen or -CN.

[0288] In some embodiments, T is -N(R11)-, and R11, when not forming a ring with R1, is C1-C4 alkyl, for example, methyl or ethyl.

[0289] In an embodiment (Embodiment A1), the compound is a compound of Formula (I), wherein: Ra and Rb are both —CH3, or Ra and Rb together form a —CH2—CH2—CH2—CH2- bridging moiety; A is -CH2- or -C(=O)-; 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)-; When R11 does not form a ring with R1 or R2, it is hydrogen, C1-C4 alkylene-R11a, C1-C4 haloalkylene-R11a or C3-C6 cycloalkyl; R11a is hydrogen, halogen, —CN or —OH; each R12 is independently hydrogen or C1-C4 alkylene-R12a; each R12a is independently hydrogen, halogen, —CN, or —OH; R13 is hydrogen; R14 is hydrogen or C1-C4 alkyl; R2 and R11 may together form a partially unsaturated 6-membered heterocyclic ring containing no additional heteroatoms when T is -N(R11)- and X is -O-; R1 and R11 may together form a 4-6 membered saturated or partially unsaturated heterocyclic ring optionally containing one further heteroatom selected from N and O as a ring member, for example a ring selected from piperidinyl, morpholinyl, pyrrolidinyl, azetidinyl, 2,5-dihydropyrrolyl and 1,1-dioxide-1,2-thiazolidin-2-yl, which heterocyclic ring is optionally substituted with one or two R1a, or R1 and R11 may together form a 5 membered heteroaryl ring optionally containing one further heteroatom selected from N, for example pyrrolyl, which heteroaryl ring is optionally substituted with one or two R1b, each R1a is independently halogen, —OH, —CN, C1-C4 alkylene-R1c, —O—C1-C4 haloalkyl, —C(═O)NH2, or oxo; each R is independently halogen, —OH, —CN, C-C alkylene-R, or —O—C-C haloalkyl; each R is independently hydrogen or -OH; When R1 does not form a ring with R11, it is -Y-R3; Y is a bond or C1-C6 alkylene, the alkylene moiety may be optionally substituted with one -OH, the alkylene moiety may include a 3-membered saturated carbocyclic ring as part of the moiety, and there is a spacer of not more than 3 carbon atoms between the connection to T and the connection to R3; R3 is hydrogen, -CN, -OH, C1-C4 haloalkyl, -O-C1-C4 alkylene-R4, -O-C1-C4 haloalkyl, -NH2, -NH(C1-C4 alkylene-R4), -N(C1-C4 alkylene-R4)2, -C(=O)-NH2, -C(=O)-NH(C1-C4 alkylene-R4), -C(=O)-OH, -C(=O)-O-C1-C4 alkylene-R4, -C(=O)-N( C1-C4 alkylene-R4), -NH-C(=O)-C1-C4 alkylene-R4, -N(C1-C4 alkyl)-C(=O)-C1-C4 alkylene-R4, ring P, ring Q, -NH-S(O2)-C1-C4 alkylene-R4, -N(C1-C4 alkyl)-S(O2)-C1-C4 alkylene-R4, -S-C1-C4 alkylene-R4 or -S(O2)-C1-C4 alkyl-R4; R4 is hydrogen; Ring P is a 3- to 6-membered saturated carbocyclic ring optionally substituted with 1 to 2 R5, or a 5- to 6-membered saturated heterocyclic ring containing one heteroatom selected from N and O and optionally substituted with 1 to 2 R5; each R5 is independently -NH2, C1-C2 alkyl, -C1-C2 alkyl-R5a, or oxo; each R5a is independently hydrogen, halogen, —NH2, —OH, —CN, or —O—C1-C2 alkyl; Ring Q is phenyl optionally substituted with one or two R6, or a 5-6 membered heteroaryl ring containing 1-2 heteroatoms selected from N, S and O, optionally substituted with one or two R6; each R6 is independently -NH2, -OH, -CN, C1-C2 alkylene-R6a, or -O-C1-C2 alkyl; each R6a is independently hydrogen, halogen, or -CN; X is —O— or —N(R10a)—, or X-R2 is halogen or hydrogen; R10a is hydrogen or -CH3, or R2 and R10a together may form a 4-7 membered saturated heterocyclic ring which optionally contains an -N(R9)- moiety as a ring member in addition to the nitrogen atom of X, and otherwise contains only carbon atoms as ring members, and when it does not contain an -N(R9)- moiety, the heterocyclic ring is optionally substituted with one R8; When R2 does not form a ring with R10a or R11, it is C1-C4 alkyl optionally substituted with R7, or a 4- or 7-membered saturated carbocyclic ring optionally substituted with one R8, or 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; R7a is hydrogen or C1-C4 alkyl-R7c; R7b is hydrogen or C1-C4 alkyl; R7c is hydrogen, halogen, —O—C1-C2 alkyl, or —O—C1-C2 haloalkyl; R8 is -N(R8a)R8b; When R8a does not form a ring with R8b, R8a is hydrogen or C1-C4 alkyl-R8c; R8b is hydrogen or C1-C4 alkyl when it does not form a ring with R8a; R8a and R8b may together form a 6-membered saturated heterocyclic ring optionally containing one or two further heteroatoms selected from N and O as ring members; R8c is hydrogen, halogen, —O—C1-C2 alkyl, or —O—C1-C2 haloalkyl; R9 is hydrogen or C1-C4 alkyl.

[0290] In an embodiment (embodiment A2), the compound is a compound of formula (I), wherein: Ra and Rb are both —CH3, or Ra and Rb together form a —CH2—CH2—CH2—CH2- bridging moiety; A is -CH2- or -C(=O)-; 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)-; When R11 does not form a ring with R1 or R2, it is hydrogen, C1-C4 alkylene-R11a, C1-C4 haloalkylene-R11a or C3-C6 cycloalkyl; R11a is hydrogen, halogen, —CN or —OH; each R12 is independently hydrogen or C1-C4 alkylene-R12a; each R12a is independently hydrogen, halogen, —CN, or —OH; R13 is hydrogen; R14 is hydrogen or C1-C4 alkyl; R2 and R11 may together form a partially unsaturated 6-membered heterocyclic ring containing no additional heteroatoms when T is -N(R11)- and X is -O-; R1 and R11 may together form a 4-6 membered saturated or partially unsaturated heterocyclic ring optionally containing one further heteroatom selected from N and O as a ring member, for example a ring selected from piperidinyl, morpholinyl, pyrrolidinyl, azetidinyl, 2,5-dihydropyrrolyl and 1,1-dioxide-1,2-thiazolidin-2-yl, which heterocyclic ring is optionally substituted with one or two R1a, or R1 and R11 may together form a 5 membered heteroaryl ring optionally containing one further heteroatom selected from N, for example pyrrolyl, which heteroaryl ring is optionally substituted with one or two R1b, each R1a is independently halogen, —OH, —CN, C1-C4 alkylene-R1c, —O—C1-C4 haloalkyl, —C(═O)NH2, or oxo; each R is independently halogen, —OH, —CN, C-C alkylene-R, or —O—C-C haloalkyl; each R is independently hydrogen or -OH; R1, when not forming a ring with R11, is hydrogen or C1-C6 alkylene-R3, the alkylene moiety may be substituted with one -OH, the alkylene moiety may include a 3-membered saturated carbocyclic ring as part of the moiety, and there is a spacer of 3 or less carbon atoms between the connection to T and the connection to R3, or R1 is ring P or ring Q; R3 is hydrogen, -CN, -OH, C1-C4 haloalkyl, -O-C1-C4 alkylene-R4, -O-C1-C4 haloalkyl, -NH2, -NH(C1-C4 alkylene-R4), -N(C1-C4 alkylene-R4)2, -C(=O)-NH2, -C(=O)-NH(C1-C4 alkylene-R4), -C(=O)-OH, -C(=O)-O-C1-C4 alkylene-R4, -C(=O)-N( C1-C4 alkylene-R4), -NH-C(=O)-C1-C4 alkylene-R4, -N(C1-C4 alkyl)-C(=O)-C1-C4 alkylene-R4, ring P, ring Q, -NH-S(O2)-C1-C4 alkylene-R4, -N(C1-C4 alkyl)-S(O2)-C1-C4 alkylene-R4, -S-C1-C4 alkylene-R4 or -S(O2)-C1-C4 alkyl-R4; R4 is hydrogen; Ring P is a 3- to 6-membered saturated carbocyclic ring optionally substituted with 1 to 2 R5, or a 5- to 6-membered saturated heterocyclic ring containing one heteroatom selected from N and O and optionally substituted with 1 to 2 R5; each R5 is independently -NH2, C1-C2 alkyl, -C1-C2 alkyl-R5a, or oxo; each R5a is independently hydrogen, halogen, —NH2, —OH, —CN, or —O—C1-C2 alkyl; Ring Q is phenyl optionally substituted with one or two R6, or a 5-6 membered heteroaryl ring containing 1-2 heteroatoms selected from N, S and O, optionally substituted with one or two R6; each R6 is independently -NH2, -OH, -CN, C1-C2 alkylene-R6a, or -O-C1-C2 alkyl; each R6a is independently hydrogen, halogen, or -CN; X is -O- or -NH(R10a)-, or X-R2 is halogen or hydrogen; R10a is hydrogen or -CH3, or R2 and R10a together may form a 4-7 membered saturated heterocyclic ring which optionally contains an -N(R9)- moiety as a ring member in addition to the nitrogen atom of X, and otherwise contains only carbon atoms as ring members, and when it does not contain an -N(R9)- moiety, the heterocyclic ring is optionally substituted with one R8; When R2 does not form a ring with R10a or R11, it is C1-C4 alkyl optionally substituted with R7, or a 4- to 7-membered saturated carbocyclic ring optionally substituted with one R8, or 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; R7 is -N(R7a)R7b; R7a is hydrogen or C1-C4 alkyl-R7c; R7b is hydrogen or C1-C4 alkyl; R7c is hydrogen, halogen, —O—C1-C2 alkyl or —O—C1-C2 haloalkyl; R8 is —N(R8a)R8b; When R8a does not form a ring with R8b, R8a is hydrogen or C1-C4 alkyl-R8c; R8b is hydrogen or C1-C4 alkyl when it does not form a ring with R8a; R8a and R8b may together form a 6-membered saturated heterocyclic ring optionally containing one or two further heteroatoms selected from N and O as ring members; R8c is hydrogen, halogen, —O—C1-C2 alkyl, or —O—C1-C2 haloalkyl; R9 is hydrogen or C1-C4 alkyl.

[0291] In an embodiment (embodiment B), the compound is a compound of formula (I), wherein: Ra and Rb are both —CH3; A is -CH2-, T is -N(R11)-, -N(R11)-S(O2)-, -C=C(R12)2, -S-, or -C(=O)-N(R14)-; When R11 does not form a ring with R1, it is hydrogen, C1-C4 alkylene-R11a, C1-C4 haloalkylene-R11a or C3-C4 cycloalkyl; R11a is hydrogen, halogen, —CN or —OH; each R12 is independently hydrogen or C1-C4 alkylene-R12a; each R12a is independently hydrogen, halogen, —CN, or —OH; R14 is hydrogen or C1-C4 alkyl; 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, which 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, which heteroaryl ring is optionally substituted with one R1b; R1a is halogen, —OH or —CN; R1b is halogen, —OH or —CN; When R1 does not form a ring with R11, it is hydrogen, C1-C3 alkylene-R3, ring P or ring Q; R3 is hydrogen, -CN, -OH, C1-C4 haloalkyl, -O-C1-C4 alkylene-R4, -O-C1-C4 haloalkyl, -NH2, -NH(C1-C4 alkylene-R4) or -N(C1-C4 alkylene-R4)2, -C(=O)-OH, -C(=O)-NH2, ring P or ring Q; R4 is hydrogen; Ring P is oxazolidinyl optionally substituted with one or two R5; each R5 is independently C1-C2 alkyl, -C1-C2 alkyl-R5a, or oxo, and ring P is not substituted with two oxo (e.g., ring P is optionally substituted with only one R5 when R5 is oxo); each R5a is independently hydrogen, halogen, —NH2, —OH, —CN, or —O—C1-C2 alkyl; Ring Q is phenyl optionally substituted with one R6, or a 5-6 membered heteroaryl ring containing 1-2 heteroatoms selected from N and O, optionally substituted with one R6; R6 is independently -NH2, -OH, -CN, C1-C2 alkylene-R6a, or -O-C1-C2 alkyl; R6a is independently hydrogen, halogen or -CN; X is —O— or —N(R10a)—, or X-R2 is halogen; R10a is hydrogen or -CH3, or R2 and R10a together may form a 6-7 membered saturated heterocyclic ring substituted with one R8 at the 3-position relative to the nitrogen atom of X, when the ring contains one -N(R9)- moiety at the 3-position relative to the nitrogen atom of X as a ring member and otherwise contains only carbon atoms as ring members and does not contain any -N(R9)- moieties; When R2 does not form a ring with R10a, it is C1-C4 alkyl optionally substituted with R7, or it is a 6- to 7-membered saturated carbocyclic ring substituted with one R8 at the 3-position relative to X, or it is a 6- to 7-membered saturated heterocyclic ring containing one -N(R9)- moiety as a ring member at the 3-position relative to X and otherwise containing only carbon atoms as ring members, or X-R2 is halogen or hydrogen, R7 is -N(R7a)R7b; R7a is hydrogen or C1-C4 alkyl-R7c; R7b is hydrogen or C1-C4 alkyl; R7c is hydrogen, halogen, —O—C1-C2 alkyl, or —O—C1-C2 haloalkyl; R8 is -N(R8a)R8b; When R8a does not form a ring with R8b, R8a is hydrogen or C1-C4 alkyl-R8c; R8a is hydrogen or C1-C4 alkyl when it does not form a ring with R8a; R8a and R8b may together form a 6-membered saturated heterocyclic ring optionally containing one or two further heteroatoms selected from N and O as ring members; R8c is hydrogen, halogen, —O—C1-C2 alkyl, or —O—C1-C2 haloalkyl; R9 is hydrogen or C1-C4 alkyl.

[0292] In an embodiment (embodiment C), the compound is a compound of formula (I), wherein: Ra and Rb are both —CH3, or Ra and Rb together form a —CH2—CH2—CH2—CH2- bridging moiety; A is -CH2- or -C(=O)-; 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)-, and when R11 does not form a ring with R1 or R2, it is -CH3, cyclopropyl, -CH2CH2CH3, -CH2CH2CN, -CH2CH2OH, -CH2CH3, or hydrogen; each R12 is independently hydrogen, —CH3, or —CH2OH; R13 is hydrogen; R14 is hydrogen or -CH3; R2 and R11 may together form a -CH2CH2- bridging moiety when T is -N(R11)- and X is -O-; R1 and R11, when T is -N(R11)-, may together form a heterocyclic ring selected from piperidinyl, morpholinyl, pyrrolidinylazetidinyl, 2,5-dihydropyrrolyl, and 1,1-dioxido-1,2-thiazolidin-2-yl, each optionally substituted with 1 to 2 R1a; each R1a is independently -OH, -CN, -OCH3, -CH2OH, -C(=O)NH2, or oxo; R1 and R11, when T is -N(R11)-, may together form a heteroaryl ring selected from pyrrolyl optionally substituted with one or two R1b; each R is independently selected from —OH, —CN, —OCH and —CHOH; When R1 does not form a ring with R11, R1 is hydrogen or -Y-R3; Y is 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-; 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; X is -O- or -N(R10a)-, or X-R2 is bromo or hydrogen; R2 and R10a may be taken together to form a piperazinyl ring; When R2 does not form a ring with R10a or R11, it is azepan-4-yl, -CH3, -CH2CH2N(CH3)2, 4-amino-cyclohexyl (e.g., cis-4-amino-cyclohexyl and trans-4-amino-cyclohexyl), 4-morpholin-4-yl-cyclohexyl (e.g., trans-4-morpholin-4-yl-cyclohexyl), 4-NH(CH2CHOCH3)-cyclohexyl (e.g., trans-4-N(CH2CHOCH3)-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 X-R2 is bromo or hydrogen.

[0293] In further embodiments, the present invention provides the following compounds and pharmaceutically acceptable salts thereof: 8-Methoxy-5,5,7-trimethyl-6H-benzo[h]quinazolin-4-amine, 8-methoxy-5,5-dimethyl-6H-benzo[h]quinazoline-4,7-diamine, 6,6-dimethyl-2,3,4,5-tetrahydroquinazolino[7,8-f][1,4]benzoxazin-7-amine, 4,6,6-trimethyl-3,5-dihydro-2H-quinazolino[7,8-f][1,4]benzoxazin-7-amine, 8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazoline-4,7-diamine, N-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]acetamide, 8-(trans-4-aminocyclohexoxy)-N7,N7-diethyl-5,5-dimethyl-6H-benzo[h]quinazoline-4,7-diamine, 8-(trans-4-aminocyclohexoxy)-N7-ethyl-5,5-dimethyl-6H-benzo[h]quinazoline-4,7-diamine, 8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-7-(1-piperidyl)-6H-benzo[h]quinazolin-4-amine, 8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-7-morpholino-6H-benzo[h]quinazolin-4-amine, 2-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-(2-hydroxyethyl)amino]ethanol, 2-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methyl-amino]ethanol, 8-(trans-4-aminocyclohexoxy)-N7-(2-methoxyethyl)-N7,5,5-trimethyl-6H-benzo[h]quinazoline-4,7-diamine, 2-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]amino]ethanol, 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, 8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-7-pyrrol-1-yl-6H-benzo[h]quinazolin-4-amine, 8-(trans-4-aminocyclohexoxy)-N7-(2-methoxyethyl)-5,5-dimethyl-6H-benzo[h]quinazoline-4,7-diamine, 8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-7-propoxy-6H-benzo[h]quinazolin-4-amine, 8-(trans-4-aminocyclohexoxy)-N7,N7,5,5-tetramethyl-6H-benzo[h]quinazoline-4,7-diamine, 1-(4-amino-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-9-yl)piperidin-4-ol, 2-[[4-amino-8-(cis-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-ethyl-amino]ethanol, 2-[[4-amino-8-(cis-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-propyl-amino]ethanol, 2-[[4-amino-8-(cis-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methyl-amino]ethanol, 1-(4-amino-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)azetidin-3-ol, 2-[[4-amino-8-(cis-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methyl-amino]-N-methyl-acetamide, 3-[(4-amino-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)amino]propane-1,2-diol, [1-(4-amino-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)azetidin-3-yl]methanol, 8-(cis-4-aminocyclohexoxy)-N7,5,5-trimethyl-N7-(tetrahydropyran-4-ylmethyl)-6H-benzo[h]quinazoline-4,7-diamine, 2-[[4-amino-8-(cis-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methyl-amino]acetonitrile, 8-(cis-4-aminocyclohexoxy)-N7,5,5-trimethyl-N7-(2-methylsulfanylethyl)-6H-benzo[h]quinazoline-4,7-diamine, 8-(cis-4-aminocyclohexoxy)-N7,5,5-trimethyl-N7-(2-methylsulfonylethyl)-6H-benzo[h]quinazoline-4,7-diamine, 2-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methyl-amino]acetonitrile, 4,7-diamino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-benzo[h]quinazolin-6-one, 2-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]amino]acetonitrile, 8-(trans-4-aminocyclohexoxy)-N7-(2-ethoxyethyl)-N7,5,5-trimethyl-6H-benzo[h]quinazoline-4,7-diamine, 8-(trans-4-aminocyclohexoxy)spiro[6H-benzo[h]quinazoline-5,1'-cyclopentane]-4,7-diamine, N-[2-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methyl-amino]ethyl]acetamide, N-[2-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methyl-amino]ethyl]methanesulfonamide, 1-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methyl-amino]-2-methyl-propan-2-ol, N-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-2-hydroxy-N-methyl-acetamide, N-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-2-hydroxy-ethanesulfonamide, 8-(trans-4-aminocyclohexoxy)-N7,5,5-trimethyl-N7-(3,3,3-trifluoropropyl)-6H-benzo[h]quinazoline-4,7-diamine, N-[4-amino-8-(4-trans-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-2-hydroxy-N-methyl-ethanesulfonamide, N-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-2-hydroxy-acetamide, 3-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methyl-amino]propanenitrile, 8-(trans-4-aminocyclohexoxy)-N7,5,5-trimethyl-N7-[2-(trifluoromethoxy)ethyl]-6H-benzo[h]quinazoline-4,7-diamine, 1-[[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methyl-amino]methyl]cyclopropanecarbonitrile, 1-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]pyrrolidine-3-carbonitrile-isomer 1, 1-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]pyrrolidine-3-carbonitrile-isomer 2, 3-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-cyclopropyl-amino]propanenitrile, 3-[[4-amino-5,5-dimethyl-8-(trans-4-morpholinocyclohexoxy)-6H-benzo[h]quinazolin-7-yl]-methyl-amino]propanenitrile, 3-[[4-amino-8-[trans-4-(2-methoxyethylamino)cyclohexoxy]-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methyl-amino]propanenitrile, 8-(trans-4-aminocyclohexoxy)-N7-but-3-ynyl-N7,5,5-trimethyl-6H-benzo[h]quinazoline-4,7-diamine, 1-(4-amino-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)pyrrolidine-3-carbonitrile, 1-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-2H-pyrrol-5-one, 8-(trans-4-aminocyclohexoxy)-7-(3-methoxypyrrol-1-yl)-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine, 4-[[4-amino-8-(4-trans-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methyl-amino]butanenitrile, 2-[[4-amino-8-(4-trans-aminocyclohexoxy)spiro[6H-benzo[h]quinazoline-5,1'-cyclopentan]-7-yl]-methyl-amino]ethanol, 2-[[4-amino-8-(4-trans-aminocyclohexoxy)spiro[6H-benzo[h]quinazoline-5,1'-cyclopentan]-7-yl]amino]ethanol, 8-methoxy-7-(3-methoxypropyl)-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine, 8-(trans-4-aminocyclohexoxy)-N7-(2-methoxyethyl)spiro[6H-benzo[h]quinazoline-5,1'-cyclopentane]-4,7-diamine, 8-(trans-4-aminocyclohexoxy)-7-(3-methoxypyrrolidin-1-yl)-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine-isomer 1, N-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-2-methoxy-N-methyl-ethanesulfonamide, ethyl 2-[[4-amino-8-(cis-4-aminocyclohexoxy)spiro[6H-benzo[h]quinazoline-5,1'-cyclopentan]-7-yl]amino]acetate, 1-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]pyrrolidine-3-carbonitrile, 8-(trans-4-aminocyclohexoxy)-N7-ethyl-N7,5,5-trimethyl-6H-benzo[h]quinazoline-4,7-diamine, 8-(trans-4-aminocyclohexoxy)-N7,5,5-trimethyl-6H-benzo[h]quinazoline-4,7-diamine, 3-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methyl-sulfamoyl]propanoic acid, 2-[[4-amino-8-(cis-4-aminocyclohexoxy)spiro[6H-benzo[h]quinazoline-5,1'-cyclopentan]-7-yl]amino]ethanol, 3-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]oxy]propanenitrile, 8-(trans-4-aminocyclohexoxy)-N7-(2-methoxyethyl)-N7-methyl-spiro[6H-benzo[h]quinazoline-5,1'-cyclopentane]-4,7-diamine, 8-(trans-4-aminocyclohexoxy)-7-(3-methoxypyrrolidin-1-yl)-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine-isomer 2, N-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-2-cyano-N-methyl-ethanesulfonamide, 8-(cis-4-aminocyclohexoxy)-N7-(2-methoxyethyl)-N7-methyl-spiro[6H-benzo[h]quinazoline-5,1'-cyclopentane]-4,7-diamine, 1-[[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]amino]methyl]cyclopropanecarbonitrile, 1-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]pyrrolidine-3-carboxamide, 3-[[4-amino-8-(azepan-4-yloxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methyl-amino]propanenitrile, 2-[[4-amino-8-(cis-4-aminocyclohexoxy)spiro[6H-benzo[h]quinazoline-5,1'-cyclopentan]-7-yl]amino]acetic acid, 8-(trans-4-aminocyclohexoxy)-N7-(2-aminoethyl)-N7,5,5-trimethyl-6H-benzo[h]quinazoline-4,7-diamine, 4-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]butanenitrile, (5R)-5-[[(4-amino-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)amino]methyl]oxazolidin-2-one, 2-[[4-amino-8-(cis-4-aminocyclohexoxy)spiro[6H-benzo[h]quinazoline-5,1'-cyclopentan]-7-yl]-methyl-amino]ethanol, 8-(trans-4-aminocyclohexoxy)-N7-cyclopropyl-5,5-dimethyl-6H-benzo[h]quinazoline-4,7-diamine, 3-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methyl-amino]propanoic acid, 3-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methyl-sulfamoyl]propanamide, 8-(cis-4-aminocyclohexoxy)-N7-(2-methoxyethyl)spiro[6H-benzo[h]quinazoline-5,1'-cyclopentane]-4,7-diamine, 3-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methyl-amino]-2,2-dimethyl-propanamide, (5R)-5-[2-[(4-amino-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)amino]ethyl]oxazolidin-2-one, 4-amino-8-(trans-4-aminocyclohexoxy)-N-(cyanomethyl)-5,5-dimethyl-6H-benzo[h]quinazoline-7-carboxamide, 3-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methyl-amino]-2,2-dimethyl-propanenitrile, 3-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]butan-1-ol, 3-[[4-amino-5,5-dimethyl-8-(4-piperidyloxy)-6H-benzo[h]quinazolin-7-yl]-methyl-amino]propanenitrile, 4-amino-8-(trans-4-aminocyclohexoxy)-N-(cyanomethyl)-N,5,5-trimethyl-6H-benzo[h]quinazoline-7-carboxamide, 3-[(4-amino-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)-methyl-amino]propanenitrile, 3-[[4-amino-8-trans-4-(dimethylamino)cyclohexoxy]-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methyl-amino]propanenitrile, 4-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]pentanenitrile, (E)-3-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]but-2-en-1-ol, 3-[[4-amino-5,5-dimethyl-8-[trans-4-(methylamino)cyclohexoxy]-6H-benzo[h]quinazolin-7-yl]-methyl-amino]propanenitrile, 8-(trans-4-aminocyclohexoxy)-N7-butyl-N7,5,5-trimethyl-6H-benzo[h]quinazoline-4,7-diamine, 8-(trans-4-aminocyclohexoxy)-N7,5,5-trimethyl-N7-(4-pyridylmethyl)-6H-benzo[h]quinazoline-4,7-diamine, 8-(trans-4-aminocyclohexoxy)-N7-isopropyl-N7,5,5-trimethyl-6H-benzo[h]quinazoline-4,7-diamine, 8-(trans-4-aminocyclohexoxy)-N7-(1H-imidazol-4-ylmethyl)-N7,5,5-trimethyl-6H-benzo[h]quinazoline-4,7-diamine, 8-(trans-4-aminocyclohexoxy)-N7-isopentyl-N7,5,5-trimethyl-6H-benzo[h]quinazoline-4,7-diamine, 8-(trans-4-aminocyclohexoxy)-N7,5,5-trimethyl-N7-(oxazol-4-ylmethyl)-6H-benzo[h]quinazoline-4,7-diamine, 8-(trans-4-aminocyclohexoxy)-N7-isobutyl-N7,5,5-trimethyl-6H-benzo[h]quinazoline-4,7-diamine, 8-(trans-4-aminocyclohexoxy)-N7,5,5-trimethyl-N7-(3-pyridylmethyl)-6H-benzo[h]quinazoline-4,7-diamine, 3-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]sulfanyl]propanenitrile, 3-[(4-amino-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)-methyl-amino]propanenitrile, 3-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methyl-amino]-2,2-dimethyl-propan-1-ol, 4-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methyl-amino]-2-methyl-butan-2-ol, 3-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]sulfonyl]propanenitrile, 4-amino-8-(trans-4-aminocyclohexoxy)-N-(cyanomethyl)-N,5,5-trimethyl-6H-benzo[h]quinazoline-7-sulfonamide, N-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-4-fluoro-N-methyl-benzenesulfonamide, 3-[(4-amino-8-bromo-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)-methyl-amino]propanenitrile, 4-amino-8-(trans-4-aminocyclohexoxy)-N-(cyanomethyl)-5,5-dimethyl-6H-benzo[h]quinazoline-7-sulfonamide, 3-(7-amino-6,6-dimethyl-3,5-dihydro-2H-quinazolino[7,8-f][1,4]benzoxazin-4-yl)propanenitrile; 3-[[4-amino-5,5-dimethyl-8-(4-methylpiperazin-1-yl)-6H-benzo[h]quinazolin-7-yl]-methyl-amino]propanenitrile, 8-(trans-4-aminocyclohexoxy)-7-(1,1-dioxo-1,2-thiazolidin-2-yl)-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine, 1-(4-amino-8-bromo-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)pyrrolidine-3-carbonitrile, (5R)-5-[[(4-amino-8-bromo-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)amino]methyl]oxazolidin-2-one, N7-[[5-(1-fluoroethyl)-1,3,4-oxadiazol-2-yl]methyl]-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazoline-4,7-diamine, 3-[[4-amino-8-[2-(dimethylamino)ethoxy]-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methyl-amino]propanenitrile, 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, 3-[(4-amino-5,5-dimethyl-8-piperazin-1-yl-6H-benzo[h]quinazolin-7-yl)-methyl-amino]propanenitrile, (5S)-5-[[(4-amino-8-bromo-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)-methyl-amino]methyl]oxazolidin-2-one, (5R)-5-[[(4-amino-8-bromo-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)amino]methyl]-3-(2-hydroxyethyl)oxazolidin-2-one, (5R)-5-[[[4-amino-8-(cis-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]amino]methyl]oxazolidin-2-one, (5R)-5-[[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]amino]methyl]oxazolidin-2-one, (5R)-5-[[[4-amino-5,5-dimethyl-8-(cis-4-morpholinocyclohexoxy)-6H-benzo[h]quinazolin-7-yl]amino]methyl]oxazolidin-2-one, (5R)-5-[[[4-amino-5,5-dimethyl-8-(trans-4-morpholinocyclohexoxy)-6H-benzo[h]quinazolin-7-yl]amino]methyl]oxazolidin-2-one, and 3-[(4-amino-8-bromo-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)-[[(5S)-2-oxooxazolidin-5-yl]methyl]amino]propanenitrile.

[0294] Some intermediates useful in the preparation of compounds of formula (I) are novel and form a further aspect of the invention. Thus, in a further aspect, the present invention provides compounds of formula (B)

[0295] [ka]

[0296] and salts thereof, wherein: A, Ra and Rb are as defined for compounds of formula (I), including their preferred definitions (including those defined in embodiment A1, embodiment A2, embodiment B or embodiment C); E1 is -OH, -halogen, -O-C1-C4 alkyl, boronic acid, boronic ester (e.g., dimethylboronic ester or pinacolboronic ester), or O-L1; L1 is methanesulfonyl, p-toluenesulfonyl or trifluoromethanesulfonyl; E2 is -OH, halogen, -NO2 or -SO2Cl.

[0297] In a further aspect, the present invention provides a compound of formula (C)

[0298] [ka]

[0299] and salts thereof, wherein: A, X, Ra and Rb are as defined for compounds of formula (I), including their preferred definitions (including those defined in embodiment A1, embodiment A2, embodiment B or embodiment C); E2 is -OH, halogen, -NO2 or -SO2Cl; R2' is as defined for R2 for compounds of Formula (I), including its preferred definitions (including those defined in Embodiment A1, Embodiment A2, Embodiment B or Embodiment C), where any functional groups within R2 are optionally protected with a suitable protecting group.

[0300] Preferably, in compounds of formula (C), the amino group in the R2' substituent 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.

[0301] In a further aspect, the present invention provides a compound of formula (D)

[0302] [ka]

[0303] and salts thereof, wherein: A, X, Ra and Rb are as defined for compounds of formula (I), including their preferred definitions (including those defined in embodiment A1, embodiment A2, embodiment B or embodiment C); T' is -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')-; R is as defined for R in compounds of Formula (I), including its preferred definitions (including those defined in Embodiment A1, Embodiment A2, Embodiment B, or Embodiment C), where any functional groups within R are optionally protected with a suitable protecting group; R12' is as defined for R12 in compounds of Formula (I), including its preferred definitions (including those defined in Embodiment A1, Embodiment A2, Embodiment B or Embodiment C), where any functional groups within R12 are optionally protected with a suitable protecting group; R13 is as defined for compounds of Formula (I), including its preferred definitions (including those defined in Embodiment A1, Embodiment A2, Embodiment B or Embodiment C); R14' is as defined for R14 in compounds of Formula (I), including its preferred definitions (including those defined in Embodiment A1, Embodiment A2, Embodiment B or Embodiment C), where any functional groups within R14 are optionally protected with a suitable protecting group; R is as defined for R in compounds of Formula (I), including its preferred definitions (including those defined in Embodiment A1, Embodiment A2, Embodiment B, or Embodiment C), where any functional groups within R are optionally protected with a suitable protecting group; R2' is as defined for R2 in compounds of Formula (I), including its preferred definitions (including those defined in Embodiment A1, Embodiment A2, Embodiment B or Embodiment C), where any functional groups within R2 are optionally protected with a suitable protecting group.

[0304] Preferably, the compound of formula (D) comprises at least one protecting group.

[0305] Preferably, in the compound of formula (D), among one or more of the substituents R1', R2', R11', R12' and R14', an amino group may optionally be protected with a suitable amino protecting group, such as allyloxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethylcarbonyl, tert-butoxycarbonyl or benzyl, and / or a hydroxyl group may optionally be protected with a suitable hydroxyl protecting group, such as methyl, benzyl or para-methoxybenzyl.

[0306] In a further aspect, the present invention provides a compound of formula (E)

[0307] [ka]

[0308] and salts thereof, wherein: A, Ra and Rb are as defined for compounds of formula (I), including their preferred definitions (including those defined in embodiment A1, embodiment A2, embodiment B or embodiment C); T' is -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')-; R is as defined for R in compounds of Formula (I), including its preferred definitions (including those defined in Embodiment A1, Embodiment A2, Embodiment B, or Embodiment C), where any functional groups within R are optionally protected with a suitable protecting group; R12' is as defined for R12 in compounds of Formula (I), including its preferred definitions (including those defined in Embodiment A1, Embodiment A2, Embodiment B or Embodiment C), where any functional groups within R12 are optionally protected with a suitable protecting group; R13 is as defined for compounds of Formula (I), including its preferred definitions (including those defined in Embodiment A1, Embodiment A2, Embodiment B or Embodiment C); R14' is as defined for R14 in compounds of Formula (I), including its preferred definitions (including those defined in Embodiment A1, Embodiment A2, Embodiment B or Embodiment C), where any functional groups within R14 are optionally protected with a suitable protecting group; R is as defined for R in compounds of Formula (I), including its preferred definitions (including those defined in Embodiment A1, Embodiment A2, Embodiment B, or Embodiment C), where any functional groups within R are optionally protected with a suitable protecting group; E1 is -OH, -halogen, -O-C1-C4 alkyl, boronic acid, boronic ester (e.g., dimethylboronic ester or pinacolboronic ester), or O-L1; L1 is methanesulfonyl, p-toluenesulfonyl or trifluoromethanesulfonyl.

[0309] Preferably, in the compound of formula (E), among one or more of the substituents R1', R11', R12' and R14', an amino group may optionally be protected with a suitable amino protecting group, such as allyloxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethylcarbonyl, tert-butoxycarbonyl or benzyl, and / or a hydroxyl group may optionally be protected with a suitable hydroxyl protecting group, such as methyl, benzyl or para-methoxybenzyl.

[0310] The present invention also relates to pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient, which can be used, as described herein, particularly for the treatment of neoplastic diseases, particularly cancer. The compositions can be formulated for non-parenteral administration, such as nasal, buccal, rectal, pulmonary, vaginal, sublingual, topical, transdermal, ophthalmic, or, particularly, oral administration, for example, in the form of oral solid dosage forms, such as granules, pellets, powders, tablets, film-coated or dragees, effervescent tablets, hard and soft gelatin or hydroxypropylmethylcellulose (HPMC) capsules, optionally coated, orally disintegrating tablets, oral solutions, lipid emulsions or lipid suspensions, or for parenteral administration, such as intravenous, intramuscular, or subcutaneous, intrathecal, intradermal, or epidural administration, to mammals, particularly humans, for example, in the form of solutions, lipid emulsions, or suspensions containing microparticles or nanoparticles. The compositions can contain the active ingredient alone or, preferably, together with a pharmaceutically acceptable carrier.

[0311] The compound of formula (I) or a pharmaceutically acceptable salt thereof can be processed with pharmaceutically inert inorganic or organic excipients to produce oral solid 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 derivatives thereof, binders such as cellulose, starch, polyvinylpyrrolidone, or derivatives thereof, glidants such as talcum, stearic acid or salts thereof, and flow agents such as fumed silica can be used as excipients for formulating and manufacturing oral solid 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. Suitable excipients for soft gelatin capsules include, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols, etc.

[0312] Suitable excipients for the preparation of oral solutions, lipid emulsions or suspensions include, for example, water, alcohols, polyols, sucrose, invert sugar, glucose, etc. Suitable excipients for parenteral preparations include, for example, water, alcohols, polyols, glycerol, vegetable oils, lecithin, surfactants, etc. Furthermore, the pharmaceutical preparation may contain preservatives, solubilizers (e.g., cyclodextrins), stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorings, salts for changing osmotic pressure, buffers, masking agents, or antioxidants. The pharmaceutical preparation may also contain other therapeutically valuable substances.

[0313] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions, and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor® EL, or phosphate-buffered saline (PBS). The carrier can be, for example, a solvent or dispersion medium containing water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. For intravenous injection of strongly lipophilic molecules, it may be advantageous to include stabilizers, such as surfactants, polymeric surfactants, polymers, complexing agents, and / or cosolvents, in the formulation, which can significantly improve the water solubility of the compound. Examples of solubilizers include polyethylene glycol, propylene glycol, ethanol, glycerol, and cyclodextrins (e.g., sulfobutylether-β-cyclodextrin).

[0314] The dosage can vary within a wide range and can, of course, be adapted to the individual requirements in each particular case. Generally, in the case of oral administration, the daily dose of the compound of general formula (I) per person is about 1 to 1000 mg, but if necessary, the lower or upper limit can be exceeded.

[0315] The compounds of formula (I) can also be used in combination with one or more other pharmaceutically active compounds that are effective against the same disease, preferably using a different mechanism of action, or that reduce or prevent possible undesirable side effects of the compounds of formula (I). The combination partners can be administered in such treatment simultaneously, for example by being incorporated into a single pharmaceutical preparation, or sequentially by administering two or more different dosage forms, each containing one or more of the combination partners.

[0316] The compounds of formula (I) or their pharmaceutically acceptable salts according to the present invention are particularly useful for treating tumor diseases, such as cancer, especially when administered in a therapeutically effective amount, for example, to a subject in need thereof. In some embodiments, the cancers treated by the compounds of the present invention can be treated by inhibiting one or more CLK enzymes. In some embodiments, the cancers treated by the compounds of the present invention can be treated by inhibiting aberrant splicing. The cancers may be driven by aberrant splicing, for example, the cancers may be splicing factor-mutated cancers. The cancers may depend on oncogenic splice variants.

[0317] In some embodiments, compounds of the present invention are potent CLK kinase inhibitors and exhibit high kinase selectivity, e.g., as indicated by a low selectivity score. In some embodiments, compounds of the present invention exhibit potent cellular activity, e.g., as indicated by antiproliferative activity and / or cell death. In some embodiments, compounds of the present invention potently suppress SR protein phosphorylation. In some embodiments, compounds of the present invention exhibit long CLK enzyme residence times, e.g., as indicated by target engagement assays, resulting in potent antiproliferative activity against cancer cells even after short-term exposure. In some embodiments, compounds of the present invention exhibit good metabolic stability. In some embodiments, compounds of the present invention exhibit good permeability, e.g., as indicated by Caco-2 permeability assays. In some embodiments, compounds of the present invention exhibit good avoidance of efflux. In some embodiments, compounds of the present invention exhibit high oral bioavailability.

[0318] In some embodiments, compounds of the invention inhibit CLK3 in an in vitro assay with an IC50 of up to 100 nM. In some embodiments, compounds of the invention inhibit CLK3 in an in vitro assay with an IC50 of up to 30 nM. An in vitro assay for measuring inhibition of CLK3 is described in the Examples below (CLK3 Kinase Assay).

[0319] Examples of neoplastic diseases for treatment with the compounds of the present invention include epithelial neoplasms, squamous cell neoplasms, basal cell neoplasms, transitional cell papillomas and transitional cell carcinomas, adenomas and adenocarcinomas, adnexal and cutaneous adnexal neoplasms, mucoepidermoid neoplasms, cystic neoplasms, mucinous and serous neoplasms, ductal, lobular and medullary neoplasms, acinar cell neoplasms, complex epithelial neoplasms, special genital neoplasms, paragangliomas and glomus tumors, nevi and melanomas, soft tissue tumors and sarcomas, fibromatous neoplasms, myxomatous neoplasms, lipomatous neoplasms, fibroid neoplasms, complex mixed neoplasms and stromal neoplasms, fibroepithelial neoplasms, synovial neoplasms, mesothelial neoplasms. These include, but are not limited to, germ cell neoplasms, trophoblastic neoplasms, mesonephromas, vascular tumors, lymphangioma, bone and chondromatous neoplasms, giant cell tumors, other bone tumors, odontogenic tumors, gliomas, neuroepithelioma and neuroendocrine neoplasms, meningiomas, nerve sheath tumors, granular cell tumors and alveolar soft part sarcoma, Hodgkin's lymphoma and non-Hodgkin's lymphoma, B-cell lymphoma, T-cell lymphoma, hairy cell lymphoma, Burkitt's lymphoma and other lymphoreticular neoplasms, plasma cell neoplasms, mast cell tumors, immunoproliferative disorders, leukemias, other myeloproliferative disorders, lymphoproliferative disorders, and myelodysplastic syndromes.

[0320] Examples of cancers of affected body organs and sites include, but are not limited to, breast, cervix, ovary, colon, rectum (including colon and rectum, i.e., colorectal cancer), lung (including small cell lung cancer, non-small cell lung cancer, large cell lung cancer, and mesothelioma), endocrine system, bone, adrenal gland, thymus, liver, stomach (gastric cancer), intestine, pancreas, bone marrow, hematological malignancies (such as lymphoma, leukemia, myeloma, or lymphoid malignancies), bladder, urinary tract, kidney, skin, thyroid, 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.

[0321] Further examples of neoplastic diseases for treatment with the compounds of the present invention are 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 cancer, bladder cancer, skin melanoma, lung adenocarcinoma, pancreatic cancer, breast cancer, cancers with splicing gene mutations, e.g. cancers with amplification or fusion of splicing factors, cancers driven by signaling of oncogenic transcription factors, cancers driven by oncogenic splice variants, cancers with partial or complete deletion of splicing factors and / or genes involved in splicing regulation.

[0322] The terms "treatment" or "treating," as used herein in the context of treating a disease or disorder, generally refer to treatments and therapies, whether in humans or animals (e.g., veterinary applications), in which some desired therapeutic effect is achieved, e.g., inhibiting the progression of the disease or disorder, including slowing the rate of progression, halting the rate of progression, alleviating the symptoms of the disease or disorder, ameliorating the disease or disorder, and curing the disease or disorder. Treatment as a preventative measure (i.e., prophylaxis) is also included. For example, use in patients who have not yet developed the disease or disorder but are at risk of developing the disease or disorder is encompassed by the term "treatment." For example, treatment includes cancer prevention, reducing the incidence of cancer, alleviating the symptoms of cancer, etc.

[0323] The term "therapeutically effective amount," as used herein, relates to an amount of a compound, or a material, composition, or dosage form containing a compound, that, when administered in accordance with a desired treatment regimen, is effective to produce some desired therapeutic effect, commensurate with a reasonable benefit / risk ratio.

[0324] The term "pharmaceutical composition" is defined herein to refer to a solid or liquid formulation containing at least one therapeutic agent, optionally together with one or more pharmaceutically acceptable excipients, administered to a subject, e.g., a mammal or human, to prevent or treat a particular disease or condition affecting the mammal.

[0325] As used herein, the term "pharmaceutically acceptable" refers to compounds and salts thereof, materials, compositions and / or dosage forms, etc., that are suitable, within the scope of sound medical judgment, for contact with the tissues of warm-blooded animals, e.g., mammals or humans, without excessive toxicity or other complications, commensurate with a reasonable benefit / risk ratio.

[0326] Compounds of formula (I) can be synthesized by the methods shown below or by analogous methods, for example, as shown in Scheme I, or, as will be apparent to those skilled in the art, may also be synthesized using synthetic routes via intermediate (E) as claimed. The schemes described herein are not intended to present an exhaustive list of methods for preparing compounds of formula (I), rather, additional techniques known to a chemist of ordinary skill in the art may be used to synthesize the compounds.

[0327] While optimal reaction conditions may vary with the particular reactants or solvents used, those skilled in the art of organic synthesis will recognize that such conditions can be determined by routine optimization procedures. In some cases, the following reaction schemes and / or the order in which reaction steps are carried out may be varied to facilitate the reaction or to avoid the formation of unwanted by-products. In addition, functional groups present at various positions on the molecule must be compatible with the proposed reagents and reactions. Such limitations on substituents compatible with the reaction conditions will be readily apparent to those skilled in the art, and alternative methods may need to be used. 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 contemplated that such protecting groups (PG) will be appropriately placed as necessary. Conventional protecting groups may be used in accordance with standard techniques well known in the art (see, for example, Wuts PGM, Greene's Protective Groups in Organic Synthesis, 5th Edition, Publisher: John Wiley & Sons, 2014). The protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the art or may be removed in a later reaction step or work-up.

[0328] In the general series of reactions outlined below in Scheme 1, the abbreviations A, T, and X and the general groups Ra, Rb, R1, and R2 are as defined for Formula (I) unless otherwise specified. The general group E1 is as defined in the claims and is generally -OH or a methoxy group or a halogen atom, a boronic acid, a boronic ester, or -O-L1, where -O-L1 is a leaving group, and L1 is selected from perfluoroalkylsulfonyl, such as triflyl (trifluoromethanesulfonyl), and sulfonyl, such as tosyl (p-toluenesulfonyl) or mesyl (methanesulfonyl). The general group E2 is a halogen atom, -OH, -NO2, or -SO2Cl. The generic groups R1', R2', R11', R12', and R14' are as defined by the claims for R1, R2, R11, R12, and R14, respectively, and are equipped with any convenient PG or functional group to allow the formation of R1, R2, R11, R12, and R14, respectively, in Step 4 of Synthetic Scheme 1. Other abbreviations used herein are either explicitly defined or as defined in the experimental section.

[0329] Compounds according to the invention, their pharmaceutically acceptable salts, solvates, and hydrates may be prepared according to the general sequence of reactions outlined below in Scheme 1, followed, if necessary, by: manipulation of substituents to give new final products, including, but not limited to, reduction, oxidation, alkylation, acylation, substitution, coupling, including transition metal catalyzed coupling, and hydrolysis reactions well known to those skilled in the art; - removal of any protecting groups, - formation of a pharmaceutically acceptable salt, or - Formation of pharmaceutically acceptable solvates or hydrates.

[0330] Scheme 1

[0331] [ka]

[0332] [ka]

[0333] If the starting materials required for the synthetic methods described herein are not commercially available, they can be prepared by procedures described in the scientific literature or can be prepared from commercially available compounds by applying processes reported in the scientific literature.For general guidance on reaction conditions and reagents, the reader is further referred to, for example, March J., Smith M., Advanced Organic Chemistry, 7th Edition, Publisher: John Wiley & Sons, 2013.

[0334] Compounds of formula (A) where A is -CH2- are prepared according to procedures described in the literature (see, for example, Fukuda et al. Bioorg. Med. Chem. Lett. 2018, 28(20), 3333-3337) or by procedures known to those skilled in the art.

[0335] Compounds of formula (A) where A is -C(=O)- may be prepared from compounds of formula (A) where A is -CH2- via oxidation carried out in a polar solvent such as water, acetone or acetonitrile or a mixture of these solvents using an oxidizing agent such as potassium permanganate or tert-butyl hydroperoxide at a temperature between 0°C and 100°C.

[0336] Compounds of formula (A) in which E1 is -OH can be prepared from compounds of formula (A) in which E1 is a methoxy group via demethylation carried out in a solvent such as dichloromethane in the presence of a Lewis acid, for example, aluminum chloride, boron tribromide or boron trifluoride, at temperatures between 0°C and 100°C.

[0337] Compounds of formula (A) where E1 is a halogen atom can be prepared from compounds of formula (A) where E1 is an -O-L1 group via a transition metal-catalyzed coupling reaction. Typical catalysts include palladium(II) acetate, tris(dibenzylideneacetone)dipalladium(0), and the like. The reaction is usually carried out at temperatures between 0°C and 150°C, more often between 80°C and 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, and a base such as sodium tert-butylate, cesium carbonate, or potassium carbonate, more frequently cesium carbonate, in an inert solvent such as toluene, tetrahydrofuran, dioxane, 1,2-dichloroethane, N,N-dimethylformamide, dimethyl sulfoxide, water, and acetonitrile, or a mixture of solvents, more frequently dioxane. Transition metal-catalyzed coupling reactions have many established protocols due to the many variables involved, including the specific palladium catalyst, ligand, additive, solvent, and temperature. Those skilled in the art will be able to identify satisfactory protocols without undue experimentation.

[0338] Alternatively, compounds of formula (A) where E1 is a halogen atom can be prepared from compounds of formula (A) where E1 is a boronic acid or boronic ester via a halogenodeboronation reaction, typically carried out in the presence of copper(II) halide in methanol at temperatures ranging from 0°C to 100°C, more frequently at 90°C.

[0339] Step 1: Compounds of formula (B) in which E2 is a halogen atom and E1 is -OH or a methoxy group can be prepared from compounds of formula (A) in which E1 is -OH or a methoxy group via electrophilic aromatic halogenation reactions, which are typically carried out in a mixture of acetic acid and trifluoroacetic acid using NCS for chlorination, NBS for bromination, and NIS for iodination.

[0340] Compounds of formula (B) where E2 is -OH can be prepared from compounds of formula (B) where E2 is a halogen atom via a transition metal catalyzed coupling reaction using the conditions described above.

[0341] Compounds of formula (B) where E2 is -NO2 can be prepared from compounds of formula (A) via an aromatic nitration reaction, which is typically carried out in an acidic solvent, such as acetic acid or sulfuric acid, using fuming nitric acid.

[0342] Compounds of formula (B) in which E2 is -SO2Cl can be prepared from compounds of formula (A) in which E1 is -OH or a methoxy group via an aromatic sulfonylation reaction typically carried out at -10°C to 110°C using chlorosulfonic acid.

[0343] Step 2: Compounds of formula (C) where X is -O- can be prepared from compounds of formula (B) where E is -OH via a substitution reaction with a compound of formula R-E, where E is a halogen atom or a leaving group -O-L, and L is a methanesulfonyl, p-toluenesulfonyl, or trifluoromethanesulfonyl group. The reaction is generally carried out at temperatures between -20°C and 100°C in a dry aprotic solvent such as dichloromethane, acetonitrile, N,N-dimethylformamide, dimethylsulfoxide, 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. Formation of the mesylate, tosylate or triflate compounds can be achieved by reacting the corresponding alcohol with methanesulfonyl chloride or methanesulfonic anhydride, p-toluenesulfonyl chloride, trifluoromethanesulfonyl chloride or trifluoromethanesulfonic anhydride, respectively, in a dry aprotic solvent such as pyridine, acetonitrile, tetrahydrofuran or dichloromethane in the presence of a base such as triethylamine at −30° C. to 80° C.

[0344] Alternatively, compounds of formula (C) where X is -O- can be prepared from compounds of formula (B) where E1 is -OH and an alcohol via Mitsunobu coupling (reviewed in O. Mitsunobu, Synthesis, Vol. 1, pages 1-28, 1981). This 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, over a wide range of temperatures, for example, -20°C to 60°C. This reaction may also be carried out using polymer-supported triphenylphosphine.

[0345] Compounds of formula (C) where X is -NH- or -N(C1-C4 alkyl)- can be prepared from compounds of formula (B) where E1 is a halogen atom or -O-L1 and an amine via a substitution reaction using the conditions described above.

[0346] Alternatively, compounds of formula (C) where X is -NH- or -N(C1-C4 alkyl)- may be prepared from compounds of formula (B) where E1 is a halogen atom or -O-L1 and an amine via a transition metal catalyzed coupling reaction using the conditions described above.

[0347] Alternatively, compounds of formula (C) where X is or -N(C1-C4 alkyl)- can be prepared from compounds of formula (C) where X is -NH- and an alkyl halide via a substitution reaction using the conditions described above.

[0348] Alternatively, compounds of formula (C) where X is -N(C-C alkyl)- can be prepared from compounds of formula (C) where X is -NH- and an aldehyde via reductive amination. The reaction is carried out in a solvent system that allows for removal of the water produced via physical or chemical means (e.g., distillation of a solvent-water azeotrope or the presence of a drying agent, such as molecular sieves, magnesium sulfate, or sodium sulfate). Such solvents are typically toluene, n-hexane, tetrahydrofuran, dichloromethane, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, 1,2-dichloroethane, or mixtures of solvents such as methanol-1,2-dichloroethane. The reaction can be catalyzed by trace amounts of acid, usually acetic acid. This intermediate imine is subsequently or simultaneously reduced using a suitable reducing agent (e.g., sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride; RO and MK Hutchins, Comprehensive Organic Synthesis, BM Trost, I. Fleming, Eds; Pergamon Press: New York (1991), vol. 8, pp. 25-78), or via hydrogenation over a noble metal catalyst, e.g., palladium on activated carbon. This reaction is usually carried out at -10°C to 110°C, preferably 0°C to 60°C. This reaction can also be carried out in one pot. It can also be carried out in the presence of a picoline-borane complex in a protic solvent, e.g., methanol or water (Tetrahedron, 2004, 60, 7899).

[0349] Compounds of formula (C), where X is -CH2- or -C(=CH2)-, can be prepared from compounds of formula (B), where 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 between an organoboronic acid and an aryl or vinyl halide or triflate. Typical catalysts include palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), bis(triphenylphosphine)palladium(II) dichloride, and [1,1'-bis(diphenylphosphino)ferrocene]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 and biphasic conditions. The reaction is typically carried out at room temperature to 150°C. Additives such as cesium fluoride, potassium fluoride, potassium hydroxide, or sodium ethylate often facilitate the coupling. Potassium trifluoroborate and organoboranes or boronic acid esters may be used in place of boronic acids. While there are many variables in this Suzuki reaction, including the specific palladium catalyst, ligand, additive, solvent, and temperature, numerous protocols have been identified. Those skilled in the art will be able to identify satisfactory protocols without undue experimentation.

[0350] Alternatively, compounds of formula (C) where X is -CH2- or -C(=CH2)- may be prepared from compounds of formula (B) where E1 is a boronic acid and compounds of formula R2'-E3 where E3 is a halogen or triflate via a Suzuki reaction using the conditions described above.

[0351] Compounds of formula (C) where X is -C(=O)- or -CN can be prepared from compounds of formula (B) where E1 is a halogen atom via a transition metal catalyzed coupling reaction using the conditions described above.

[0352] Step 3a: Compounds of formula (D-1), in which R12' and R13 are as defined by the claims for R12 and R13 and are equipped with any convenient PG or functional group, allowing for the subsequent formation of R12 in the synthesis, can be prepared from compounds of formula (C) in which E2 is a halogen atom via a Suzuki reaction using the conditions described above.

[0353] Step 3b: Compounds of formula (D-2) where R1' is not -H can be prepared from compounds of formula (C) where E2 is -OH via a substitution reaction using the conditions described above.

[0354] Step 3c: Compounds of formula (D-3) in which R1' and R11' are -H can be prepared from compounds of formula (C) in which E2 is -NO2 via reduction of the nitro group. Typical reducing agents that can be used in such reactions are alkali metal hydrides, such as lithium aluminum hydride or sodium borohydride, in the presence of cobalt(II) chloride or nickel(II) chloride, or metals such as iron or zinc in acidic media such as hydrochloric acid or acetic acid. Alternatively, the nitro group can be reduced to the amine by hydrogenation over a noble metal catalyst, such as palladium on activated carbon, Raney nickel, or platinum oxide. This catalytic hydrogenation reaction can be carried out in a solvent such as ethanol, methanol, or ethyl acetate at ambient temperature. Furthermore, additional reagents such as aluminum amalgam or ferrous sulfate can also be used to reduce the nitro group.

[0355] Compounds of formula (D-3) in which R1' is as defined by the claims for R1 and is provided with any convenient PG or functional group, allowing for subsequent formation of R1 in the synthesis, and in which R11' is -H can be prepared from compounds of formula (D-3) in which R1' and R11' are -H via reductive amination, substitution or coupling reactions.

[0356] In the case of amide coupling reactions, the reaction is carried out in the presence of an activating agent such as N,N'-dicyclohexylcarbodiimide or N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride, with the addition of a carboxylic acid derivative and, optionally, 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, may also be used. Optionally, a base such as triethylamine, N,N-diisopropylethylamine, or pyridine may be added to carry out the coupling. The amide coupling is carried out at temperatures between -20°C and 100°C in an inert solvent, preferably a dry aprotic solvent such as dichloromethane, acetonitrile, N,N-dimethylformamide, or chloroform. Alternatively, the carboxylic acid may be activated by conversion to the corresponding acid chloride (by reaction with oxalyl chloride or thionyl chloride) or the corresponding activated ester, such as an N-hydroxysuccinimidyl ester (Org. Process Res. & Dev., 2002, 863) or a benzothiazolyl thioester (J. Antibiotics, 2000, 1071). The resulting activated product can be reacted with a compound of formula (D-3) in which R and R are —H at temperatures between −20° C. and 100° C. in an aprotic solvent such as dichloromethane, chloroform, acetonitrile, N,N-dimethylformamide, or tetrahydrofuran. Optionally, a base such as triethylamine, N,N-diisopropylethylamine, pyridine, sodium hydroxide, sodium carbonate, or potassium carbonate can be added to carry out the coupling.

[0357] Compounds of formula (D-3), in which R1' and R11' are as defined by the claims for R1 and R11 and are provided with any convenient PG or functional group, the synthesis of which allows subsequent formation of R1 and R11, can be prepared from compounds of formula (D-3) in which R1' and R11' are -H via reductive amination, substitution or coupling reactions.

[0358] Furthermore, compounds of formula (D-3) in which R is -H and R is as defined in the claims for R, and equipped with any convenient PG or functional group, the synthesis of which allows for subsequent formation of R, can be reacted with sulfonyl chloride. Further removal of any PG or modification of the functional group can lead to the preparation of compounds of formula (I) in which T is -N(R)-S(O)-.

[0359] Step 3d: Compounds of formula (D-4) can be prepared from compounds of formula (C) where E2 is a halogen atom via a substitution or transition metal catalyzed coupling reaction using the conditions previously described.

[0360] Compounds of formula (D-4) in which R1' is not -H can be prepared from compounds of formula (D-4) in which R1' is -H via a substitution reaction.

[0361] Step 3e: In compounds of formula (D-5), R' is not -H. Compounds of formula (D-5) can be prepared from compounds of formula (D-4) where R' is not -H via oxidation reactions carried out in polar solvents such as water, acetone, acetonitrile, dichloromethane, or ethanol using oxidizing agents such as hydrogen peroxide, potassium permanganate, sodium perborate, or potassium hydrogen persulfate at temperatures between 0°C and 100°C. Depending on the oxidation conditions, the corresponding sulfoxide analogs of (D-5) and (Ie) can also be prepared.

[0362] Step 3f: Compounds of formula (D-6), in which R1' and R14' are as defined by the claims for R1 and R14 and are equipped with any convenient PG or functional group that allows the formation of R1 and R14, can be prepared from compounds of formula (C) in which E2 is -SO2Cl and an amine via a coupling reaction.

[0363] Step 3g: Compounds of formula (D-7), in which R1' and R14' are as defined by the claims for R1 and R14 and are equipped with any convenient PG or functional group allowing the formation of R1 and R14, can be prepared from compounds of formula (C), in which E2 is a halogen atom, via an arylcarbonylation reaction followed by a coupling reaction with an amine, using the conditions described above.

[0364] Step 4a-g: Compounds of formula (Iag) can be prepared from compounds of formula (D-1-7) after removal of any protecting groups or further modification of the substituents R1', R2', R11', R12' and R14', respectively.

[0365] All aspects and embodiments of the invention described herein may be combined in any combination where possible.

[0366] Numerous publications are cited herein in order to more fully describe and disclose the invention and the state of the art to which this invention pertains. Each of these references is incorporated by reference in its entirety into this disclosure to the same extent as if each individual reference was specifically and individually indicated to be incorporated by reference.

[0367] Certain embodiments of the present 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. [Brief explanation of the drawings]

[0368] [Figure 1]Representative Western blots showing the reduction of phosphorylated SRSF6 (P-SRSF6) by compounds of the present invention in MDA-MB468 cells are shown. GAPDH was probed to adjust for equal protein loading by Western blotting and for sample normalization. Numbers below the blots indicate the percent inhibition of P-SRSF6 signal at 100 nM (A) or 10 nM (B) compared to the DMSO control. [Figure 2A] This figure shows the change in tumor volume (Tvol) in female NOD / SCID mice treated with vehicle or 45 mg / kg of Example 13 BID*BIW on days 1-10 and 50 mg / kg of Example 13 BID*BIW on days 11-22. NOD / SCID mice weighing approximately 23 g were inoculated subcutaneously in the flank with 1 x 10 SW480 human colorectal cancer cells in 50% Matrigel™. When tumors reached a mean volume of 100-150 mm, pair-matching was performed and animals were assigned to treatment and vehicle control groups (n = 8 per group). Tumor volumes (expressed in mm) were measured twice weekly using calipers on days 1, 4, 8, 11, 15, 18, 22, and 23 of the treatment period. The mean TVol (± standard error of the mean (SEM)) for each treatment group is shown. Tumor volumes treated with 45 mg / kg Example 13 BID*BIW were consistently smaller compared to vehicle-treated tumor volumes throughout the treatment period. [Figure 2B] Figure 1 shows the change in body weight (BW) of female NOD / SCID mice treated with vehicle or 45 mg / kg of Example 13 BID*BIW on days 1-10 and 50 mg / kg of Example 13 BID*BIW on days 11-22. NOD / SCID mice weighing approximately 23 g were inoculated subcutaneously in the flank with 1x10 SW480 human colorectal cancer cells in 50% Matrigel™. When tumors reached a mean volume of 100-150 mm, pair-matching was performed and animals were assigned to treatment and vehicle control groups (n=8 / group). Percentage changes in BW (expressed in g, ±SEM) were observed on days 1, 4, 8, 11, 15, 18, 22, and 23 of the treatment period. [Figure 2C]Figure 1 shows the change in tumor volume (Tvol) in female NOD / SCID mice treated with vehicle or 45 mg / kg of Example 13 BID*BIW on days 1-10 and 50 mg / kg of Example 13 BID*BIW on days 11-22. NOD / SCID mice weighing approximately 23 g were inoculated subcutaneously in the flank with 1x10 SW480 human colorectal cancer cells in 50% Matrigel™. When tumors reached a mean volume of 100-150 mm3, pair-matching was performed and animals were divided into treatment and vehicle control groups (n=8 / group). Changes in TVol, expressed in mm3, for vehicle- and Example 13-treated mice are shown. The TVol ratio (T / C) for Example 13-treated vs. vehicle control is shown. DETAILED DESCRIPTION OF THE INVENTION

[0369] Preparation of Examples All reagents and solvents were generally used as received from commercial suppliers. Unless otherwise specified, reactions are routinely carried out in well-dried glassware under an argon or nitrogen atmosphere in anhydrous solvents. Evaporation was performed by rotary evaporation under reduced pressure, and the work-up procedure was carried out after removing residual solids by filtration. All temperatures are given in degrees Celsius (°C) and are approximate; operations are carried out at room temperature (rt), which typically ranges from 18°C ​​to 25°C, unless otherwise noted. The compound was purified using column chromatography (by flash procedure) Conventional flash chromatography is often replaced by an automated system. This does not change the separation process itself. Those skilled in the art will be able to replace a conventional flash chromatography process with an automated process, and vice versa. For example, typical automated systems such as those provided by Buchi or Isco (combiflash) can be used. Unless otherwise specified, the reaction mixture can often be separated by preparative HPLC using, for example, water and acetonitrile as an eluent system. Those skilled in the art will find suitable conditions for each separation, and the compounds can be isolated after purification as parent compounds or in the form of the corresponding trifluoroacetic acid (TFA) salt or respective formate salt. Reactions requiring elevated temperatures are usually carried out using conventional heating equipment, but unless otherwise specified, can also be carried out using a microwave apparatus (CEM Explorer) at a power of 250 W. The hydrogenation or hydrocracking reaction can be carried out using balloon hydrogen gas or using a Parr apparatus system or other suitable hydrogenation apparatus; Concentration of solutions and drying of solids were carried out under reduced pressure unless otherwise specified. Generally, the course of reactions was followed by TLC, HPLC, or LC / MS, reaction times are given for illustration only, and yields are given for illustration only and are not necessarily the maximum achievable. The structure and purity of the final products of the present invention are generally confirmed by NMR spectroscopy, HPLC and mass spectrometry.

[0370] Proton NMR spectra were recorded on a Bruker 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 in Hertz (Hz). Peaks are designated as broad singlet (br), singlet (s), doublet (d), triplet (t), quartet (q), doublet of doublet (dd), doublet of triplet (td), or multiplet (m).

[0371] HPLC of the final product is generated using a Dionex Ultimate 3000 instrument coupled to a Dionex MSQ in ESI mode and the following conditions: Mobile phase A: Water containing 0.1% formic acid Mobile phase B: acetonitrile containing 0.1% formic acid Column: YMC triart C18 5μm 100mm x 4.6mm Column temperature: 25℃ Detection: UV 250nm Injection: 2 μL of 10 mM sample in DMSO Flow rate: 1.6mL / min Gradient Time (min) Mobile phase B % 0 5 8 95 10 95 10.1 5 Equilibrium 13 5 equilibrium

[0372] Mass spectra were generated using a q-Tof Ultima (Waters AG or Thermo Scientific MSQ Plus) mass spectrometer in either positive or negative ESI mode. The system was equipped with a standard Lockspray interface. Each intermediate is purified to the required standard in subsequent steps and characterized in sufficient detail to confirm that the assigned structure is correct. Analytical and preparative HPLC on non-chiral phases was performed using RP-C18 based columns. The following abbreviations may be used (for a comprehensive list of standard abbreviations and acronyms, The Journal of Organic Chemistry Guidelines for Authors may also be consulted): Ac2O acetic anhydride AcOH acetic acid ACN Acetonitrile Boc tert-butoxycarbonyl group t-BuBrettPhos Di-tert-butyl(2',4',6'-triisopropyl-3,6-dimethoxy-[1,1'-biphenyl]-2-yl)phosphine t-BuOH tert-butanol t-BuOK Potassium tert-butoxide CAN Diammonium Cerium(IV) Nitrate Compounds with CAS Chemical Abstracts Services Registry Numbers CDCl3 deuterated chloroform Cu(OAc)2 Cupric Acetate DABCO 1,4-diazabicyclo(2,2,2)octane DCE 1,2-dichloroethane DCM dichloromethane Diox 1,4-dioxane DIPEA N,N-Diisopropylethylamine DMAP 4-dimethylaminopyridine DMF N,N-dimethylformamide DMSO dimethyl sulfoxide DMSO-d6 Deuterated Dimethyl Sulfoxide EA Ethyl acetate EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride ELSD Evaporative Light Scattering Detection EtOH ethanol Example: Example HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HPLC High Performance Liquid Chromatography LC / MS Liquid Chromatography Coupled with Mass Spectrometry MeI methyl iodide MeOH Methanol Me4Si Tetramethylsilane MMNO 4-Methylmorpholine N-oxide MS mass spectrometry Ms methanesulfonyl MsCl methanesulfonyl chloride MW Microwave NaBH3CN Sodium cyanoborohydride NaBH(OAc)3 Sodium triacetoxyborohydride NaOAc Sodium Acetate NBS N-Bromosuccinimide NCS N-chlorosuccinimide NIS N-iodosuccinimide NMM 4-methylmorpholine NMR nuclear magnetic resonance Ns Nosyl(4-nitrobenzenesulfonyl) NsCl 4-Nitrobenzenesulfonyl chloride Pd / C Palladium activated carbon Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0) Pd(dppf)Cl2 [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride PE Petroleum Ether PMB para-methoxybenzyl PMB-Cl para-methoxybenzyl chloride Py pyridine rt room temperature SiHEt3 Triethylsilane TBAF Tetrabutylammonium fluoride TBAI Tetrabutylammonium iodide TBDPS tert-butyldiphenylsilyl TBDPSCl tert-butyldiphenylsilyl chloride TBHP tert-butyl hydroperoxide TBS tert-butyldimethylsilyl TBSCl tert-butyldimethylsilyl chloride TEA Triethylamine TFA trifluoroacetic acid Tf triflate TfOH trifluoromethanesulfonic acid THF tetrahydrofuran TMS trimethylsilyl Ts Tosyl(4-toluenesulfonyl) TsCl 4-toluenesulfonyl chloride v / v volume ratio Xant-Phos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

[0373] The following examples refer to compounds of formula (I) shown in Table 1.

[0374] The examples listed in the table below can be prepared using the procedures described above, and detailed synthetic methods are detailed below. The example numbers used in the left-most column are used in this application to identify each compound.

[0375] [Table 1-1]

[0376] [Table 1-2]

[0377] [Table 1-3]

[0378] [Table 1-4]

[0379] [Table 1-5]

[0380] [Table 1-6]

[0381] [Table 1-7]

[0382] [Table 1-8]

[0383]

Table 1-9

[0384]

Table 1-10

[0385]

Table 1-11

[0386]

Table 1-12

[0387]

Table 1-13

[0388]

Table 1-14

[0389]

Table 1-15

[0390]

Table 1-16

[0391]

Table 1-17

[0392]

Table 1-18

[0393]

Table 1-19

[0394]

Table 1-20

[0395]

Table 1-21

[0396]

Table 1-22

[0397]

Table 1-23

[0398]

Table 1-24

[0399]

Table 1-25

[0400]

Table 1-26

[0401]

Table 1-27

[0402]

Table 1-28

[0403]

Table 1-29

[0404] Example 1: Preparation of 8-methoxy-5,5,7-trimethyl-6H-benzo[h]quinazolin-4-amine:

[0405] [ka]

[0406] Step 1: Preparation of 2-[2-(3-methoxyphenyl)-1,1-dimethyl-ethyl]propanenitrile: 3-Methoxybenzylmagnesium chloride (96 mL, 24 mmol, 0.25 M THF solution) was added dropwise to a stirred solution of isopropylidenemalononitrile (2 g, 18.5 mmol) in THF (50 mL) at 0 °C. The resulting solution was stirred at rt for 3 h. 1N aqueous HCl was then added at 0 °C, and the resulting mixture was concentrated. The residue was extracted with EA and HO. The combined organic layers were dried over NaSO, filtered, concentrated, and purified by column chromatography (silica gel, PE:EA, 5:1, v:v) to give 2-[2-(3-methoxyphenyl)-1,1-dimethyl-ethyl]propanedinitrile as a yellow oil (1.69 g, 38% yield). 1 HNMR(400MHz,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). MS m / z (+ESI): 229.1 [M+H] + .

[0407] Step 2: Preparation of 1-amino-6-methoxy-3,3-dimethyl-4H-naphthalene-2-carbonitrile: TfOH (1.04 g, 6.24 mmol) was added to a stirred solution of 2-[2-(3-methoxyphenyl)-1,1-dimethyl-ethyl]propanedinitrile (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 NaHCO was added, and the mixture was extracted with DCM. The combined organic layers were dried over NaSO, 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. 1 HNMR(400MHz,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). MS m / z (+ESI): 229.1 [M+H] + .

[0408] Step 3: Preparation of 8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine: 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 rt, the reaction mixture was diluted with HO and extracted with EA. The combined organic layers were dried over NaSO, 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 pale yellow solid (700 mg, 63% yield). 1HNMR(400MHz,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). MS m / z (+ESI): 256.1 [M+H] + .

[0409] 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: 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, and the residue was dissolved in HO, neutralized with saturated aqueous KCO, and extracted with EA. The combined organic layers were dried over NaSO, 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 pale yellow solid (403 mg, 79% yield). MS m / z (+ESI): 276.1, 278.1 [M+H] + .

[0410] Step 5: Preparation of 8-methoxy-5,5,7-trimethyl-6H-benzo[h]quinazolin-4-amine: CHB(OH) (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 (1:4 ratio) in Diox (5 mL) and HO (1 mL), followed by KPO (63 mg, 0.30 mmol) and Pd(dppf)Cl (219 mg, 0.30 mmol). After stirring at 90 °C for 20 h, 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). 1 HNMR(400MHz,DMSO-d6+D2O) δppm: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). MS m / z (+ESI): 270.1 [M+H] + .

[0411] Example 2: Preparation of 8-methoxy-5,5-dimethyl-6H-benzo[h]quinazoline-4,7-diamine:

[0412] [ka]

[0413] Step 1: Preparation of 8-methoxy-5,5-dimethyl-7-nitro-6H-benzo[h]quinazolin-4-amine: HNO (14.6 mL, 228.2 mmol) was added dropwise to a stirred solution of HSO (29 mL) at 0 °C to give 8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine (4.5 g, 17.55 mmol), followed by the addition of HO (14.5 mL). After stirring at rt for 2 h, the reaction mixture was poured into saturated aqueous NaHCO and extracted with EA. The combined organic layers were washed with brine, dried over NaSO, 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). 1 HNMR(400MHz,DMSO-d6+D2O) δppm: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). MS m / z (+ESI): 301.2 [M+H] + .

[0414] Step 2: Preparation of 8-methoxy-5,5-dimethyl-6H-benzo[h]quinazoline-4,7-diamine: 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 give 8-methoxy-5,5-dimethyl-6H-benzo[h]quinazoline-4,7-diamine as a pale yellow solid (178 mg, 66% yield). 1HNMR(400MHz,DMSO-d6+D2O) δppm: 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). MS m / z (+ESI): 271.1 [M+H] + .

[0415] Examples 3 and 4: Preparation of 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:

[0416] [ka]

[0417] Step 1: Preparation of 4-amino-5,5-dimethyl-6H-benzo[h]quinazolin-8-ol: BBr3 (1 M in DCM, 4.8 mL, 4.80 mmol) was added dropwise 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) at −40° C. 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 HO, and dried under reduced pressure to give 4-amino-5,5-dimethyl-6H-benzo[h]quinazolin-8-ol (350 mg, 82% yield). 1 HNMR(400MHz,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 (br, 2H), 2.67 (s, 2H), 1.26 (s, 6H). MS m / z (+ESI): 242.2 [M+H] + .

[0418] Step 2: Preparation of 4-amino-7-chloro-5,5-dimethyl-6H-benzo[h]quinazolin-8-ol: 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). MS m / z (+ESI): 276.1, 278.1 [M+H] + .

[0419] Step 3: Preparation of tert-butyl N-[2-[(4-amino-7-chloro-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl)oxy]ethyl]carbamate: 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 CsCO (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, 79% yield). 1HNMR(400MHz,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 (br, 1H), 6.50 (br, 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). MS m / z (+ESI): 419.2, 421.3 [M+H] + .

[0420] Step 4: Preparation of 8-(2-aminoethoxy)-7-chloro-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine: 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, then concentrated and purified 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, 98% yield). MS m / z (+ESI): 319.2, 321.2 [M+H] + .

[0421] Step 5: Preparation of 6,6-dimethyl-2,3,4,5-tetrahydroquinazolino[7,8-f][1,4]benzoxazin-7-amine: 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 Diox (10 mL), followed by Pd(dba) (55 mg, 0.06 mmol) and Xant-Phos (70 mg, 0.12 mmol). After stirring at 120 °C for 18 h, 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 pale yellow solid (166 mg, 36% yield). 1 H NMR (400 MHz, DMSO-d6+D2O)δppm: 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). MS m / z (+ESI): 283.2 [M+H] + .

[0422] Step 6: Preparation of 4,6,6-trimethyl-3,5-dihydro-2H-quinazolino[7,8-f][1,4]benzoxazin-7-amine: H2CO (11 mg, 0.13 mmol) was added 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), 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, 72% yield). 1H NMR (400 MHz, DMSO-d6+D2O)δppm: 8.54 (s, 1H), 7.42 (d, J = 8.4 Hz, 1H), 6.92 (d, J = 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). MS m / z (+ESI): 297.2 [M+H] + .

[0423] Example 5: Preparation of 8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazoline-4,7-diamine

[0424] [ka]

[0425] Step 1: Preparation of [cis-4-(tert-butoxycarbonylamino)cyclohexyl] 4-methylbenzenesulfonate: 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 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, 71% yield). 1HNMR(400MHz,DMSO-d6)δ ppm: 7.78 (d, J =8.0Hz,2H),7.47(d,J = 8.0 Hz, 2H), 6.81 (d, J =7.2Hz,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). MS m / z (+ESI): 370.1 [M+H] + .

[0426] Step 2: Preparation of 4-amino-5,5-dimethyl-7-nitro-6H-benzo[h]quinazolin-8-ol: The title compound was prepared as a pale yellow solid (260 mg, 35% yield) according to Scheme 1 and analogously to Example 2 (Step 1) using 4-amino-5,5-dimethyl-6H-benzo[h]quinazolin-8-ol (700 mg, 2.32 mmol) as the starting material. 1 HNMR(400MHz,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). MS m / z (+ESI): 287.2 [M+H] + .

[0427] 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: CsCO (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 at 80 °C for 40 h, the reaction mixture was filtered. The filtrate was concentrated, and the residue was purified by 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 pale yellow solid (400 mg, 91% yield). MS m / z (+ESI): 484.4 [M+H] + .

[0428] Step 4: Preparation of tert-butyl N-[trans-4-[(4,7-diamino-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl)oxy]cyclohexyl]carbamate: Pd(OH) (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 under a stream of hydrogen for 20 h, 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 pale yellow solid (340 mg, 96% yield), which was used in the next step without further purification. MS m / z (+ESI): 454.3 [M+H] + .

[0429] Step 5: Preparation of 8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazoline-4,7-diamine: The title compound was prepared as a pale yellow solid (246 mg, 97% yield) in analogy to Example 4 (Step 4) according to Scheme 1 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 the starting material. 1 HNMR(400MHz,DMSO-d6+D2O) δppm: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). MS m / z (+ESI): 354.3 [M+H] + .

[0430] Example 6: Preparation of N-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]acetamide

[0431] [ka]

[0432] 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 NaHCO (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 HO. The combined organic layers were dried over NaSO, 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). 1 HNMR(400MHz,DMSO-d6+D2O) δppm: 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). MS m / z (+ESI): 396.2 [M+H] + .

[0433] Example 7: Preparation of 8-(trans-4-aminocyclohexoxy)-N,N-diethyl-5,5-dimethyl-6H-benzo[h]quinazoline-4,7-diamine

[0434] [ka]

[0435] Step 1: Preparation of tert-butyl N-[trans-4-[[4-amino-7-(diethylamino)-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate: NaBHCN (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 HO. The combined organic layers were dried over NaSO, 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. MS m / z (+ESI): 510.3 [M+H] + .

[0436] Step 2: Preparation of 8-(trans-4-aminocyclohexoxy)-N7,N7-diethyl-5,5-dimethyl-6H-benzo[h]quinazoline-4,7-diamine: The title compound was prepared as a pale yellow solid (44 mg, 99% yield) in analogy to Example 4 (Step 4) according to Scheme 1 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 the starting material. 1HNMR(400MHz,DMSO-d6+D2O) δppm:8.54(s,1H),7.71(d,J = 8.8 Hz, 1H), 7.20 (d, J =8.8Hz,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). MS m / z (+ESI): 410.3 [M+H] + .

[0437] Example 8: Preparation of 8-(trans-4-aminocyclohexoxy)-N7-ethyl-5,5-dimethyl-6H-benzo[h]quinazoline-4,7-diamine

[0438] [ka]

[0439] 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: Acetaldehyde (5 mg, 0.12 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 (60 mg, 0.12 mmol) in MeOH (5 mL). After stirring for 2 h, NaBHCN (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 HO. The combined organic layers were dried over NaSO, 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). MS m / z (+ESI): 482.2 [M+H] + .

[0440] Step 2: Preparation of 8-(trans-4-aminocyclohexoxy)-N7-ethyl-5,5-dimethyl-6H-benzo[h]quinazoline-4,7-diamine: The title compound was prepared as an off-white solid (38 mg, 97% yield) in analogy to Example 4 (Step 4) according to Scheme 1 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 the starting material. 1 HNMR(400MHz,DMSO-d6+D2O) δppm: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). MS m / z (+ESI): 382.2 [M+H] + .

[0441] Example 9: Preparation of 8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-7-(1-piperidyl)-6H-benzo[h]quinazolin-4-amine

[0442] [ka]

[0443] 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: 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 a drop of AcOH and NaBHCN (31 mg, 0.16 mmol). After stirring for 2 h, the reaction mixture was extracted with DCM and HO. The combined organic layers were washed with brine, dried over NaSO, 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). MS m / z (+ESI): 522.3 [M+H] + .

[0444] Step 2: Preparation of 8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-7-(1-piperidyl)-6H-benzo[h]quinazolin-4-amine: 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 HCOH (2 mL) was stirred for 16 h, then concentrated and purified 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). 1HNMR(400MHz,DMSO-d6+D2O) δppm: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). MS m / z (+ESI): 422.3 [M+H] + .

[0445] Example 11: Preparation of 2-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-(2-hydroxyethyl)amino]ethanol

[0446] [ka]

[0447] 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: The title compound was prepared as a colorless oil (120 mg, 90% yield) in analogy to Example 7 (Step 1) according to Scheme 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. MS m / z (+ESI): 714.5 [M+H] + .

[0448] Step 2: Preparation of 2-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-(2-hydroxyethyl)amino]ethanol: TFA (234 μL, 3.12 mmol) and 4 M aqueous HCl (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-yl]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). 1 HNMR(400MHz,DMSO-d6+D2O) δppm: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). MS m / z (+ESI): 442.4 [M+H] + .

[0449] Examples 15, 16 and 17: Preparation of 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:

[0450] [ka]

[0451] 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: 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 at 40° C. for 16 hours, 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). MS m / z (+ESI): 524.4 [M+H] + and 504.4 [M+H] + .

[0452] 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: 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 was obtained as a yellow viscous oil (226 mg, 39% yield), 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 was obtained as a yellow semi-solid (91 mg, 21% yield). MS m / z (+ESI): 524.3 [M+H] + .

[0453] 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: The title compound was prepared as a white solid (37 mg, 34% yield) in analogy to Example 4 (Step 4) according to Scheme 1 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 the starting material. 1HNMR(400MHz,DMSO-d6+D2O) δppm: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). MS m / z (+ESI): 424.4 [M+H] + . [α] D 26 =-6°(c = 0.1, MeOH).

[0454] 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: The title compound was prepared as a white solid (27 mg, 44% yield) in analogy to Example 4 (Step 4) according to Scheme 1 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 the starting material. 1 HNMR(400MHz,DMSO-d6+D2O) δppm: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). MS m / z (+ESI): 424.4 [M+H] + . [α]D 26 =+7.5°(c = 0.1, MeOH).

[0455] Step 5: Preparation of 8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-7-pyrrol-1-yl-6H-benzo[h]quinazolin-4-amine: The title compound was prepared as a white solid (36 mg, 37% yield) in analogy to Example 4 (Step 4) according to Scheme 1 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 the starting material. 1 HNMR(400MHz,DMSO-d6+D2O) δppm: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). MS m / z (+ESI): 404.3 [M+H] + .

[0456] Example 19: Preparation of 8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-7-propoxy-6H-benzo[h]quinazolin-4-amine

[0457] [ka]

[0458] Step 1: Preparation of 7-chloro-8-[(4-methoxyphenyl)methoxy]-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine: 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 CsCO (1.35 g, 4.06 mmol). After stirring at 60 °C for 20 h, the reaction mixture was concentrated and extracted with DCM and HO. The combined organic layers were dried over NaSO, 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). 1 HNMR(400MHz,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). MS m / z (+ESI): 396.2 [M+H] + .

[0459] Step 2: Preparation of 4-amino-8-[(4-methoxyphenyl)methoxy]-5,5-dimethyl-6H-benzo[h]quinazolin-7-ol: 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 HO (0.5 mL), followed by Pd(dba) (110 mg, 0.12 mmol) and t-BuBrettPhos (118 mg, 0.24 mmol). After stirring at 110 °C for 2 h, 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). MS m / z (+ESI): 378.2 [M+H] + .

[0460] Step 3: Preparation of 8-[(4-methoxyphenyl)methoxy]-5,5-dimethyl-7-propoxy-6H-benzo[h]quinazolin-4-amine: The title compound was prepared as a pale yellow solid (150 mg, 73% yield) in analogy to Example 4 (Step 4) according to Scheme 1 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 starting materials. MS m / z (+ESI): 420.3 [M+H] + .

[0461] Step 4: Preparation of 4-amino-5,5-dimethyl-7-propoxy-6H-benzo[h]quinazolin-8-ol: 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, then concentrated and purified 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). 1 HNMR(400MHz,DMSO-d6+D2O) δppm: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 (qt, J1=7.2Hz,J2= 6.8 Hz, 2H), 1.23 (s, 6H), 0.95 (t,J= 7.2 Hz, 3H). MS m / z (+ESI): 300.2 [M+H] + .

[0462] Step 5: Preparation of 8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-7-propoxy-6H-benzo[h]quinazolin-4-amine: The title compound was prepared as a white solid according to Scheme 1, similar to 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 tert-butyl N-(cis-4-hydroxycyclohexyl)carbamate as starting materials. 1HNMR(400MHz,DMSO-d6+D2O) δppm: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 (qt, J1=7.2Hz,J2= 6.8 Hz, 2H), 1.46 (m, 4H), 1.24 (s, 6H), 0.96 (t, J = 7.2 Hz 3H). MS m / z (+ESI): 397.3 [M+H] + .

[0463] Example 21: Preparation of 1-(4-amino-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-9-yl)piperidin-4-ol

[0464] [ka]

[0465] Step 1: Preparation of 3-[tert-butyl(diphenyl)silyl]oxypentanedial: MMNO (3.2 g, 26.51 mmol) was added to a stirred solution of tert-butylcyclopent-3-en-1-yloxy-diphenyl-silane (3.8 g, 10.60 mmol) in THF (40 mL) and HO (10 mL), followed by potassium osmate(VI) dihydrate (40 mg, 0.11 mmol). After stirring for 20 h, NaIO (2.74 g, 12.73 mmol) was added, and the resulting suspension was stirred for 3 h and then filtered. 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]oxypentanedial as an off-white viscous oil (2 g, 27% yield). 1HNMR(400MHz,CDCl3)δ ppm: 9.65 (t, J =1.6Hz,2H),7.66(m,4H),7.42(m,6H),4.72(m,1H),2.66(m,4H),1.05(s,9H).

[0466] Step 2: Preparation of 7-[4-[tert-butyl(diphenyl)silyl]oxy-1-piperidyl]-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine: 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 NaBHCN (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). MS m / z (+ESI): 593.5 [M+H] + .

[0467] Step 3: Preparation of 1-(4-amino-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-9-yl)piperidin-4-ol: 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 at 60° C. for 20 hours, 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, 45% yield). 1 HNMR(400MHz,DMSO-d6+D2O) δppm: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). MS m / z (+ESI): 355.3 [M+H] + .

[0468] Example 22: Preparation of 2-[[4-amino-8-(4-cis-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-ethyl-amino]ethanol

[0469] [ka]

[0470] This starting material was prepared from 8-methoxy-5,5-dimethyl-6H-benzo[h]quinazoline-4,7-diamine and tert-butyl N-(trans-4-hydroxycyclohexyl)carbamate according to the procedure described in Example 5 (Steps 1-4).

[0471] 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: 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 CsCO (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 HO. The combined organic layers were dried over NaSO, 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). MS m / z (+ESI): 540.3 [M+H] + .

[0472] Step 2: Preparation of ethyl 2-[[4-amino-8-[cis-4-(tert-butoxycarbonylamino)cyclohexoxy]-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-ethyl-amino]acetate: 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 NaBHCN (182 mg, 2.75 mmol) and a drop of AcOH. After stirring for 3 h, the reaction mixture was quenched with aqueous NHCl and extracted with DCM. The combined organic layers were dried over NaSO, 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]-ethyl-amino]acetate as a yellow solid (2100 mg, 57% yield). MS m / z (+ESI): 563.8 [M+H] + .

[0473] Step 3: Preparation of ethyl 2-[[4-amino-8-(cis-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-ethyl-amino]acetate: The title compound was prepared as a yellow solid (150 mg, 86% yield) in analogy to Example 4 (Step 4) according to Scheme 1 using ethyl 2-[[4-amino-8-[cis-4-(tert-butoxycarbonylamino)cyclohexoxy]-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-ethyl-amino]acetate (200 mg, 0.30 mmol) as the starting material. MS m / z (+ESI): 468.3 [M+H] + .

[0474] Step 4: Preparation of 2-[[4-amino-8-(cis-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-ethyl-amino]ethanol: LiAlH (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]-ethyl-amino]acetate (140 mg, 0.24 mmol) in THF (5 mL). After stirring for 1 h, the reaction mixture was quenched with HO, 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]-ethyl-amino]ethanol as an off-white solid (52 mg, 50% yield). 1 HNMR(400MHz,DMSO-d6+D2O) δppm: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). MS m / z (+ESI): 426.5 [M+H] + .

[0475] Example 25: Preparation of 1-(4-amino-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)azetidin-3-ol

[0476] [ka]

[0477] Step 1: Preparation of (2R)-1-[(4-amino-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)amino]-3-chloro-propan-2-ol: (R)-(-)-epichlorohydrin (133 μL, 1.66 mmol) was added to a stirred solution of 8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-4,7-diamine (500 mg, 1.66 mmol) in CHCl (3 mL), followed by the addition of Zn(ClO) (126 mg, 0.33 mmol). After stirring at 80 °C for 18 h, the reaction mixture was extracted with DCM and HO. The combined organic layers were dried over NaSO, 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 pale yellow solid (490 mg, 32% yield), which was used in the next step without further purification. MS m / z (+ESI): 363.2, 365.2 [M+H] + .

[0478] Step 2: Preparation of 8-methoxy-5,5-dimethyl-N7-[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-3-chloro-propyl]-6H-benzo[h]quinazoline-4,7-diamine: 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-chloro-propan-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 HO. The combined organic layers were dried over NaSO, 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-chloro-propyl]-6H-benzo[h]quinazoline-4,7-diamine as a colorless oil (170 mg, 59% yield). MS m / z (+ESI): 477.2, 479.2 [M+H] + .

[0479] Step 3: Preparation of 7-[3-[tert-butyl(dimethyl)silyl]oxyazetidin-1-yl]-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine: CsCO (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-chloro-propyl]-6H-benzo[h]quinazolin-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 at 120 °C for 3 h under microwave irradiation, the reaction mixture was concentrated and extracted with EA and HO. The combined organic layers were dried over NaSO, 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. MS m / z (+ESI): 441.2 [M+H] + .

[0480] Step 4: Preparation of 1-(4-amino-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)azetidin-3-ol: 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 hours, 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, 46% yield). 1HNMR(400MHz,DMSO-d6+D2O) δppm: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). MS m / z (+ESI): 327.3 [M+H] + .

[0481] Example 26: Preparation of 2-[[4-amino-8-(cis-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methyl-amino]-N-methyl-acetamide

[0482] [ka]

[0483] The starting material was prepared from 4-amino-5,5-dimethyl-6H-benzo[h]quinazolin-8-ol and tert-butyl N-(trans-4-hydroxycyclohexyl)carbamate, ethyl bromoacetate and formaldehyde according to the procedure described in Example 23.

[0484] Step 1: Preparation of 2-[[4-amino-8-[cis-4-(tert-butoxycarbonylamino)cyclohexoxy]-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methyl-amino]acetic acid: LiOH.HO (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]-methyl-amino]acetate (150 mg, 0.23 mmol) in THF (6 mL), MeOH (2 mL), and HO (2 mL). After stirring for 1 h, the reaction mixture was concentrated. The residue was diluted with HO, and the pH was adjusted to 5 with 3 M aqueous HCl. The resulting suspension was filtered, and the cake was washed with water and dried under vacuum to give 2-[[4-amino-8-[cis-4-(tert-butoxycarbonylamino)cyclohexoxy]-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methyl-amino]acetic acid as a yellow solid (120 mg, 84% yield), which was used in the next step without further purification. MS m / z (+ESI): 526.3 [M+H] + .

[0485] Step 2: Preparation of tert-butyl N-[cis-4-[[4-amino-5,5-dimethyl-7-[methyl-[2-(methylamino)-2-oxo-ethyl]amino]-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate: 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]-methyl-amino]acetic acid (110 mg, 0.18 mmol) in DMF (5 mL), followed by HATU (103 mg, 0.27 mmol) and NaHCO (76 mg, 0.89 mmol). After stirring for 1 h, the reaction mixture was concentrated and extracted with EA and HO. The combined organic layers were dried over NaSO, filtered, and concentrated to give tert-butyl N-[cis-4-[[4-amino-5,5-dimethyl-7-[methyl-[2-(methylamino)-2-oxo-ethyl]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. MS m / z (+ESI): 539.3 [M+H] + .

[0486] Step 3: Preparation of 2-[[4-amino-8-(cis-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methyl-amino]-N-methyl-acetamide: The title compound was prepared as a yellow solid (34 mg, 50% yield) in analogy to Example 9 (Step 2) according to Scheme 1 using tert-butyl N-[cis-4-[[4-amino-5,5-dimethyl-7-[methyl-[2-(methylamino)-2-oxo-ethyl]amino]-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate (90 mg, 0.14 mmol) as the starting material. 1HNMR(400MHz,DMSO-d6+D2O) δppm: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). MS m / z (+ESI): 439.4 [M+H] + .

[0487] Example 28: Preparation of [1-(4-amino-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)azetidin-3-yl]methanol

[0488] [ka]

[0489] Step 1: Preparation of N7-[2-(chloromethyl)allyl]-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazoline-4,7-diamine: 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 CsCO (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 HO. The combined organic layers were dried over NaSO, filtered, and concentrated. The residue was purified by combiflash to give N-[2-(chloromethyl)allyl]-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazoline-4,7-diamine as a yellow solid (320 mg, 46% yield). 1HNMR(400MHz,DMSO-d6)δ ppm: 8.23 ​​(s, 1H), 7.67 (d, J =8.8Hz,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 =6.8Hz,2H),2.75(s,2H),1.26(s,6H). MS m / z (+ESI): 359.2, 361.3 [M+H] + .

[0490] Step 2: Preparation of 2-[[(4-amino-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)amino]methyl]-3-chloro-propan-1-ol: A 1 M solution of borane THF complex (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 at rt for 2 h, 2.5 M aqueous NaOH (3.2 mL, 8.02 mmol) was added dropwise to the reaction mixture, followed by HO (0.82 mL, 8.02 mmol). After stirring at rt for 2 h, the resulting solution was extracted with DCM and HO. The combined organic layers were dried over NaSO, 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-chloro-propan-1-ol as a pale yellow solid (180 mg, 53% yield). MS m / z (+ESI): 377.2, 379.3 [M+H] + .

[0491] Step 3: Preparation of N7-[2-[[tert-butyl(diphenyl)silyl]oxymethyl]-3-chloro-propyl]-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazoline-4,7-diamine: 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-chloro-propan-1-ol (180 mg, 0.43 mmol) in DCM (2 mL), followed by imidazole (148 mg, 2.15 mmol). After stirring at 120 °C for 2 h, the reaction mixture was extracted with DCM and HO. The combined organic layers were dried over NaSO, filtered, and concentrated to give N-[2-[[tert-butyl(diphenyl)silyl]oxymethyl]-3-chloro-propyl]-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazoline-4,7-diamine as a pale yellow oil (600 mg, 34% yield), which was used in the next step without further purification. MS m / z (+ESI): no mass signal.

[0492] 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: The title compound was prepared as a yellow oil (560 mg, 66% yield) in analogy to Example 25 (Step 3) according to Scheme 1 using N7-[2-[[tert-butyl(diphenyl)silyl]oxymethyl]-3-chloro-propyl]-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazoline-4,7-diamine (600 mg, 0.15 mmol) as the starting material. MS m / z (+ESI): no mass signal.

[0493] Step 5: Preparation of [1-(4-amino-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)azetidin-3-yl]methanol: 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 hours, 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, 34% yield). 1 HNMR(400MHz,DMSO-d6+D2O) δppm: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). MS m / z (+ESI): 341.2 [M+H] + .

[0494] Example 32: Preparation of 8-(cis-4-aminocyclohexoxy)-N7,5,5-trimethyl-N7-(2-methylsulfonylethyl)-6H-benzo[h]quinazoline-4,7-diamine

[0495] [ka]

[0496] This starting material was prepared from 4-amino-5,5-dimethyl-6H-benzo[h]quinazolin-8-ol according to the procedures described in Examples 5 and 8, and using tert-butyl N-(trans-4-hydroxycyclohexyl)carbamate, (methylthio)acetaldehyde, and formaldehyde.

[0497] 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: Potassium peroxomonosulfate (4.5% activated 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 HO (2 mL). After stirring for 1 h, the reaction suspension was filtered, the filtrate was concentrated, and the crude product was purified by 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). MS m / z (+ESI): 574.3 [M+H] + .

[0498] Step 2: Preparation of 8-(cis-4-aminocyclohexoxy)-N7,5,5-trimethyl-N7-(2-methylsulfonylethyl)-6H-benzo[h]quinazoline-4,7-diamine: The title compound was prepared as a yellow solid (83 mg, 73% yield) in analogy to Example 9 (Step 2) according to Scheme 1 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 the starting material. 1HNMR(400MHz,DMSO-d6+D2O) δppm: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). MS m / z (+ESI): 474.3 [M+H] + .

[0499] Example 34: Preparation of 4,7-diamino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-benzo[h]quinazolin-6-one:

[0500] [ka]

[0501] Step 1: Preparation of 4-amino-8-methoxy-5,5-dimethyl-benzo[h]quinazolin-6-one: 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, and then a TBHP solution (100 g, 782 mmol) was added dropwise over 3 h. After stirring at 50 °C for 16 h, the reaction mixture was cooled to rt, and HO (150 mL) was added dropwise over 30 min. After stirring at 0 °C for 16 h, the resulting precipitate was collected by filtration, washed with a mixture of ACN (25 mL) and HO (75 mL), and dried under vacuum to give 4-amino-8-methoxy-5,5-dimethyl-benzo[h]quinazolin-6-one as a pale gray solid (26.3 g, 69% yield), which was used in the next step without further purification. 1HNMR(400MHz,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) MS m / z (+ESI): 270.2 [M+H] + .

[0502] Step 2: Preparation of 4-amino-8-methoxy-5,5-dimethyl-7-nitro-benzo[h]quinazolin-6-one: KHNO (2.53 g, 24.5 mmol) was added portionwise to a stirred solution of 4-amino-8-methoxy-5,5-dimethyl-benzo[h]quinazolin-6-one (5.1 g, 18.8 mmol) in HSO (10 mL) at 0 °C. After stirring at rt for 1 h, the reaction mixture was poured into ice water and basified with 2 N aqueous NaOH to pH 9. The resulting precipitate was collected by filtration to give 4-amino-8-methoxy-5,5-dimethyl-7-nitro-benzo[h]quinazolin-6-one as a pale yellow solid (5.9 g, 65% yield), which was used in the next step without further purification. MS m / z (+ESI): 315.1 [M+H] + .

[0503] Step 3: Preparation of 4-amino-8-hydroxy-5,5-dimethyl-7-nitro-benzo[h]quinazolin-6-one: LiCl (1.61 g, 36.7 mmol) was added to a stirred suspension of 4-amino-8-methoxy-5,5-dimethyl-7-nitro-benzo[h]quinazolin-6-one (5.5 g, 12.25 mmol) in DMF (30 mL). After stirring at 170 °C for 2 h, the solvent was removed to give 4-amino-8-hydroxy-5,5-dimethyl-7-nitro-benzo[h]quinazolin-6-one as a yellow liquid (5.2 g, 98% yield), which was used in the next step without further purification. MS m / z (+ESI): 301.1 [M+H] + .

[0504] Step 4: Preparation of tert-butyl N-[trans-4-(4-amino-5,5-dimethyl-7-nitro-6-oxo-benzo[h]quinazolin-8-yl)oxycyclohexyl]carbamate: The title compound was prepared as a yellow solid (6 g, 59% yield) in analogy to Example 5 (Step 3) according to Scheme 1 using [cis-4-(tert-butoxycarbonylamino)cyclohexyl]4-methylbenzenesulfonate (14.9 g, 36.3 mmol) as the starting material. 1 HNMR(400MHz,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 = 7.6 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). MS m / z (+ESI): 498.2 [M+H] + .

[0505] Step 5: Preparation of tert-butyl N-[trans-4-(4,7-diamino-5,5-dimethyl-6-oxo-benzo[h]quinazolin-8-yl)oxycyclohexyl]carbamate: 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-oxo-benzo[h]quinazolin-8-yl)oxycyclohexyl]carbamate (100 mg, 0.18 mmol) in EtOH (10 mL). After stirring under a stream of hydrogen for 20 h, 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-oxo-benzo[h]quinazolin-8-yl)oxycyclohexyl]carbamate as a yellow solid (90 mg, 95% yield), which was used in the next step without further purification. MS m / z (+ESI): 468.3 [M+H] + .

[0506] Step 6: Preparation of 4,7-diamino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-benzo[h]quinazolin-6-one: The title compound was prepared as a yellow solid (42 mg, 62% yield) in analogy to Example 9 (Step 2) according to Scheme 1 using tert-butyl N-[trans-4-(4,7-diamino-5,5-dimethyl-6-oxo-benzo[h]quinazolin-8-yl)oxycyclohexyl]carbamate (90 mg, 0.17 mmol) as the starting material. 1 HNMR(400MHz,DMSO-d6+D2O) δppm:8.30(s,1H),7.82(d,J = 8.4 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H), 4.37 (m, 1H), 3.01 (m, 1H), 2.11 (m, 2H), 1.97 (m, 2H), 1.48 (m, 10H). MS m / z (+ESI): 368.3 [M+H] + .

[0507] Examples 38 and 39: Preparation of N-[2-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methyl-amino]ethyl]acetamide and N-[2-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methyl-amino]ethyl]methanesulfonamide

[0508] [ka]

[0509] This starting material was prepared from 4-amino-5,5-dimethyl-6H-benzo[h]quinazolin-8-ol and tert-butyl N-(cis-4-hydroxycyclohexyl)carbamate, 1,3-dihydro-1,3-dioxo-2H-isoindole-2-acetaldehyde and formaldehyde according to the procedures described in Examples 5 and 8.

[0510] 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: N2H4.HO (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-methyl-amino]-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate (220 mg, 0.31 mmol) in EtOH (2 mL). After stirring at 70 °C for 2 h, the solvent was removed and the crude product was purified by 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). MS m / z (+ESI): 511.4 [M+H] + .

[0511] 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: AcO (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 pyridine (13 μL, 0.16 mmol). After stirring for 2 h, the reaction mixture was extracted with DCM and HO. The combined organic layers were dried over NaSO, 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. MS m / z (+ESI): 553.3 [M+H] + .

[0512] Step 3: Preparation of N-[2-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methyl-amino]ethyl]acetamide: The title compound was prepared as a white solid (36 mg, 80% yield) as in Example 9 (Step 2) according to Scheme 1 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 the starting material. 1HNMR(400MHz,DMSO-d6+D2O) δppm: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). MS m / z (+ESI): 453.5 [M+H] + .

[0513] Step 4: Preparation of tert-butyl N-[trans-4-[[4-amino-7-[2-(methanesulfonamido)ethyl-methyl-amino]-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate: 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 TEA (42 μL, 0.30 mmol). After stirring for 2 h, the reaction mixture was extracted with DCM and HO. The combined organic layers were dried over Na2SO4, filtered, and concentrated to give tert-butyl N-[trans-4-[[4-amino-7-[2-(methanesulfonamido)ethyl-methyl-amino]-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. MS m / z (+ESI): 589.3 [M+H] + .

[0514] Step 5: Preparation of N-[2-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methyl-amino]ethyl]methanesulfonamide: The title compound was prepared as a white solid (11 mg, 20% yield) as in Example 9 (Step 2) according to Scheme 1 using tert-butyl N-[trans-4-[[4-amino-7-[2-(methanesulfonamido)ethyl-methyl-amino]-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate (70 mg, 0.10 mmol) as the starting material. 1 HNMR(400MHz,DMSO-d6+D2O) δppm: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) MS m / z (+ESI): 489.3 [M+H] + .

[0515] Example 42: Preparation of N-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-2-hydroxy-ethanesulfonamide

[0516] [ka]

[0517] 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: 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, 0.56 mmol) and pyridine (458 μL, 5.60 mmol). After stirring at 80° C. for 16 h, the solvent was removed and the residue was extracted with EA and HO. 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. MS m / z (+ESI): 576.3 [M+H] + .

[0518] Step 2: Preparation of N-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-2-hydroxy-ethanesulfonamide: The title compound was prepared as a white solid (33 mg, 36% yield) in analogy to Example 4 (Step 1) according to Scheme 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 the starting material. 1HNMR(400MHz,DMSO-d6+D2O) δppm:8.24(s,1H),8.00(d,J = 8.8 Hz, 1H), 7.11 (d, J =8.8Hz,1H),4.42(m,1H),3.82(t,J = 7.2 Hz, 2H), 3.26 (t, J =7.2Hz,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). MS m / z (+ESI): 462.3 [M+H] + .

[0519] Example 48: Preparation of 1-[[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methyl-amino]methyl]cyclopropanecarbonitrile

[0520] [ka]

[0521] 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: 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 DABCO (2.25 g, 19.84 mmol). After stirring for 16 h, the reaction mixture was extracted with DCM and HO. The combined organic layers were dried over Na2SO4, filtered, concentrated, and purified by 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). MS m / z (+ESI): 639.3 [M+H] + .

[0522] Step 2: Preparation of tert-butyl N-[trans-4-[[4-amino-7-[(1-cyanocyclopropyl)methyl-(2-nitrophenyl)sulfonyl-amino]-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate: The title compound was prepared as a pale yellow solid (255 mg, 76% yield) in analogy to Example 4 (Step 3) according to Scheme 1 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 starting materials. MS m / z (+ESI): 718.3 [M+H] + .

[0523] 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: 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 KCO (120 mg, 0.86 mmol). After stirring at 50 °C for 3 h, the reaction mixture was extracted with DCM and HO. The combined organic layers were dried over Na2SO4, filtered, concentrated and purified by 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). MS m / z (+ESI): 533.3 [M+H] + .

[0524] Step 4: Preparation of 1-[[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methyl-amino]methyl]cyclopropanecarbonitrile: The title compound was prepared as a white solid (34 mg, 58% yield) according to Scheme 1, similar to 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 the starting material. 1HNMR(400MHz,DMSO-d6+D2O) δppm: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). MS m / z (+ESI): 477.2 [M+H] + .

[0525] Examples 49 and 50: Preparation of 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:

[0526] [ka]

[0527] Step 1: Preparation of 2,5-dimethoxytetrahydrofuran-3-carbonitrile: 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 Hanus's solution (109 μL, 0.42 mmol). After stirring for 16 h, the reaction mixture was quenched with saturated aqueous Na2SO3 and then extracted with EA and HO. 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, 36% yield). 1 HNMR(400MHz,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).

[0528] Step 2: Preparation of 2-formyl-4-oxobutanenitrile: A solution of 2,5-dimethoxytetrahydrofuran-3-carbonitrile (500 mg, 2.54 mmol) in 1 N aqueous HCl (3 mL) was stirred at 80° C. for 1 h and then used directly in the next step.

[0529] 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: The title compound was prepared as a yellow solid (575 mg, 51% yield) in analogy to Example 7 (Step 1) according to Scheme 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 the starting material. 1HNMR(400MHz,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). MS m / z (+ESI): 533.4 [M+H] + .

[0530] 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 HO (132 μL, 1.67 mmol) was added to a stirred DMSO 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), followed by KCO (119 mg, 0.84 mmol). After stirring at 50 °C for 16 h, the reaction mixture was concentrated and purified by 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). 1HNMR(400MHz,DMSO-d6)δ ppm: 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), 6.32 (s, 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), 1.26 (s, 3H), 1.23 (s, 3H). MS m / z (+ESI): 551.3 [M+H] + .

[0531] Step 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-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: 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 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 prepared as yellow solids (137 mg, 43% yield each) according to Scheme 1 and analogously to Example 15 (Step 2). MS m / z (+ESI): 551.3 [M+H] + .

[0532] 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: 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 POCl (8 mL) was stirred at 60° C. for 2 h and then concentrated. 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, 51% yield). 1 HNMR(400MHz,DMSO-d6+D2O) δppm: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). MS m / z (+ESI): 433.2 [M+H] + . [α] D 25 =-20.0°(c = 0.07, MeOH).

[0533] 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: The title compound was prepared as an off-white solid (46 mg, 47% yield) as in Example 49 (Step 6) according to Scheme 1 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 the starting material. 1 HNMR(400MHz,DMSO-d6+D2O) δppm: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). MS m / z (+ESI): 433.2 [M+H] + . [α] D 25 =22.8°(c = 0.07, MeOH).

[0534] Example 51: Preparation of 3-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-cyclopropyl-amino]propanenitrile

[0535] [ka]

[0536] 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: Cyclopropylboronic acid (444 mg, 4.96 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 Cu(OAc) (421 mg, 1.98 mmol), 2,2'-bipyridine (316 mg, 1.98 mmol), and TEA (419 μL, 2.98 mmol). After stirring at 60 °C for 3 h, the reaction mixture was filtered. The filtrate was concentrated and purified by 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 pale yellow solid (230 mg, 42% yield). 1 HNMR(400MHz,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). MS m / z (+ESI): 494.4 [M+H] + .

[0537] 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: The title compound was prepared as a white solid (182 mg, 91% yield) in analogy to Example 8 (Step 1) according to Scheme 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 the starting material. MS m / z (+ESI): 556.3, 558.3 ​​[M+H] + .

[0538] 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: 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 HO (0.3 mL), followed by NaI (43 mg, 0.28 mmol). After stirring at 70 °C for 8 h, the reaction mixture was extracted with DCM and HO. The combined organic layers were dried over Na2SO4, filtered, concentrated and purified by 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). MS m / z (+ESI): 547.4 [M+H] + .

[0539] Step 4: Preparation of 3-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-cyclopropyl-amino]propanenitrile: The title compound was prepared as a white solid (39 mg, 48% yield) as in Example 9 (Step 2) according to Scheme 1 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 the starting material. 1 HNMR(400MHz,DMSO-d6+D2O) δppm: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). MS m / z (+ESI): 447.3 [M+H] + .

[0540] Example 52: Preparation of 3-[[4-amino-5,5-dimethyl-8-(trans-4-morpholinocyclohexoxy)-6H-benzo[h]quinazolin-7-yl]-methyl-amino]propanenitrile

[0541] [ka]

[0542] Step 1: Preparation of 2-[2-(3-methoxyphenyl)-1,1-dimethyl-ethyl]propanenitrile: 3-Methoxybenzylmagnesium chloride (96 mL, 24 mmol, 0.25 M THF solution) was added dropwise to a stirred solution of isopropylidenemalononitrile (2 g, 18.5 mmol) in THF (50 mL) at 0 °C. The resulting solution was stirred at rt for 3 h. 1N aqueous HCl was then added at 0 °C, and the resulting mixture was concentrated. The residue was extracted with EA and HO. The combined organic layers were dried over NaSO, filtered, concentrated, and purified by column chromatography (silica gel, PE:EA, 5:1, v:v) to give 2-[2-(3-methoxyphenyl)-1,1-dimethyl-ethyl]propanedinitrile as a yellow oil (1.69 g, 38% yield). 1 HNMR(400MHz,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). MS m / z (+ESI): 229.1 [M+H] + .

[0543] Step 2: Preparation of 1-amino-6-methoxy-3,3-dimethyl-4H-naphthalene-2-carbonitrile: TfOH (1.04 g, 6.24 mmol) was added to a stirred solution of 2-[2-(3-methoxyphenyl)-1,1-dimethyl-ethyl]propanedinitrile (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 NaHCO was added, and the mixture was extracted with DCM. The combined organic layers were dried over NaSO, 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. 1HNMR(400MHz,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). MS m / z (+ESI): 229.1 [M+H] + .

[0544] Step 3: Preparation of 8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine: 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 rt, the reaction mixture was diluted with HO and extracted with EA. The combined organic layers were dried over NaSO, 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 pale yellow solid (700 mg, 63% yield). 1 HNMR(400MHz,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). MS m / z (+ESI): 256.1 [M+H] + .

[0545] Step 4: Preparation of 4-amino-5,5-dimethyl-6H-benzo[h]quinazolin-8-ol: BBr3 (1 M in DCM, 4.8 mL, 4.80 mmol) was added dropwise 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) at −40° C. 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 HO, and dried under reduced pressure to give 4-amino-5,5-dimethyl-6H-benzo[h]quinazolin-8-ol (350 mg, 82% yield). 1 HNMR(400MHz,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 (br, 2H), 2.67 (s, 2H), 1.26 (s, 6H). MS m / z (+ESI): 242.2 [M+H] + .

[0546] Step 5: Preparation of 4-amino-5,5-dimethyl-7-nitro-6H-benzo[h]quinazolin-8-ol: HNO3 (7.5 mL, 117.2 mmol) was added dropwise 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) at 0 °C. After stirring for 48 h, the reaction mixture was poured into 200 mL of ice water and neutralized with NaHCO3. The resulting mixture was extracted with EA. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by combiflash to give 4-amino-5,5-dimethyl-7-nitro-6H-benzo[h]quinazolin-8-ol as a yellow solid (260 mg, 35% yield). 1HNMR(400MHz,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). MS m / z (+ESI): 287.2 [M+H] + .

[0547] Step 6: Preparation of [cis-4-(tert-butoxycarbonylamino)cyclohexyl] 4-methylbenzenesulfonate: 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 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, 71% yield). 1 HNMR(400MHz,DMSO-d6)δ ppm: 7.78 (d, J =8.0Hz,2H),7.47(d,J = 8.0 Hz, 2H), 6.81 (d, J =7.2Hz,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). MS m / z (+ESI): 370.1 [M+H] + .

[0548] 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: CsCO (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 at 80 °C for 40 h, the reaction mixture was filtered. The filtrate was concentrated, and the residue was purified by 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 pale yellow solid (400 mg, 91% yield). 1 HNMR(400MHz,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). MS m / z (+ESI): 484.4 [M+H] + .

[0549] Step 8: Preparation of tert-butyl N-[trans-4-[(4,7-diamino-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl)oxy]cyclohexyl]carbamate: Pd(OH) (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 under a stream of hydrogen for 20 h, 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 pale yellow solid (340 mg, 96% yield), which was used in the next step without further purification. 1 HNMR(400MHz,DMSO-d6)δ ppm: 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), 6.28 (br, 2H), 4.51 (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), 1.28 (s, 6H). MS m / z (+ESI): 454.3 [M+H] + .

[0550] Step 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 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 Py (40 mL). After stirring for 30 min, the reaction mixture was poured into HO. 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 pale yellow solid (6 g, 94% yield). 1 HNMR(400MHz,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). MS m / z (+ESI): 639.0 [M+H] + .

[0551] Step 10: Preparation of tert-butyl N-[trans-4-[[4-amino-7-[2-cyanoethyl-(4-nitrophenyl)sulfonyl-amino]-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate 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 Py (33 mL) and HO (6.6 mL), followed by DMAP (452 ​​mg, 3.66 mmol). After stirring at 100 °C for 3 h, the reaction mixture was cooled to rt, and then HO (500 mL) was added. 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-7-[2-cyanoethyl-(4-nitrophenyl)sulfonyl-amino]-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate as a pale yellow solid (5.5 g, 92% yield). 1 HNMR(400MHz,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). MS m / z (+ESI): 692.0 [M+H] + .

[0552] 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 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)sulfonyl-amino]-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate (5.5 g, 6.76 mmol) in DMF (40 mL), followed by KCO (2.57 g, 18.43 mmol). After stirring at 55 °C for 1.5 h, the solvent was removed and the crude product was extracted with EA and HO. The combined organic layers were dried over Na2SO4, filtered, concentrated, and the residue was purified by 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 pale yellow solid (2.95 g, 71% yield). 1 HNMR(400MHz,DMSO-d6)δ ppm: 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), 6.33 (s, 2H), 4.27 (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), 1.38 (s, 9H), 1.33 (m, 2H), 1.27 (s, 6H). MS m / z (+ESI): 507.4 [M+H] + .

[0553] Step 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 HCO (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 NaBHCN (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 HO. 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. MS m / z (+ESI): 521.4 [M+H] + .

[0554] Step 13: Preparation of 3-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methyl-amino]propanenitrile: 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 HCOH (25 mL) was stirred for 2.5 h. The solvent was then 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]methyl-amino]propanenitrile as a white solid (2.15 g, 97% yield). 1 HNMR(400MHz,DMSO-d6+D2O) δppm:8.21(s,1H),7.87(d,J = 8.8 Hz, 1H), 7.02 (d, J = 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) MS m / z (+ESI): 421.3 [M+H] + .

[0555] Step 14: Preparation of 3-[[4-amino-5,5-dimethyl-8-(trans-4-morpholinocyclohexoxy)-6H-benzo[h]quinazolin-7-yl]-methyl-amino]propanenitrile: 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]-methyl-amino]propanenitrile (265 mg, 0.57 mmol) in ACN (5 mL), followed by KCO (340 mg, 2.43 mmol). After stirring at 70 °C for 18 h, the suspension was extracted with DCM and HO. The combined organic layers were dried over NaSO, 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]-methyl-amino]propanenitrile as a white solid (491 g, 60% yield). 1 HNMR(400MHz,DMSO-d6+D2O) δppm: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). MS m / z (+ESI): 491.3 [M+H] + .

[0556] Example 54: Preparation of 8-(trans-4-aminocyclohexoxy)-N7-but-3-ynyl-N7,5,5-trimethyl-6H-benzo[h]quinazoline-4,7-diamine

[0557] [ka]

[0558] Step 1: Preparation of 8-(trans-4-aminocyclohexoxy)-N7,5,5-trimethyl-N7-(4-trimethylsilylbut-3-ynyl)-6H-benzo[h]quinazoline-4,7-diamine: The title compound was prepared as a pale yellow solid according to Scheme 1, similar to 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. MS m / z (+ESI): 492.1 [M+H] + .

[0559] Step 2: Preparation of 8-(trans-4-aminocyclohexoxy)-N7-but-3-ynyl-N7,5,5-trimethyl-6H-benzo[h]quinazoline-4,7-diamine: KCO (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, 80% yield). 1HNMR(400MHz,DMSO-d6+D2O) δppm: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). MS m / z (+ESI): 420.2 [M+H] + .

[0560] Example 56: Preparation of 1-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-2H-pyrrol-5-one:

[0561] [ka]

[0562] 2-Hydroxybutanedial (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 pale yellow solid (10 mg, 6% yield). 1HNMR(400MHz,DMSO-d6+D2O) δppm: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). MS m / z (+ESI): 420.4 [M+H] + .

[0563] Example 57: Preparation of 8-(trans-4-aminocyclohexoxy)-7-(3-methoxypyrrol-1-yl)-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine

[0564] [ka]

[0565] 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: 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 CHCl (3 mL), followed by the addition of I (0.4 mg, 0.02 mmol). After stirring at 70°C for 8 hours, 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, 49% yield). 1 HNMR(400MHz,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). MS m / z (+ESI): 534.3 [M+H] + .

[0566] Step 2: Preparation of 8-(trans-4-aminocyclohexoxy)-7-(3-methoxypyrrol-1-yl)-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine: The title compound was prepared as a black solid (22 mg, 22% yield) in analogy to Example 9 (Step 2) according to Scheme 1 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 the starting material. 1 HNMR(400MHz,DMSO-d6+D2O) δppm: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). MS m / z (+ESI): 434.3 [M+H] + .

[0567] Example 61: Preparation of 8-methoxy-7-(3-methoxypropyl)-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine

[0568] [ka]

[0569] Step 1: Preparation of 7,9-dibromo-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine: 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 NaHCO (200 mL) was added to the residue, and the resulting suspension was filtered. The cake was washed with HO 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, 96% yield). 1 HNMR(400MHz,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). MS m / z (+ESI): 412.0, 414.0 [M+H] + .

[0570] Step 2: Preparation of 7-bromo-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine: 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 under a stream of hydrogen for 24 h, 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, 52% yield). MS m / z (+ESI): 334.1, 336.1 [M+H] + .

[0571] Step 3: Preparation of 8-methoxy-7-[(E)-3-methoxyprop-1-enyl]-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine: 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, 0.46 mmol) in Diox (10 mL) and HO (2 mL), followed by Pd(PPh) (54 mg, 0.04 mmol), Pd(dppf)Cl (34 mg, 0.04 mmol), and KOH (131 mg, 2.29 mmol). After stirring at 110° C. for 2 h, the reaction mixture was filtered through decalite, concentrated, and purified by 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). 1 HNMR(400MHz,DMSO-d6+D2O) δppm: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). MS m / z (+ESI): 326.3 [M+H] + .

[0572] Step 4: Preparation of 8-methoxy-7-(3-methoxypropyl)-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine: 10% Pd / C (130 mg, 0.13 mmol) was added followed by NHHCO (78 mg, 1.22 mmol) 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 HO (0.5 mL). After stirring under a stream of hydrogen at 80 °C for 2 h, 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). 1 HNMR(400MHz,DMSO-d6+D2O) δppm: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). MS m / z (+ESI): 328.4 [M+H] + .

[0573] Example 89: Preparation of (5R)-5-[2-[(4-amino-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)amino]ethyl]oxazolidin-2-one

[0574] [ka]

[0575] Step 1: Preparation of (2R)-4-[tert-butyl(diphenyl)silyl]oxy-1-chloro-butan-2-ol: The title compound was prepared as a colorless oil (3.3 g, 80% yield) according to Scheme 1, analogous to Example 28 (Step 3), using (3R)-4-chlorobutane-1,3-diol (1.5 g, 10.84 mmol) as the starting material. 1 HNMR(400MHz,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).

[0576] Step 2: Preparation of (2R)-1-azido-4-[tert-butyl(diphenyl)silyl]oxy-butan-2-ol: NaN (87 mg, 1.31 mmol) was added to a stirred solution of (2R)-4-[tert-butyl(diphenyl)silyl]oxy-1-chloro-butan-2-ol (100 mg, 0.26 mmol) in DMF (1 mL). After stirring at 90 °C for 16 h, the reaction mixture was extracted with EA and HO. The combined organic layers were dried over NaSO, 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]oxy-butan-2-ol as a colorless oil (86 mg, 80% yield). 1 HNMR(400MHz,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).

[0577] Step 3: Preparation of (2R)-1-amino-4-[tert-butyl(diphenyl)silyl]oxy-butan-2-ol: 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 under a stream of hydrogen for 2 h, 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, 94% yield), which was used in the next step without further purification. 1 HNMR (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 (overlapped 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). MS m / z (+ESI): 344.3 [M+H] + .

[0578] Step 4: Preparation of (5R)-5-[2-[tert-butyl(diphenyl)silyl]oxyethyl]oxazolidin-2-one: DIPEA (250 μL, 1.41 mmol) was added to a stirred solution of (2R)-1-amino-4-[tert-butyl(diphenyl)silyl]oxy-butan-2-ol (90 mg, 0.23 mmol) in DCM (2 mL). The reaction mixture was then cooled to 0 °C, after which triphosgene (35 mg, 0.12 mmol) was added. After stirring at 0 °C for 1 h, the reaction mixture was extracted with DCM and HO. The combined organic layers were dried over NaSO, 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, 52% yield). 1 HNMR(400MHz,DMSO-d6)δ ppm: 7.64 (m, 4H), 7.44 (m, 7H), 4.71 (m, 1H), 3.74 (m, 2H), 3.55 (t, J = 8.4 Hz, 1H), 3.15 (t, J = 8.0 Hz, 1H), 1.90 (m, 2H), 0.99 (s, 9H).

[0579] Step 5: Preparation of (5R)-5-[2-[tert-butyl(diphenyl)silyl]oxyethyl]-3-[(4-methoxyphenyl)methyl]oxazolidin-2-one: To a solution of (5R)-5-[2-[tert-butyl(diphenyl)silyl]oxyethyl]oxazolidin-2-one (820 mg, 2.00 mmol) in DMF (10 mL) was added cesium carbonate (1.99 g, 5.99 mmol) and 1-(chloromethyl)-4-methoxybenzene (484 mg, 2.99 mmol). The reaction was stirred at 15 °C for 16 h. The reaction was then diluted with EA and water. After separation, the combined organic layer was dried over NaSO, 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, 92% yield). 1 HNMR(400MHz,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).

[0580] Step 6: (5R)-5-(2-hydroxyethyl)-3-[(4-methoxyphenyl)methyl]oxazolidin-2-one: 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) was added TBAF (1.70 g, 5.51 mmol). The reaction was then heated at 70 °C for 1 h. The reaction was diluted with EA and water, and the organic phase was separated, dried over Na2SO4, filtered, and evaporated in vacuo to give 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). 1 HNMR(400MHz,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 (overlapping with H2O peak, 3H), 3.05 (dd, J = 8.8 Hz, 7.2 Hz, 1H), 1.72 (m, 2H).

[0581] Step 7: Preparation of 2-[(5R)-3-[(4-methoxyphenyl)methyl]-2-oxo-oxazolidin-5-yl]ethyl 4-methylbenzenesulfonate: The title compound was prepared as a colorless oil according to Scheme 1, analogous to Examples 5, 19 and 21, using (5R)-5-(2-hydroxyethyl)-3-[(4-methoxyphenyl)methyl]oxazolidin-2-one as the starting material. 1 HNMR(400MHz,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). MS m / z (+ESI): 406.1 [M+H] + .

[0582] Step 8: Preparation of N-(4-amino-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)-2-nitro-benzenesulfonamide: The title compound was prepared as an off-white solid (1.2 g, 71% yield) in analogy to Example 48 (Step 1) according to Scheme 1 using 8-methoxy-5,5-dimethyl-6H-benzo[h]quinazoline-4,7-diamine (1.0 g, 3.33 mmol) as the starting material. 1HNMR(400MHz,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). MS m / z (+ESI): 456.2 [M+H] + .

[0583] 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-oxo-oxazolidin-5-yl]ethyl]-2-nitro-benzenesulfonamide The title compound was prepared as a yellow solid (800 mg, 76% yield) in analogy to Example 5 (Step 3) according to Scheme 1 using N-(4-amino-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)-2-nitro-benzenesulfonamide (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 starting materials. 1HNMR(400MHz,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 (br, 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). MS m / z (+ESI): 689.3 [M+H] + .

[0584] 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 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 HO (3 mL). After stirring for 1 h, the reaction mixture was concentrated and purified by 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). MS m / z (+ESI): 569.2 [M+H] + .

[0585] 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: The title compound was prepared as a white solid (61 mg, 19% yield) in analogy to Example 48 (Step 3) according to Scheme 1 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 the starting material. 1 HNMR(400MHz,DMSO-d6+D2O) δppm: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). MS m / z (+ESI): 384.1 [M+H] + .

[0586] Example 90: Preparation of 4-amino-8-(trans-4-aminocyclohexoxy)-N-(cyanomethyl)-5,5-dimethyl-6H-benzo[h]quinazoline-7-carboxamide

[0587] [ka]

[0588] tert-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 using 4-amino-5,5-dimethyl-6H-benzo[h]quinazolin-8-ol and CAS 167081-25-6 as starting materials, similar to Examples 5 and 61.

[0589] Step 1: Preparation of methyl 4-amino-8-[trans-4-(tert-butoxycarbonylamino)cyclohexoxy]-5,5-dimethyl-6H-benzo[h]quinazoline-7-carboxylate: Pd(dppf)Cl (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 at 120 °C under a stream of CO (3.5 MPa) for 8 h, the catalyst was removed by filtration. The solution was concentrated, and the residue was purified by 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). MS m / z (+ESI): 497.3 [M+H] + .

[0590] Step 2: Preparation of 4-amino-8-[trans-4-(tert-butoxycarbonylamino)cyclohexoxy]-5,5-dimethyl-6H-benzo[h]quinazoline-7-carboxylic acid: NaOH (39 mg, 0.98 mm) 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 at 75 °C for 16 h, the pH of the reaction mixture was adjusted to 3 with 1 M aqueous HCl. The resulting mixture was extracted with EA and HO. The combined organic layers were dried over NaSO, 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). MS m / z (+ESI): 483.3 [M+H] + .

[0591] Step 3: Preparation of 4-amino-8-(trans-4-aminocyclohexoxy)-N-(cyanomethyl)-5,5-dimethyl-6H-benzo[h]quinazoline-7-carboxamide: The title compound was prepared as a white solid, similar to Examples 6 and 9, according to Scheme 1 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. 1HNMR(400MHz,DMSO-d6+D2O) δppm: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). MS m / z (+ESI): 421.1 [M+H] + .

[0592] Example 92: Preparation of 3-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]butan-1-ol:

[0593] [ka]

[0594] 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: The title compound was prepared as an off-white solid (360 mg, 71% yield) as analogous to Example 61 (Step 3) according to Scheme 1 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. MS m / z (+ESI): 523.4 [M+H] + .

[0595] 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: Isobutyl chloroformate (113 μL, 0.83 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 NMM (93 μL, 0.83 mmol). After stirring at 0 °C for 30 min, a solution of NaBH (64 mg, 1.65 mmol) in HO (3 mL) was added, and the resulting suspension was stirred at 0 °C for 1 h. The reaction mixture was quenched with saturated aqueous NH Cl and extracted with EA. The combined organic layers were washed with brine, dried over Na SO , filtered, and concentrated. The residue was purified by combiflash to give 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). MS m / z (+ESI): 509.4 [M+H] + .

[0596] Step 3: Preparation of 3-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]butan-1-ol: The title compound was prepared as a white solid according to Scheme 1, similar 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 the starting material. 1HNMR(400MHz,DMSO-d6+D2O) δppm: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). MS m / z (+ESI): 411.2 [M+H] + .

[0597] Example 97: Preparation of 4-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]pentanenitrile:

[0598] [ka]

[0599] 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: TsCl (58 mg, 0.30 mmol) was added to a stirred solution of tert-butyl N-[trans-4-[[4-amino-7-(3-hydroxy-1-methyl-propyl)-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). MS m / z (+ESI): 665.3 [M+H] + .

[0600] 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: 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 at 80 °C for 1 h, the reaction mixture was diluted with HO. The resulting suspension was filtered, and the cake was washed with HO and dried under high vacuum to give 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 as a white solid (93 mg, 91% yield). MS m / z (+ESI): 520.3 [M+H] + .

[0601] Step 3: Preparation of 4-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]pentanenitrile: The title compound was prepared as a white solid (52 mg, 50% yield) as in Example 9 (Step 2) according to Scheme 1 using 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 (50 mg, 0.08 mmol) as the starting material. 1HNMR(400MHz,DMSO-d6+D2O) δppm: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). MS m / z (+ESI): 420.2 [M+H] + .

[0602] Example 108: Preparation of 3-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]sulfanyl]propanenitrile:

[0603] [ka]

[0604] 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: (1R,2R)-N,N-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 Diox (3 mL), followed by NaI (53 mg, 0.35 mmol) and CuI (17 mg, 0.09 mmol). After stirring at 110 °C for 24 h, 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). MS m / z (+ESI): 564.9 [M+H] + .

[0605] 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: 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 Diox (15 mL), followed by Xant-Phos (167 mg, 0.28 mmol), Pd(dba) (132 mg, 0.14 mmol), and DIPEA (504 μL, 0.37 mmol). After stirring at 110 °C for 16 h, 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). MS m / z (+ESI): 524.1 [M+H] + .

[0606] Step 3: Preparation of 3-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]sulfanyl]propanenitrile: The title compound was prepared as a white solid (47 mg, 63% yield) in analogy to Example 9 (Step 2) according to Scheme 1 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 the starting material. 1 HNMR(400MHz,DMSO-d6+D2O) δppm: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). MS m / z (+ESI): 424.2 [M+H] + .

[0607] Example 109: Preparation of 3-[(4-amino-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)-methyl-amino]propanenitrile:

[0608] [ka]

[0609] Step 1: Preparation of (4-amino-5,5-dimethyl-7-nitro-6H-benzo[h]quinazolin-8-yl)trifluoromethanesulfonate: 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 KCO (5.98 g, 42.44 mmol). After stirring at 50 °C for 2 h, the reaction mixture was filtered. The filtrate was concentrated, and the residue was purified by combiflash to give (4-amino-5,5-dimethyl-7-nitro-6H-benzo[h]quinazolin-8-yl)trifluoromethanesulfonate as a pale yellow solid (3 g, 46% yield). MS m / z (+ESI): 419.0 [M+H] + .

[0610] Step 2: Preparation of 5,5-dimethyl-6H-benzo[h]quinazoline-4,7-diamine: 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 Pd(PPh3)4 (304 mg, 0.26 mmol). After stirring at 50 °C for 2 h, the reaction mixture was filtered. The filtrate was concentrated, and the residue was purified by combiflash to give 5,5-dimethyl-6H-benzo[h]quinazoline-4,7-diamine as a pale yellow solid (600 g, 77% yield). MS m / z (+ESI): 271.1 [M+H] + .

[0611] Step: Preparation of 3-[(4-amino-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)-methyl-amino]propanenitrile: The title compound was prepared as a white solid according to Scheme 1, similar to 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. 1 HNMR(400MHz,DMSO-d6+D2O) δppm: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). MS m / z (+ESI): 308.2 [M+H] + .

[0612] Example 113: Preparation of 4-amino-8-(trans-4-aminocyclohexoxy)-N-(cyanomethyl)-N,5,5-trimethyl-6H-benzo[h]quinazoline-7-sulfonamide

[0613] [ka]

[0614] 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: The title compound was prepared as a yellow solid (200 mg, 71% yield) in analogy to Example 108 (Step 2) according to Scheme 1 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]+ .

[0615] 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: 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 HO (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 NaHCO (2 g) was added. The resulting suspension was filtered. The filtrate was concentrated and extracted with DCM and HO. The combined organic layers were dried over NaSO, 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. MS m / z (+ESI): 537.0 [M+H] + .

[0616] Step 3: Preparation of tert-butyl N-[trans-4-[[4-amino-7-[cyanomethyl(methyl)sulfamoyl]-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]oxy]cyclohexyl]carbamate: 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 (4 mL) and Py (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). MS m / z (+ESI): 571.0 [M+H] + .

[0617] Step 4: Preparation of 4-amino-8-(trans-4-aminocyclohexoxy)-N-(cyanomethyl)-N,5,5-trimethyl-6H-benzo[h]quinazoline-7-sulfonamide: The title compound was prepared as a white solid (105 mg, 88% yield) as in Example 9 (Step 2) according to Scheme 1 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 the starting material. 1 HNMR(400MHz,DMSO-d6+D2O) δppm: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). MS m / z (+ESI): 471.1 [M+H] + .

[0618] Example 115: Preparation of 3-[(4-amino-8-bromo-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)-methyl-amino]propanenitrile:

[0619] [ka]

[0620] [4-Amino-7-[2-cyanoethyl(methyl)amino]-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]trifluoromethanesulfonate was prepared as a white solid according to Scheme 1, similar 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. MS m / z (+ESI): 456.2 [M+H] + .

[0621] Step 1: Preparation of [4-amino-7-[2-cyanoethyl(methyl)amino]-5,5-dimethyl-6H-benzo[h]quinazolin-8-yl]boronic acid: 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)Cl (78 mg, 0.10 mmol) and KCO (223 mg, 1.58 mmol). After stirring at 90 °C for 8 h, the reaction mixture was filtered. The filtrate was concentrated, and the residue was purified by 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). 1 HNMR(400MHz,DMSO-d6+D2O) δppm: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). MS m / z (+ESI): 352.3 [M+H] + .

[0622] Step 2: Preparation of 3-[(4-amino-8-bromo-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)-methyl-amino]propanenitrile: CuBr (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 HO (10 mL). After stirring at 80 °C for 10 h, the reaction mixture was filtered. The filtrate was concentrated, and the residue was extracted with DCM and HO. The combined organic layers were dried over NaSO, 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)-methyl-amino]propanenitrile as a white solid (44 g, 26% yield). 1 HNMR(400MHz,DMSO-d6+D2O) δppm:8.27(s,1H),7.82(d,J =8.4Hz,1H),7.55(d,J =8.4Hz,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). MS m / z (+ESI): 386.0, 388.1 [M+H] + .

[0623] Example 118: Preparation of 3-[[4-amino-5,5-dimethyl-8-(4-methylpiperazin-1-yl)-6H-benzo[h]quinazolin-7-yl]-methyl-amino]propanenitrile:

[0624] [ka]

[0625] Step 1: Preparation of 5,5-dimethyl-8-(4-methylpiperazin-1-yl)-7-nitro-6H-benzo[h]quinazolin-4-amine: 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 at 50 °C for 16 h, the reaction mixture was concentrated, and the residue was extracted with EA and HO. The combined organic layers were dried over NaSO, 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, 99% yield), which was used in the next step without further purification. 1 HNMR(400MHz,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). MS m / z (+ESI): 369.0 [M+H] + .

[0626] Step 2: Preparation of 3-[[4-amino-5,5-dimethyl-8-(4-methylpiperazin-1-yl)-6H-benzo[h]quinazolin-7-yl]-methyl-amino]propanenitrile: The title compound was prepared as a white solid according to Scheme 1, similar 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 starting materials. 1H 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). MS m / z (+ESI): 406.2 [M+H] + .

[0627] Example 120: Preparation of 1-(4-amino-8-bromo-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)pyrrolidine-3-carbonitrile:

[0628] [ka]

[0629] Step 1: Preparation of 8-bromo-5,5-dimethyl-7-nitro-6H-benzo[h]quinazolin-4-amine: 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 at 130 °C for 16 h, the reaction mixture was diluted with HO (150 mL). The resulting suspension was filtered, and the cake was washed with HO and dried under high vacuum. The resulting off-white solid was poured into THF (300 mL) and saturated aqueous NaHCO (100 mL). After stirring for 10 min, the organic layer was separated, washed with HO and brine, dried over NaSO, filtered, and concentrated to give 8-bromo-5,5-dimethyl-7-nitro-6H-benzo[h]quinazolin-4-amine (950 mg, 72% yield) as a yellow solid, which was used in the next step without further purification. 1HNMR(400MHz,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). MS m / z (+ESI): 348.9, 350.9 [M+H] + .

[0630] Step 2: Preparation of 8-bromo-5,5-dimethyl-6H-benzo[h]quinazoline-4,7-diamine: Iron (1.24 g, 21.77 mmol) was added to a stirred suspension of 8-bromo-5,5-dimethyl-7-nitro-6H-benzo[h]quinazolin-4-amine (950 mg, 2.18 mmol) in EtOH (80 mL) and HO (8 mL), followed by the addition of NH4Cl (594 mg, 10.88 mmol). After stirring at 80 °C for 1 h, the reaction mixture was filtered. The filtrate was concentrated, and the residue was poured into HO (60 mL). The resulting suspension was sonicated, filtered, and the cake was washed with HO 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. 1 HNMR(400MHz,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). MS m / z (+ESI): 319.0, 321.0 [M+H] + .

[0631] Step 3: Preparation of 1-(4-amino-8-bromo-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)pyrrolidine-3-carbonitrile: The title compound was prepared as a white solid (50 mg, 15% yield) as in Example 9 (Step 1) according to Scheme 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. 1 HNMR(400MHz,DMSO-d6+D2O) δppm:8.28(s,1H),7.84(d,J =8.4Hz,1H),7.57(d,J =8.4Hz,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). MS m / z (+ESI): 398.1, 400.1 [M+H] + .

[0632] Example 121: Preparation of (5R)-5-[[(4-amino-8-bromo-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)amino]methyl]oxazolidin-2-one

[0633] [ka]

[0634] Step 1: Preparation of (4-amino-5,5-dimethyl-7-nitro-6H-benzo[h]quinazolin-8-yl)trifluoromethanesulfonate: 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 KCO (5.98 g, 42.44 mmol). After stirring at 50 °C for 2 h, the reaction mixture was filtered. The filtrate was concentrated, and the residue was purified by combiflash to give (4-amino-5,5-dimethyl-7-nitro-6H-benzo[h]quinazolin-8-yl)trifluoromethanesulfonate as a pale yellow solid (3 g, 46% yield). MS m / z (+ESI): 419.0 [M+H] + .

[0635] Step 2: Preparation of 8-bromo-5,5-dimethyl-7-nitro-6H-benzo[h]quinazolin-4-amine: 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 at 130 °C for 16 h, the reaction mixture was diluted with HO (150 mL). The resulting suspension was filtered, and the cake was washed with HO and dried under high vacuum. The resulting off-white solid was poured into THF (300 mL) and saturated aqueous NaHCO (100 mL). After stirring for 10 min, the organic layer was separated, washed with HO and brine, dried over NaSO, filtered, and concentrated to give 8-bromo-5,5-dimethyl-7-nitro-6H-benzo[h]quinazolin-4-amine (950 mg, 72% yield) as a yellow solid, which was used in the next step without further purification. 1 HNMR(400MHz,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). MS m / z (+ESI): 348.9, 350.9 [M+H] + .

[0636] Step 3: Preparation of 8-bromo-5,5-dimethyl-6H-benzo[h]quinazoline-4,7-diamine: Iron (1.24 g, 21.77 mmol) was added to a stirred suspension of 8-bromo-5,5-dimethyl-7-nitro-6H-benzo[h]quinazolin-4-amine (950 mg, 2.18 mmol) in EtOH (80 mL) and HO (8 mL), followed by the addition of NH4Cl (594 mg, 10.88 mmol). After stirring at 80 °C for 1 h, the reaction mixture was filtered. The filtrate was concentrated, and the residue was poured into HO (60 mL). The resulting suspension was sonicated, filtered, and the cake was washed with HO 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. 1 H NMR (400 MHz, DMSO-d6)δppm: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). MS m / z (+ESI): 319.0, 321.0 [M+H] + .

[0637] Step 4: Preparation of N-(4-amino-8-bromo-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)-4-nitro-benzenesulfonamide: NsCl (1.06 g, 4.66 mmol) was added to a stirred solution of 8-bromo-5,5-dimethyl-6H-benzo[h]quinazolin-4,7-diamine (700 mg, 1.86 mmol) in Py (12 mL). After stirring for 5 h, the reaction mixture was poured into HO. The resulting mixture was concentrated, and the residue was purified by combiflash to give N-(4-amino-8-bromo-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)-4-nitro-benzenesulfonamide as a yellow solid (320 mg, 22% yield). 1 H NMR (400 MHz, DMSO-d6)δppm: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 (br, 2H), 2.70 (s, 2H), 1.18 (s, 6H). MS m / z (+ESI): 504.0, 506.0 [M+H] + .

[0638] Step 5: Preparation of (5S)-5-(iodomethyl)oxazolidin-2-one: In a sealed tube, NaI (637 mg, 4.20 mmol) was added to a stirred solution of (5S)-5-(chloromethyl)oxazolidin-2-one (200 mg, 1.40 mmol) in acetone (2 mL). After stirring at 80° C. for 16 h, 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, 34% yield). 1 HNMR(400MHz,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). MS m / z (+ESI): 228.0 [M+H] + .

[0639] 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 (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-nitro-benzenesulfonamide (300 mg, 0.53 mmol) in DMF (15 mL), followed by CsCO (1.78 g, 5.35 mmol). After stirring at 100 °C for 16 h, the solvent was removed and the residue was extracted with EA and HO. The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated, and the residue was purified by 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). 1 HNMR(400MHz,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). MS m / z (+ESI): 603.1, 605.1 [M+H] + .

[0640] Step 7: Preparation of (5R)-5-[[(4-amino-8-bromo-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)amino]methyl]oxazolidin-2-one: 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 KCO (177 mg, 1.25 mmol). After stirring at 50 °C for 2 h, 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). 1 HNMR(400MHz,DMSO-d6+D2O) δppm: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). MS m / z (+ESI): 418.2, 420.2 [M+H] + .

[0641] Example 122: 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

[0642] [ka]

[0643] Step 1: Preparation of ethyl 2-[2-(2-fluoropropanoyl)hydrazino]-2-oxo-acetate: 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, 79% yield). 1 HNMR(400MHz,CDCl3)δ ppm: 9.37 (s, 1H), 8.76 (s, 1H), 5.18 (dq, J = 6.8, 48.4 Hz, 1H), 4.41 (q, J = 7.2 Hz, 2H), 1.66 (dd, J = 6.8, 25.2 Hz, 3H), 1.41 (t, J = 7.2 Hz, 3H).

[0644] Step 2: Preparation of ethyl 5-(1-fluoroethyl)-1,3,4-oxadiazole-2-carboxylate: 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, 59% yield). 1 HNMR(400MHz,CDCl3)δ ppm: 5.84 (m, 1H), 4.55 (q, J = 7.2 Hz, 2H), 1.88 (m, 3H), 1.48 (t, J = 7.2 Hz, 3H).

[0645] 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: The title compound was prepared as an off-white solid according to Scheme 1, similar 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 starting materials. 1 HNMR(400MHz,DMSO-d6+D2O) δppm:8.21(s,1H),7.69(d,J = 8.4 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 5.90 (dq, 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). MS m / z (+ESI): 399.3 [M+H] + .

[0646] Biological Examples CLK3 kinase assay CLK3 kinase activity was measured essentially using LANCE® Ultra technology (PerkinElmer) as recommended by the supplier. Briefly, 2.5 μL of test sample in 4% DMSO at 4x the desired final concentration was dispensed into a white, low-volume, round-bottom 384-well plate (Corning, catalog no. 4512). 5 μL of a mixture containing recombinant human CLK3 (Thermo Fisher Scientific, catalog no. PV3826) and the labeled peptide substrate, ULight™-CREBtide (PerkinElmer, catalog no. TRF0107), prepared in 1.33x kinase buffer (Thermo Fisher Scientific, catalog no. PV3189) was added. Finally, the reaction was initiated by adding 2.5 μL of a 4x ATP solution in kinase buffer. The plate was sealed with adhesive foil and incubated in the dark at 30°C for 3 hours. The final concentrations of CLK3, ULight™-CREBtide, and ATP were 0.5 nM, 50 nM, and 300 μM, respectively. The reaction was then terminated by adding 5 μL of 40 mM EDTA. Eu-anti-phospho-CREB antibody (PerkinElmer, catalog no. TRF0200) diluted in LANCE® detection buffer (PerkinElmer, catalog no. CR97) was then added to a final concentration of 2 nM, and the reaction was incubated for 1 hour in the dark at room temperature. Signals were measured using a Synergy 4 reader (BioTek) using 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 ​​were calculated by normalizing the raw data using solvent control wells (0% inhibition) and wells without ATP (100% inhibition). The IC was calculated by fitting the concentration-response data to a sigmoidal four-parameter logistic model. 50 Values ​​were calculated. The results are shown below in Table 2. The IC50 value of CLK3 is determined from replicate measurements at 10 different concentrations (serial 1:3 dilutions).

[0647] MDA-MB-231 and CAL-51 proliferation assays Cells (MDA-MB-231 (American Type Culture Collection (ATCC), #HTB-26) or CAL-51 (Deutsche Sammlung von Mikroorganismen und Zellkulturen (DSMZ), #ACC302), as applicable) were cultured using standard techniques in DMEM high glucose (4.5 g / L) containing L-glutamine (BioConcept, catalog number 1-26F03-I) supplemented with 1% sodium pyruvate (Sigma, catalog number S8636), 1% penicillin-streptomycin (BioConcept, catalog number 4-01F00H), and 10% FBS (Sigma, catalog number F9665). Cells were seeded at a density of 750 cells / well into black, clear-bottom 384-well tissue culture plates (Greiner Bio-One, catalog no. 781091) containing 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 desired final concentration. The solution was then diluted 1:40 with culture medium, and 5 μL aliquots were mixed into wells containing cells. The final concentration of DMSO was 0.5%. The plates were incubated for 72 hours, and then cell number was determined using YO-PRO™-1 Iodide (ThermoFisher Scientific, catalog no. Y3603) essentially as recommended by the manufacturer. Briefly, a 12.5 μM solution of YO-PRO™-1 Iodide in 5x YO-PRO buffer (100 mM Na-citrate, 130 mM NaCl, pH 4) was mixed 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 for 30 minutes in the dark. Fluorescence intensity signals were then measured using a Synergy4 reader (BioTek) with 485 / 20 nm and 530 / 25 nm filters for excitation and emission, respectively.Relative proliferation values ​​were calculated by normalizing raw data using the signal obtained from DMSO-treated cells (100% proliferation) and cells assessed upon compound addition (0% proliferation). Concentration-response data were fitted to a sigmoidal four-parameter logistic model, with the maximum value constrained to 100%. GI. 50 Values ​​were calculated from the curves as the compound concentration that reduced amplification by 50%. The results are shown in Table 2 below:

[0648] [Table 2-1]

[0649] [Table 2-2]

[0650] [Table 2-3]

[0651] [Table 2-4]

[0652] Inhibition evaluation of phospho-SRSF6 levels in MDA-MB-468 cells MDA-MB-468 cells (ATCC, HTB-132) were cultured in DMEM (BioConcept catalog no. 1-26F03) supplemented with 10% FBS (Sigma catalog no. F9665), 1% sodium pyruvate (Sigma catalog no. S8636), and 1% penicillin-streptomycin (BioConcept catalog no. 4-01F00-H). When cells reached 70% confluency in 6-well plates (TPP catalog no. 92006), they were treated with either test compound vehicle DMSO or experimental compounds at final concentrations of 10 or 100 nM for 2 hours. The culture medium was then removed, and the cells were harvested by detachment 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 100x ThermoScientific Catalog No. 1861281) and 1 mM PMSF (Fluka Catalog No. 93482). The cleared lysates were stored in Eppendorf tubes at -80°C until use, and the protein concentrations in the lysates were determined using the Pierce 660nm Protein Assay Reagent (ThermoScientific Catalog No. 22660). 20 μg of protein was diluted in 4x Laemmli buffer containing 10% beta-mercaptoethanol (Biorad catalog no. 161-0747), separated by SDS-PAGE using a 10% gel, and then transferred to a PVDF membrane (Trans Blot Turbo Transfer Pack BioRad catalog no. 1704156) by Trans-Blot® Turbo™ System semi-dry blotting method (BioRad). Primary antibodies were incubated overnight at 4°C in TBS-0.1% Tween-20 buffer containing 3% BSA bovine albumin Fr.V (Millipore catalog no. 81-053-3).The following primary antibodies were used: mouse anti-phosphoepitope SR protein clone 1H4 (Millipore catalog no. MABE50) diluted 1:5000, and rabbit anti-GAPDH clone 14C10 (Cell Signaling catalog no. 2118S) diluted 1:2000 to control for equal protein loading. HRP-conjugated secondary antibodies diluted 1:5000 in TBS-0.1% Tween-20 buffer containing 5% nonfat dry milk (Sigma catalog no. M7409) were incubated for 1 hour at room temperature. The following secondary antibodies were used: goat anti-mouse-HRP (Jackson catalog no. 115-035-146) and goat anti-rabbit-HRP (Jackson catalog no. 111-035-144). The membrane was incubated with ECL Prime Western blot detection reagent (Amersham catalog no. RPN2236), and specific signals were detected using a Fusion SOLO S instrument (Vilber Lourmat). The pixel intensities of phospho-SRSF6 (MW 55 kDa relative to the marker) and GAPDH (MW 37 kDa) signals in Western blots were determined using Evolution-Capt image analysis software (v17.01, Vilber Lourmat). DMSO control was used to set the phospho-SRSF6 signal to the baseline, and the phospho-SRSF6 signal of each sample was normalized by its respective GAPDH signal. The percentage intensity of the P-SRSF6 signal at 10 and 100 nM compounds compared to the DMSO control was calculated (see Figure 1).

[0653] Several examples of the present invention were tested for inhibition of phospho-SRSF6 levels in MDA-MB-468 cells and showed greater than 50% inhibition levels compared to the DMSO control when tested at concentrations of 100 or 10 nM. The results are shown in Table 3 below.

[0654] [Table 3]

[0655] Mouse xenograft model The efficacy of Example 13 was evaluated in a mouse xenograft model. For this purpose, an SW480 colorectal cancer xenograft model was used, in which tumor cells were injected subcutaneously into the flank of immunodeficient NOD / SCID mice (which lack functional / mature T and B cells, functional immature macrophages, and residual NK cell function). SW480 cells (ATCC, #CCL-228) were cultured at 37°C in RPMI high glucose medium supplemented with 10% heat-inactivated fetal bovine serum. SW480 cells were harvested in the logarithmic growth phase.

[0656] In this study, 8-9 week-old female NOD / SCID mice weighing approximately 23 g were used (Jiangsu GemPharmatech Co., Ltd.). 1 x 10 7 SW480 cells were subcutaneously inoculated in a mixture of PBS and Matrigel™ (1:1) at a final injection volume of 0.2 mL per mouse. 3 After reaching an average size of 1000 mg / kg, the mice were pair-matched to be divided into 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, twice weekly (BID*BIW) at a dose of 10 mL / kg for 3 weeks. The solution of Example 13 was orally administered at 45 mg / kg on days 1-10 and 50 mg / kg on days 11-22 at a dose of 10 mL / kg BID*BIW (doses represent free base equivalents).

[0657] Tumor volume (mm 3The tumor volume (represented by σ) was measured in two dimensions using calipers on days 1, 4, 8, 11, 15, 18, 22, and 23 of the treatment period. Figures 2A and 2B show tumor growth and body weight changes during the treatment period. Results represent the mean ± SEM (n = 8). Figure 2C shows the change in tumor volume at the end of the study. The change in tumor volume between the vehicle and Example 13-treated groups was compared by two-tailed t-test using GraphPad™ Prism version 9. During the treatment period, the tumor volumes of mice treated with Example 13 at 45 mg / kg twice daily and twice weekly (BID*BIW) were consistently smaller than those of vehicle-treated animals (Figures 2A and 2B). At the end of the study (day 23), the tumor volume of the Example 13-treated group was 61% of the volume of the vehicle-treated group (Figure 2C), p = 0.06. Treatment with Example 13 was tolerable, with a maximum weight loss of 5% on day 17 (FIG. 2B).

Claims

1. A compound of formula I, 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, wherein: Ra and Rb are both —CH ３ or Ra and Rb together represent -CH ２ -CH ２ -CH ２ - or -CH ２ -CH ２ -CH ２ -CH ２ - forms a bridging moiety, and A is -CH ２ - or -C(=O)-, T is -N(R11)-, -N(R11)-C(=O)-, -N(R11)-S(O ２ )-, -O-, -C(R12)(R13)-, -C=C(R12) ２ , -S-, -S(O)-, -S(O ２ ) -, -S(O ２ )—N(R14)— or —C(═O)—N(R14)—; When R11 does not form a ring with R1 or R2, it is hydrogen, C1-C4 alkylene-R11a, C1-C4 haloalkylene-R11a or C3-C6 cycloalkyl, wherein the cycloalkyl is optionally substituted with one or two R11b; each R12, when not forming a ring with R2, is independently hydrogen, C1-C4 alkylene-R12a, C1-C4 haloalkylene-R12a, or C3-C6 cycloalkyl, wherein said cycloalkyl is optionally substituted with one or two R12b; When R14 does not form a ring with R1 or R2, it is hydrogen, C1-C4 alkylene-R14a, C1-C4 haloalkylene-R14a or C3-C6 cycloalkyl, said cycloalkyl being optionally substituted with one or two R14b; Each R11a, R12a and R14a is independently hydrogen, halogen, —OH, —CN, —NH ２ , —O—C1-C2 alkyl, —O—C1-C2 haloalkyl, —NH(C1-C2 alkyl) or —N(C1-C2 alkyl) ２ and Each R11b, R12b and R14b is independently a halogen, —OH, —CN, —NH ２ , —O—C1-C2 alkyl, —O—C1-C2 haloalkyl, —NH(C1-C2 alkyl) or —N(C1-C2 alkyl) ２ and R13 is hydrogen, C1-C4 alkyl or C1-C4 haloalkyl; R2 and R11, R2 and R12, or R2 and R14 may together form a partially unsaturated 6- to 7-membered heterocyclic ring containing no additional heteroatoms, said heterocyclic ring being optionally substituted with one or two R2a; Each R2a is independently a halogen, —OH, —CN, or —NH ２ , —O—C1-C2 alkyl, —O—C1-C2 haloalkyl, —NH(C1-C2 alkyl) or —N(C1-C2 alkyl) ２ and 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 further heteroatoms selected from N, O and S as ring members, said heterocyclic ring being 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 further heteroatoms selected from N and O as ring members, said heteroaryl ring being optionally substituted with one to three R1b; Each R1a is independently a halogen, —OH, —CN, or —NH ２ , 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)NH ２ , —C(═O)NH(C1-C4 alkyl), —C(═O)N(C1-C4 alkyl) ２ or oxo, Each R1b is independently a halogen, —OH, —CN, or —NH ２ , 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)NH ２ , —C(═O)NH(C1-C4 alkyl) or —C(═O)N(C1-C4 alkyl) ２ and Each R1c is independently hydrogen, halogen, —OH, —CN, or —NH ２ , —O—C1-C2 alkyl, —O—C1-C2 haloalkyl, —NH(C1-C2 alkyl) or —N(C1-C2 alkyl) ２ and When R1 does not form a ring with R11 or R14, R1 is hydrogen or —Y—R3; Y is a bond or C1-C6 alkylene, in which case one non-terminal —CH ２ the - moiety may be replaced by -O-, the alkylene moiety may be substituted by one or two moieties independently selected from -OH, -O-C1-C4 alkyl and -O-C1-C4 haloalkyl, and the alkylene moiety may contain a 3-5 membered saturated or partially unsaturated carbocyclic ring as part of said moiety; R3 is hydrogen, —CN, —OH, C1-C4 haloalkyl, C2-C4 alkenylene-R4, C2-C4 alkynylene-R4, —O—C1-C4 alkylene-R4, —O—C1-C4 haloalkyl, —NH ２ , —NH(C1-C4 alkylene-R4), —N(C1-C4 alkylene-R4) ２ , —C(═O)—OH, —C(═O)—O—C1-C4 alkylene-R4, —C(═O)—NH ２ , —C(═O)—NH(C1-C4 alkylene-R4), —C(═O)—N(C1-C4 alkylene-R4) ２ , —NH—C(═O)—C1-C4 alkylene-R4, —N(C1-C4 alkyl)-C(═O)—C1-C4 alkylene-R4, ring P, ring Q, —O-ring P, —O-ring Q, —NH—S(O ２ )-C1-C4 alkylene-R4, -N(C1-C4 alkyl)-S(O ２ )-C1-C4 alkylene-R4, -S-C1-C4 alkylene-R4 or -S(O ２ )-C1-C4 alkyl-R4, provided that (i) Y is a bond, and (ii) T is not -N(R11)-, -C(R12)(R13)-, or -C=C(R12). ２ If neither of the above is true, then the atom of R3 connected to Y is not a heteroatom, R4 is hydrogen, halogen, or —NH ２ , —NH(C1-C2 alkyl) or —N(C1-C2 alkyl) ２ and Ring P is a 3- to 6-membered saturated or partially unsaturated carbocyclic ring optionally substituted with 1 to 3 R5, or a 3- to 6-membered saturated or partially unsaturated heterocyclic ring containing 1 or 2 heteroatoms selected from N and O, optionally substituted with 1 to 3 R5, each R5 independently being halogen, -NH ２ , —OH, —CN, C1-C4 alkylene-R5a, —O—C1-C4 alkylene-R5a or oxo; Each R5a is independently hydrogen, halogen, or —NH ２ , —OH, —CN, or —O—C1-C2 alkyl; Ring Q is phenyl optionally substituted with 1-3 R6, or a 5-6 membered heteroaryl ring containing 1 or 2 heteroatoms selected from N, S and O, optionally substituted with 1-3 R6; Each R6 is independently a halogen, -NH ２ , —OH, —CN, C1-C4 alkylene-R6a or —O—C1-C4 alkylene-R6a; Each R6a is independently hydrogen, halogen, or —NH ２ , —OH, —CN, or —O—C1-C2 alkyl; X is -O-, -C(=O)-, -C(=CH ２ )-, -N(R10a)-, or -CH(R10b)-; and when R2 is halogen or -CN, X is a bond; and when X is -C(=O)-, R2 is not hydrogen or X-R2 is hydrogen; R10a is hydrogen or C1-C4 alkyl when it does not form a ring with R2; R10b is hydrogen or C1-C4 alkyl; R2 and R10a may together form a 4-7 membered saturated or partially unsaturated heterocyclic ring which optionally contains an —N(R9)— moiety as a ring member in addition to the nitrogen atom of X and otherwise contains only carbon atoms as ring members, and which is optionally substituted by one or two R8; R2 and R10b may together 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 an —N(R9)— moiety as a ring member and otherwise containing only carbon atoms as ring members, and optionally substituted by one or two R8; R2, when not forming a ring with R10a, R10b, R11, R12 or R14, is hydrogen, halogen, —CN, C1-C4 alkyl optionally substituted with one or two R7, or a 4- to 7-membered saturated or partially unsaturated carbocyclic ring optionally substituted with one or two R8, or 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; each R7 is independently -CN, -OH, halogen, -N(R7a)R7b, or -NH(-C(=O)-C1-C4 alkyl); each R7a and R7b, when not taken together to form a ring, is independently hydrogen, C1-C4 alkylene-R7c, or C1-C4 haloalkylene-R7c; each R7c is independently hydrogen, halogen, —O—C1-C2 alkyl, or —O—C1-C2 haloalkyl; R7a and R7b may together form a 4-7 membered saturated or partially unsaturated heterocyclic ring optionally containing one or two additional heteroatoms selected from N, O and S as ring members, said heterocyclic ring being optionally substituted with one or two R7d; Each R7d is independently a halogen, —OH, —CN, or —NH ２ , C1-C2 alkyl, C1-C2 haloalkyl, —O—C1-C2 alkyl, —O—C1-C2 haloalkyl, —NH(C1-C2 alkyl) or —N(C1-C2 alkyl) ２ and each R8 is independently -CN, -OH, halogen, -N(R8a)R8b, -NH(-C(=O)-C1-C4 alkyl), C1-C4 alkyl, or C1-C4 haloalkyl; each R8a and R8b, when not taken together to form a ring, is independently hydrogen, C1-C4 alkylene-R8c, or C1-C4 haloalkylene-R8c; R8c is hydrogen, halogen, —O—C1-C2 alkyl, or —O—C1-C2 haloalkyl; R8a and R8b may together form a 4-7 membered saturated or partially unsaturated heterocyclic ring optionally containing one or two additional heteroatoms selected from N, O and S as ring members, said heterocyclic ring being optionally substituted with one or two R8d; Each R8d is independently a halogen, —OH, —CN, or —NH ２ , C1-C2 alkyl, C1-C2 haloalkyl, —O—C1-C2 alkyl, —O—C1-C2 haloalkyl, —NH(C1-C2 alkyl) or —N(C1-C2 alkyl) ２ and R9 is hydrogen, C1-C4 alkylene-R9a, C1-C4 haloalkylene-R9a or —C(═O)—C1-C4 alkyl; The compound, or a pharmaceutically acceptable salt thereof, wherein R9a is hydrogen, halogen, --O--C1-C2 alkyl, or --O--C1-C2 haloalkyl.

2. Ra and Rb are both —CH ３ and A is -CH ２ -, and T is -N(R11)-, -N(R11)-S(O ２ )-, -O-, -C(R12)(R13)-, -C=C(R12) ２ 2. The compound of claim 1, wherein the aryl group is —C(═O)—N(R14)—, —S—, or —C(═O)—N(R14)—, or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R2 and R11, R2 and R12, R2 and R14, R1 and R11, and R1 and R14 do not combine to form a heterocyclic ring.

4. R3 is hydrogen, —CN, —OH, C1-C4 haloalkyl, —O—C1-C4 alkylene-R4, —O—C1-C4 haloalkyl, —NH ２ , —NH(C1-C4 alkylene-R4), —N(C1-C4 alkylene-R4) ２ , -C(=O)-OH, -C(=O)-NH ２ 3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R is ring P or ring Q.

5. T is —N(R11)—, —N(R11)—C(═O)—, or —N(R11)—S(O ２ ) - and When R1 does not form a ring with R11, it is —Y—R3; or or R1 and R11 may together form a saturated or partially unsaturated 4-7 membered heterocyclic ring optionally containing 1 or 2 further heteroatoms selected from N, O and S as ring members, said heterocyclic ring being optionally substituted with 1 to 3 R1a, or R1 and R11 may together form a 5-6 membered heteroaryl ring optionally containing 1 to 3 further heteroatoms selected from N and O as ring members, said heteroaryl ring being optionally substituted with 1 to 3 R1b; 5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein R11 is C1-C4 alkylene-R11a, C1-C4 haloalkylene-R11a, or C3-C6 cycloalkyl, wherein the cycloalkyl is optionally substituted with one or two R11b.

6. T is —N(R11)—, —N(R11)—C(═O)—, or —N(R11)—S(O ２ ) - and When R1 does not form a ring with R11, it is —Y—R3; or Y is C1-C6 alkylene, in which case one non-terminal —CH ２ the - moiety may be replaced by -O-, the alkylene moiety may be substituted by one or two moieties independently selected from -OH, -O-C1-C4 alkyl and -O-C1-C4 haloalkyl, and the alkylene moiety may contain a 3- to 5-membered saturated or partially unsaturated carbocyclic ring as part of said moiety; or R1 and R11 may together form a saturated or partially unsaturated 4-7 membered heterocyclic ring optionally containing 1 or 2 further heteroatoms selected from N, O and S as ring members, said heterocyclic ring being optionally substituted with 1 to 3 R1a, or R1 and R11 may together form a 5-6 membered heteroaryl ring optionally containing 1 to 3 further heteroatoms selected from N and O as ring members, said heteroaryl ring being optionally substituted with 1 to 3 R1b; 5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein R11 is C1-C4 alkylene-R11a, C1-C4 haloalkylene-R11a, or C3-C6 cycloalkyl, wherein the cycloalkyl is optionally substituted with one or two R11b.

7. T is —N(R11)— or —N(R11)—S(O ２ ) - and When R11 does not form a ring with R1, it is C1-C4 alkylene-R11a, C1-C4 haloalkylene-R11a or C3-C4 cycloalkyl; R11a is hydrogen, halogen, —CN or —OH; R1 and R11 may together form a 5- to 6-membered saturated heterocyclic ring containing no further heteroatoms as ring members, said heterocyclic ring being optionally substituted with one R1a, or R1 and R11 may together form a 5-membered heteroaryl ring containing no further heteroatoms as ring members, said heteroaryl ring being optionally substituted with one R1b; R1a is halogen, —OH or —CN; R1b is halogen, —OH or —CN; When R1 does not form a ring with R11, R1 is C1-C3 alkylene-R3, ring P or ring Q; R3 is hydrogen, —CN, —OH, C1-C4 haloalkyl, —O—C1-C4 alkylene-R4, —O—C1-C4 haloalkyl, —NH ２ , —NH(C1-C4 alkylene-R4) or —N(C1-C4 alkylene-R4) ２ , -C(=O)-OH, -C(=O)-NH ２ , ring P or ring Q; Ring P is oxazolidinyl optionally substituted with one or two R5; each R5 is independently C1-C2 alkyl, -C1-C2 alkyl-R5a, or oxo, and ring P is not substituted with two oxo; Ring Q is phenyl optionally substituted with one R6, or a 5-6 membered heteroaryl ring containing 1-2 heteroatoms selected from N and O, optionally substituted with one R6; Each R6 is independently -NH ２ , —OH, —CN, C1-C2 alkylene-R6a or —O—C1-C2 alkyl; 5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein each R6a is independently hydrogen, halogen, or -CN.

8. The compound according to claim 5, or a pharmaceutically acceptable salt thereof, wherein R2, when not forming a ring with R10a, R10b, R11, R12, or R14, is C1-C4 alkyl, or a 4- or 7-membered saturated carbocyclic ring optionally substituted with one R8, or 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.

9. 8. The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein R2 is C1-C4 alkyl or a 6-membered saturated carbocyclic ring substituted with one R8 at the 3-position ("para") to X, and R8 is -N(R8a)R8b, or X-R2 is bromine.

10. Ra and Rb are both —CH ３ or Ra and Rb together represent -CH ２ -CH ２ -CH ２ -CH ２ - forming cross-linked moieties, A is -CH ２ - or -C(=O)-, T is -N(R11)-, -N(R11)-S(O ２ )-, -O-, -C(R12)(R13)-, -C=C(R12) ２ , -S-, -S(O ２ ) -, -S(O ２ )—N(R14)— or —C(═O)—N(R14)—; When R11 does not form a ring with R1 or R2, it is hydrogen, C1-C4 alkylene-R11a, C1-C4 haloalkylene-R11a or C3-C6 cycloalkyl; R11a is hydrogen, halogen, —CN or —OH; each R12 is independently hydrogen or C1-C4 alkylene-R12a; each R12a is independently hydrogen, halogen, —CN, or —OH; R13 is hydrogen; R14 is hydrogen or C1-C4 alkyl; R2 and R11 may, when T is -N(R11)- and X is -O-, together form a partially unsaturated 6-membered heterocyclic ring containing no further heteroatoms; R1 and R11 may together form a 4-6 membered saturated or partially unsaturated heterocyclic ring optionally containing one further heteroatom selected from N and O as a ring member, said heterocyclic ring being optionally substituted with one or two R1a, or R1 and R11 may together form a 5 membered heteroaryl ring optionally containing one further heteroatom selected from N as a ring member, said heteroaryl ring being optionally substituted with one or two R1b; Each R1a is independently selected from halogen, —OH, —CN, C1-C4 alkylene-R1c, —O—C1-C4 haloalkyl, —C(═O)NH ２ or oxo, each R1b is independently halogen, —OH, —CN, C1-C4 alkylene-R1c, or —O—C1-C4 haloalkyl; each R1c is independently hydrogen or —OH; When R1 does not form a ring with R11, R1 is —Y—R3; Y is a bond or C1-C6 alkylene, said alkylene moiety optionally being substituted with one -OH, said alkylene moiety optionally including a 3-membered saturated carbocyclic ring as part of said moiety, and there is a spacer of 3 or less carbon atoms between the connection to T and the connection to R3; R3 is hydrogen, —CN, —OH, C1-C4 haloalkyl, —O—C1-C4 alkylene-R4, —O—C1-C4 haloalkyl, —NH ２ , —NH(C1-C4 alkylene-R4), —N(C1-C4 alkylene-R4) ２ , -C(=O)-NH ２ , —C(═O)—NH(C1-C4 alkylene-R4), —C(═O)—OH, —C(═O)—O—C1-C4 alkylene-R4, —C(═O)—N(C1-C4 alkylene-R4) ２ , —NH—C(═O)—C1-C4 alkylene-R4, —N(C1-C4 alkyl)-C(═O)—C1-C4 alkylene-R4, ring P, ring Q, —NH—S(O ２ )-C1-C4 alkylene-R4, -N(C1-C4 alkyl)-S(O ２ )-C1-C4 alkylene-R4, -S-C1-C4 alkylene-R4 or -S(O ２ )-C1-C4 alkyl-R4, wherein R4 is hydrogen; Ring P is a 3-6 membered saturated carbocyclic ring optionally substituted with 1-2 R5, or a 5-6 membered saturated heterocyclic ring containing one heteroatom selected from N and O and optionally substituted with 1-2 R5; Each R5 is independently -NH ２ , C1-C2 alkyl, —C1-C2 alkyl-R5a or oxo; Each R5a is independently hydrogen, halogen, or —NH ２ , —OH, —CN, or —O—C1-C2 alkyl; Ring Q is phenyl optionally substituted with one or two R6, or a 5-6 membered heteroaryl ring containing 1-2 heteroatoms selected from N, S and O, optionally substituted with one or two R6; Each R6 is independently -NH ２ , —OH, —CN, C1-C2 alkylene-R6a or —O—C1-C2 alkyl; each R6a is independently hydrogen, halogen, or -CN; X is —O— or —N(R10a)—, or X—R2 is halogen or hydrogen; R10a is hydrogen or —CH ３ or R2 and R10a together may form a 4-7 membered saturated heterocyclic ring optionally substituted with one R8, which heterocyclic ring optionally contains an —N(R9)— moiety as a ring member in addition to the nitrogen atom of X, but otherwise contains only carbon atoms as ring members and does not contain an —N(R9)— moiety; When R2 does not form a ring with R10a or R11, it is C1-C4 alkyl optionally substituted with R7, or a 4- or 7-membered saturated carbocyclic ring optionally substituted with one R8, or a 6- 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; R7a is hydrogen or C1-C4 alkyl; R7b is hydrogen or C1-C4 alkyl; R8 is —N(R8a)R8b; R8a, when not forming a ring with R8b, is hydrogen or C1-C4 alkyl; R8b is hydrogen or C1-C4 alkyl when it does not form a ring with R8a; R8a and R8b may together form a 6-membered saturated heterocyclic ring optionally containing one or two further heteroatoms selected from N and O as ring members; 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R9 is hydrogen or C1-C4 alkyl.

11. Ra and Rb are both —CH ３ and A is -CH ２ - and T is -N(R11)-, -N(R11)-S(O ２ )-, -C=C(R12) ２ , —S— or —C(═O)—N(R14)—; When R11 does not form a ring with R1, it is hydrogen, C1-C4 alkylene-R11a, C1-C4 haloalkylene-R11a or C3-C4 cycloalkyl; R11a is hydrogen, halogen, —CN or —OH; each R12 is independently hydrogen or C1-C4 alkylene-R12a; each R12a is independently hydrogen, halogen, —CN, or —OH; R14 is hydrogen or C1-C4 alkyl; R1 and R11 may together form a 5- to 6-membered saturated heterocyclic ring containing no further heteroatoms as ring members, said heterocyclic ring being optionally substituted with one R1a, or R1 and R11 may together form a 5-membered heteroaryl ring containing no further heteroatoms as ring members, said heteroaryl ring being optionally substituted with one R1b; R1a is halogen, —OH or —CN; R1b is halogen, —OH or —CN; When R1 does not form a ring with R11, R1 is hydrogen, C1-C3 alkylene-R3, ring P or ring Q; R3 is hydrogen, —CN, —OH, C1-C4 haloalkyl, —O—C1-C4 alkylene-R4, —O—C1-C4 haloalkyl, —NH ２ , —NH(C1-C4 alkylene-R4) or —N(C1-C4 alkylene-R4) ２ , -C(=O)-OH, -C(=O)-NH ２ , ring P or ring Q; R4 is hydrogen; Ring P is oxazolidinyl optionally substituted with one or two R5; each R5 is independently C1-C2 alkyl, -C1-C2 alkyl-R5a, or oxo, and ring P is not substituted with two oxo; Ring Q is phenyl optionally substituted with one R6, or a 5-6 membered heteroaryl ring containing 1-2 heteroatoms selected from N and O, optionally substituted with one R6; R6 is independently —NH ２ , —OH, —CN, C1-C2 alkylene-R6a or —O—C1-C2 alkyl; R6a is independently hydrogen, halogen or -CN; X is —O— or —N(R10a)—, or X—R2 is halogen and R10a is hydrogen or —CH ３ or, when R2 and R10a together contain one —N(R9)— moiety as a ring member at the 3-position relative to the nitrogen atom of X and otherwise contain only carbon atoms as ring members but no —N(R9)— moieties, the heterocyclic ring may form a 6-7 membered saturated heterocyclic ring substituted with one R8 at the 3-position relative to the nitrogen atom of X, When R2 does not form a ring with R10a, it is C1-C4 alkyl optionally substituted with R7, or it is a 6- to 7-membered saturated carbocyclic ring substituted with one R8 at the 3-position relative to X, or it is a 6- to 7-membered saturated heterocyclic ring containing one —N(R9)— moiety as a ring member at the 3-position relative to X and otherwise containing only carbon atoms as ring members, or X-R2 is halogen or hydrogen, R7 is —N(R7a)R7b; R7a is hydrogen or C1-C4 alkyl-R7c; R7b is hydrogen or C1-C4 alkyl; R7c is hydrogen, halogen, —O—C1-C2 alkyl, or —O—C1-C2 haloalkyl; R8 is —N(R8a)R8b; When R8a does not form a ring with R8b, R8a is hydrogen or C1-C4 alkyl-R8c; R8b is hydrogen or C1-C4 alkyl when it does not form a ring with R8a; R8a and R8b may together form a 6-membered saturated heterocyclic ring optionally containing one or two further heteroatoms selected from N and O as ring members; R8c is hydrogen, halogen, —O—C1-C2 alkyl, or —O—C1-C2 haloalkyl; 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R9 is hydrogen or C1-C4 alkyl.

12. 2. The compound of claim 1, wherein the compound is selected from one of the following compounds or a pharmaceutically acceptable salt thereof: 8-methoxy-5,5,7-trimethyl-6H-benzo[h]quinazolin-4-amine, 8-methoxy-5,5-dimethyl-6H-benzo[h]quinazoline-4,7-diamine, 6,6-dimethyl-2,3,4,5-tetrahydroquinazolino[7,8-f][1,4]benzoxazin-7-amine, 4,6,6-trimethyl-3,5-dihydro-2H-quinazolino[7,8-f][1,4]benzoxazin-7-amine, 8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazoline-4,7-diamine, N-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]acetamide, 8-(trans-4-aminocyclohexoxy)-N7,N7-diethyl-5,5-dimethyl-6H-benzo[h]quinazoline-4,7-diamine, 8-(trans-4-aminocyclohexoxy)-N7-ethyl-5,5-dimethyl-6H-benzo[h]quinazoline-4,7-diamine, 8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-7-(1-piperidyl)-6H-benzo[h]quinazolin-4-amine, 8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-7-morpholino-6H-benzo[h]quinazolin-4-amine, 2-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-(2-hydroxyethyl)amino]ethanol, 2-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methyl-amino]ethanol, 8-(trans-4-aminocyclohexoxy)-N7-(2-methoxyethyl)-N7,5,5-trimethyl-6H-benzo[h]quinazoline-4,7-diamine, 2-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]amino]ethanol, 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, 8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-7-pyrrol-1-yl-6H-benzo[h]quinazolin-4-amine, 8-(trans-4-aminocyclohexoxy)-N7-(2-methoxyethyl)-5,5-dimethyl-6H-benzo[h]quinazoline-4,7-diamine, 8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-7-propoxy-6H-benzo[h]quinazolin-4-amine, 8-(trans-4-aminocyclohexoxy)-N7,N7,5,5-tetramethyl-6H-benzo[h]quinazoline-4,7-diamine, 1-(4-amino-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-9-yl)piperidin-4-ol, 2-[[4-amino-8-(cis-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-ethyl-amino]ethanol, 2-[[4-amino-8-(cis-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-propyl-amino]ethanol, 2-[[4-amino-8-(cis-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methyl-amino]ethanol, 1-(4-amino-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)azetidin-3-ol, 2-[[4-amino-8-(cis-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methyl-amino]-N-methyl-acetamide, 3-[(4-amino-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)amino]propane-1,2-diol, [1-(4-amino-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)azetidin-3-yl]methanol, 8-(cis-4-aminocyclohexoxy)-N7,5,5-trimethyl-N7-(tetrahydropyran-4-ylmethyl)-6H-benzo[h]quinazoline-4,7-diamine, 2-[[4-amino-8-(cis-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methyl-amino]acetonitrile, 8-(cis-4-aminocyclohexoxy)-N7,5,5-trimethyl-N7-(2-methylsulfanylethyl)-6H-benzo[h]quinazoline-4,7-diamine, 8-(cis-4-aminocyclohexoxy)-N7,5,5-trimethyl-N7-(2-methylsulfonylethyl)-6H-benzo[h]quinazoline-4,7-diamine, 2-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methyl-amino]acetonitrile, 4,7-diamino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-benzo[h]quinazolin-6-one, 2-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]amino]acetonitrile, 8-(trans-4-aminocyclohexoxy)-N7-(2-ethoxyethyl)-N7,5,5-trimethyl-6H-benzo[h]quinazoline-4,7-diamine, 8-(trans-4-aminocyclohexoxy)spiro[6H-benzo[h]quinazoline-5,1′-cyclopentane]-4,7-diamine, N-[2-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methyl-amino]ethyl]acetamide, N-[2-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methyl-amino]ethyl]methanesulfonamide, 1-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methyl-amino]-2-methyl-propan-2-ol, N-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-2-hydroxy-N-methyl-acetamide, N-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-2-hydroxy-ethanesulfonamide, 8-(trans-4-aminocyclohexoxy)-N7,5,5-trimethyl-N7-(3,3,3-trifluoropropyl)-6H-benzo[h]quinazoline-4,7-diamine, N-[4-amino-8-(4-trans-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-2-hydroxy-N-methyl-ethanesulfonamide, N-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-2-hydroxy-acetamide, 3-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methyl-amino]propanenitrile, 8-(trans-4-aminocyclohexoxy)-N7,5,5-trimethyl-N7-[2-(trifluoromethoxy)ethyl]-6H-benzo[h]quinazoline-4,7-diamine, 1-[[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methyl-amino]methyl]cyclopropanecarbonitrile, 1-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]pyrrolidine-3-carbonitrile-isomer 1, 1-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]pyrrolidine-3-carbonitrile-isomer 2, 3-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-cyclopropyl-amino]propanenitrile, 3-[[4-amino-5,5-dimethyl-8-(trans-4-morpholinocyclohexoxy)-6H-benzo[h]quinazolin-7-yl]-methyl-amino]propanenitrile, 3-[[4-amino-8-[trans-4-(2-methoxyethylamino)cyclohexoxy]-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methyl-amino]propanenitrile, 8-(trans-4-aminocyclohexoxy)-N7-but-3-ynyl-N7,5,5-trimethyl-6H-benzo[h]quinazoline-4,7-diamine, 1-(4-amino-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)pyrrolidine-3-carbonitrile, 1-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-2H-pyrrol-5-one, 8-(trans-4-aminocyclohexoxy)-7-(3-methoxypyrrol-1-yl)-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine, 4-[[4-amino-8-(4-trans-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methyl-amino]butanenitrile, 2-[[4-amino-8-(4-trans-aminocyclohexoxy)spiro[6H-benzo[h]quinazolin-5,1'-cyclopentan]-7-yl]-methyl-amino]ethanol, 2-[[4-amino-8-(4-trans-aminocyclohexoxy)spiro[6H-benzo[h]quinazoline-5,1'-cyclopentan]-7-yl]amino]ethanol, 8-methoxy-7-(3-methoxypropyl)-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine, 8-(trans-4-aminocyclohexoxy)-N7-(2-methoxyethyl)spiro[6H-benzo[h]quinazoline-5,1′-cyclopentane]-4,7-diamine, 8-(trans-4-aminocyclohexoxy)-7-(3-methoxypyrrolidin-1-yl)-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine-isomer 1, N-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-2-methoxy-N-methyl-ethanesulfonamide, ethyl 2-[[4-amino-8-(cis-4-aminocyclohexoxy)spiro[6H-benzo[h]quinazoline-5,1'-cyclopentan]-7-yl]amino]acetate, 1-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]pyrrolidine-3-carbonitrile, 8-(trans-4-aminocyclohexoxy)-N7-ethyl-N7,5,5-trimethyl-6H-benzo[h]quinazoline-4,7-diamine, 8-(trans-4-aminocyclohexoxy)-N7,5,5-trimethyl-6H-benzo[h]quinazoline-4,7-diamine, 3-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methyl-sulfamoyl]propanoic acid, 2-[[4-amino-8-(cis-4-aminocyclohexoxy)spiro[6H-benzo[h]quinazoline-5,1′-cyclopentan]-7-yl]amino]ethanol, 3-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]oxy]propanenitrile, 8-(trans-4-aminocyclohexoxy)-N7-(2-methoxyethyl)-N7-methyl-spiro[6H-benzo[h]quinazoline-5,1′-cyclopentane]-4,7-diamine, 8-(trans-4-aminocyclohexoxy)-7-(3-methoxypyrrolidin-1-yl)-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine-isomer 2, N-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-2-cyano-N-methyl-ethanesulfonamide, 8-(cis-4-aminocyclohexoxy)-N7-(2-methoxyethyl)-N7-methyl-spiro[6H-benzo[h]quinazoline-5,1′-cyclopentane]-4,7-diamine, 1-[[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]amino]methyl]cyclopropanecarbonitrile, 1-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]pyrrolidine-3-carboxamide, 3-[[4-amino-8-(azepan-4-yloxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methyl-amino]propanenitrile, 2-[[4-amino-8-(cis-4-aminocyclohexoxy)spiro[6H-benzo[h]quinazoline-5,1′-cyclopentan]-7-yl]amino]acetic acid, 8-(trans-4-aminocyclohexoxy)-N7-(2-aminoethyl)-N7,5,5-trimethyl-6H-benzo[h]quinazoline-4,7-diamine, 4-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]butanenitrile, (5R)-5-[[(4-amino-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)amino]methyl]oxazolidin-2-one, 2-[[4-amino-8-(cis-4-aminocyclohexoxy)spiro[6H-benzo[h]quinazoline-5,1′-cyclopentan]-7-yl]-methyl-amino]ethanol, 8-(trans-4-aminocyclohexoxy)-N7-cyclopropyl-5,5-dimethyl-6H-benzo[h]quinazoline-4,7-diamine, 3-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methyl-amino]propanoic acid, 3-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methyl-sulfamoyl]propanamide, 8-(cis-4-aminocyclohexoxy)-N7-(2-methoxyethyl)spiro[6H-benzo[h]quinazoline-5,1′-cyclopentane]-4,7-diamine, 3-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methyl-amino]-2,2-dimethyl-propanamide, (5R)-5-[2-[(4-amino-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)amino]ethyl]oxazolidin-2-one, 4-amino-8-(trans-4-aminocyclohexoxy)-N-(cyanomethyl)-5,5-dimethyl-6H-benzo[h]quinazoline-7-carboxamide, 3-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methyl-amino]-2,2-dimethyl-propanenitrile, 3-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]butan-1-ol, 3-[[4-amino-5,5-dimethyl-8-(4-piperidyloxy)-6H-benzo[h]quinazolin-7-yl]-methyl-amino]propanenitrile, 4-amino-8-(trans-4-aminocyclohexoxy)-N-(cyanomethyl)-N,5,5-trimethyl-6H-benzo[h]quinazoline-7-carboxamide, 3-[(4-amino-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)-methyl-amino]propanenitrile, 3-[[4-amino-8-trans-4-(dimethylamino)cyclohexoxy]-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methyl-amino]propanenitrile, 4-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]pentanenitrile, (E)-3-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]but-2-en-1-ol, 3-[[4-amino-5,5-dimethyl-8-[trans-4-(methylamino)cyclohexoxy]-6H-benzo[h]quinazolin-7-yl]-methyl-amino]propanenitrile, 8-(trans-4-aminocyclohexoxy)-N7-butyl-N7,5,5-trimethyl-6H-benzo[h]quinazoline-4,7-diamine, 8-(trans-4-aminocyclohexoxy)-N7,5,5-trimethyl-N7-(4-pyridylmethyl)-6H-benzo[h]quinazoline-4,7-diamine, 8-(trans-4-aminocyclohexoxy)-N7-isopropyl-N7,5,5-trimethyl-6H-benzo[h]quinazoline-4,7-diamine, 8-(trans-4-aminocyclohexoxy)-N7-(1H-imidazol-4-ylmethyl)-N7,5,5-trimethyl-6H-benzo[h]quinazoline-4,7-diamine, 8-(trans-4-aminocyclohexoxy)-N7-isopentyl-N7,5,5-trimethyl-6H-benzo[h]quinazoline-4,7-diamine, 8-(trans-4-aminocyclohexoxy)-N7,5,5-trimethyl-N7-(oxazol-4-ylmethyl)-6H-benzo[h]quinazoline-4,7-diamine, 8-(trans-4-aminocyclohexoxy)-N7-isobutyl-N7,5,5-trimethyl-6H-benzo[h]quinazoline-4,7-diamine, 8-(trans-4-aminocyclohexoxy)-N7,5,5-trimethyl-N7-(3-pyridylmethyl)-6H-benzo[h]quinazoline-4,7-diamine, 3-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]sulfanyl]propanenitrile, 3-[(4-amino-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)-methyl-amino]propanenitrile, 3-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methyl-amino]-2,2-dimethyl-propan-1-ol, 4-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methyl-amino]-2-methyl-butan-2-ol, 3-[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]sulfonyl]propanenitrile, 4-amino-8-(trans-4-aminocyclohexoxy)-N-(cyanomethyl)-N,5,5-trimethyl-6H-benzo[h]quinazoline-7-sulfonamide, N-[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-4-fluoro-N-methyl-benzenesulfonamide, 3-[(4-amino-8-bromo-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)-methyl-amino]propanenitrile, 4-amino-8-(trans-4-aminocyclohexoxy)-N-(cyanomethyl)-5,5-dimethyl-6H-benzo[h]quinazoline-7-sulfonamide, 3-(7-amino-6,6-dimethyl-3,5-dihydro-2H-quinazolino[7,8-f][1,4]benzoxazin-4-yl)propanenitrile, 3-[[4-amino-5,5-dimethyl-8-(4-methylpiperazin-1-yl)-6H-benzo[h]quinazolin-7-yl]-methyl-amino]propanenitrile, 8-(trans-4-aminocyclohexoxy)-7-(1,1-dioxo-1,2-thiazolidin-2-yl)-5,5-dimethyl-6H-benzo[h]quinazolin-4-amine, 1-(4-amino-8-bromo-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)pyrrolidine-3-carbonitrile, (5R)-5-[[(4-amino-8-bromo-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)amino]methyl]oxazolidin-2-one, N7-[[5-(1-fluoroethyl)-1,3,4-oxadiazol-2-yl]methyl]-8-methoxy-5,5-dimethyl-6H-benzo[h]quinazoline-4,7-diamine, 3-[[4-amino-8-[2-(dimethylamino)ethoxy]-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]-methyl-amino]propanenitrile, 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, 3-[(4-amino-5,5-dimethyl-8-piperazin-1-yl-6H-benzo[h]quinazolin-7-yl)-methyl-amino]propanenitrile, (5S)-5-[[(4-amino-8-bromo-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)-methyl-amino]methyl]oxazolidin-2-one, (5R)-5-[[(4-amino-8-bromo-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)amino]methyl]-3-(2-hydroxyethyl)oxazolidin-2-one, (5R)-5-[[[4-amino-8-(cis-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]amino]methyl]oxazolidin-2-one, (5R)-5-[[[4-amino-8-(trans-4-aminocyclohexoxy)-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl]amino]methyl]oxazolidin-2-one, (5R)-5-[[[4-amino-5,5-dimethyl-8-(cis-4-morpholinocyclohexoxy)-6H-benzo[h]quinazolin-7-yl]amino]methyl]oxazolidin-2-one, (5R)-5-[[[4-amino-5,5-dimethyl-8-(trans-4-morpholinocyclohexoxy)-6H-benzo[h]quinazolin-7-yl]amino]methyl]oxazolidin-2-one, and 3-[(4-amino-8-bromo-5,5-dimethyl-6H-benzo[h]quinazolin-7-yl)-[[(5S)-2-oxooxazolidin-5-yl]methyl]amino]propanenitrile.

13. structure: 【Chemistry 2】 2. The compound of claim 1, represented by: or a pharmaceutically acceptable salt thereof.

14. structure: 【Transformation 3】 2. The compound of claim 1, represented by: or a pharmaceutically acceptable salt thereof.

15. structure: 【Chemistry 4】 2. The compound of claim 1, represented by: or a pharmaceutically acceptable salt thereof.

16. structure: 【Transformation 5】 2. The compound of claim 1, represented by: or a pharmaceutically acceptable salt thereof.

17. structure: 【Transformation 6】 2. The compound of claim 1, represented by: or a pharmaceutically acceptable salt thereof.

18. A pharmaceutical composition for use in treating a neoplastic disease, such as cancer, comprising a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof.

19. A pharmaceutical composition comprising a compound of formula (I) as defined in any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof and optionally a pharmaceutically acceptable excipient.

20. A compound of formula (B), 【Transformation 7】 or a salt thereof, wherein: A, Ra and Rb are as defined in any one of claims 1 to 17 for compounds of formula (I), E1 is —OH, -halogen, —O—C1-C4 alkyl, boronic acid, boronic ester, or O-L1; L1 is methanesulfonyl, p-toluenesulfonyl or trifluoromethanesulfonyl; E2 is -OH, halogen, -NO ２ Or -SO ２ Cl, or a salt thereof; A compound of formula (C), 【Transformation 8】 or a salt thereof, wherein: A, X, Ra and Rb are as defined in any one of claims 1 to 17 for compounds of formula (I), E2 is -OH, halogen, -NO ２ Or -SO ２ Cl, R2' is as defined for R2 for compounds of formula (I) in any one of claims 1 to 17, and any functional group contained in R2 is optionally protected with a suitable protecting group, or a salt thereof; or A compound of formula (D), 【Chemistry 9】 or a salt thereof, wherein: A, X, Ra and Rb are as defined in any one of claims 1 to 17 for compounds of formula (I), T' is -N(R11')-, -N(R11')-C(=O)-, -N(R11')-S(O ２ )-, -O-, -C(R12')(R13)-, -C=C(R12') ２ , -S-, -S(O)-, -S(O ２ ) -, -S(O ２ )—N(R14′)— or —C(═O)—N(R14′)—; R11' is as defined in any one of claims 1 to 17 for R11 in compounds of formula (I), and any functional group contained in R11 is optionally protected with a suitable protecting group; R12' is as defined in any one of claims 1 to 17 for R12 in compounds of formula (I), and any functional group contained in R12 is optionally protected with a suitable protecting group; R13 is as defined in any one of claims 1 to 17 for compounds of formula (I), R14' is as defined in any one of claims 1 to 17 for R14 in compounds of formula (I), and any functional group contained in R14 is optionally protected with a suitable protecting group; R1' is as defined in any one of claims 1 to 17 for R1 in compounds of formula (I), and any functional group contained in R1 is optionally protected with a suitable protecting group; R2' is as defined in any one of claims 1 to 17 for R2 in the compound of formula (I), and any functional group contained in R2 is optionally protected with a suitable protecting group, or a salt thereof; or A compound of formula (E), 【Chemistry 10】 or a salt thereof, wherein: A, Ra and Rb are as defined in any one of claims 1 to 17 for compounds of formula (I), T' is -N(R11')-, -N(R11')-C(=O)-, -N(R11')-S(O ２ )-, -O-, -C(R12')(R13)-, -C=C(R12') ２ , -S-, -S(O)-, -S(O ２ ) -, -S(O ２ )—N(R14′)— or —C(═O)—N(R14′)—; R11' is as defined in any one of claims 1 to 17 for R11 in compounds of formula (I), and any functional group contained in R11 is optionally protected with a suitable protecting group; R12' is as defined in any one of claims 1 to 17 for R12 in compounds of formula (I), and any functional group contained in R12 is optionally protected with a suitable protecting group; R13 is as defined in any one of claims 1 to 17 for compounds of formula (I), R14' is as defined in any one of claims 1 to 17 for R14 in compounds of formula (I), and any functional group contained in R14 is optionally protected with a suitable protecting group; R1' is as defined in any one of claims 1 to 17 for R1 in compounds of formula (I), and any functional group contained in R1 is optionally protected with a suitable protecting group; E1 is —OH, -halogen, —O—C1-C4 alkyl, boronic acid, boronic ester, or O-L1; The compound or a salt thereof, wherein L1 is methanesulfonyl, p-toluenesulfonyl or trifluoromethanesulfonyl.

Images