Compound

Abstract

The present invention relates to compounds that can be useful for inhibiting RAS protein.More specifically, the present invention relates to compounds that inhibit a wide range of KRAS mutant proteins.Therefore, the compounds of the present invention can be used to treat symptoms mediated by KRAS protein.For example, the compounds can be used in treating cancer.

Description

[Technical field]

[0001] The present invention relates to compounds and their use methods.In particular, the compounds of the present invention are useful for inhibiting RAS protein.More specifically, the present invention relates to compounds for inhibiting a wide range of KRAS proteins, including mutant and wild-type KRAS.Therefore, the compounds of the present invention can be used to treat symptoms mediated by KRAS protein.For example, the compounds of the present invention can be used to treat cancer. [Background technology]

[0002] RAS (HRAS, KRAS4A and 4B, NRAS) proteins are a group of closely related monomeric globular proteins that act as molecular switches, cycling between inactive (GDP-bound) and active (GTP-bound) states to transmit upstream cellular signals to downstream effectors and control a variety of processes, including cell proliferation. RAS is the most frequently mutated oncogene in cancer (~30%), with KRAS being the most common mutated isoform accounting for ~85% of RAS mutations (Hobbs et al, Journal of Cell Science(2016) 129, 1287-1292 doi:10.1242 / jcs.182873).

[0003] KRAS G12D is a missense gain-of-function mutation resulting from an amino acid substitution of glycine (G) with aspartic acid at codon 12, and is the most common mutation accounting for ~26% of all KRAS mutations in cancer. KRAS G12D mutations are present in 36% of patients with pancreatic cancer, 13% of patients with colorectal cancer, 10% of patients with rectal cancer, 6% of patients with endometrial cancer, 4% of patients with non-small cell lung cancer, 4% of patients with gastric cancer, 3% of patients with ovarian cancer, and 2% of patients with small cell lung cancer (e.g., The AACR Project GENIE Consortium,(2017) Cancer Discovery; 7(8):818-831. Dataset version 8). Many of these patients with G12D mutations have few effective targeted therapeutic options and represent a high unmet need. The mainstay of treatment for many of these patients remains chemotherapy combinations with their associated severe side effects and lack of efficacy.

[0004] Other KRAS missense gain-of-function mutations resulting in amino acid substitutions for codon 12, codon 13, and codon 61, as well as amplification of the KRAS wild-type protein, also promote cancer development. KRAS mutations are found in approximately one in seven cancer patients (Hoffman et al, Cancer Discovery (2022) 12, 924-937). Activating KRAS mutations are highly prevalent in solid tumors, occurring in 35% of lung cancers, 45% of colorectal cancers, and 90% of pancreatic cancers. G12D, G12V, and G12C are the most frequent KRAS mutations, occurring in more than half of KRAS-involved cancers. Other KRAS mutations include KRAS G12V, KRAS G12A, KRAS G13D, and KRAS Q61H. KRAS gene amplification is found in approximately 7% of cancers with KRAS alterations, and is common in ovarian, breast, lung, fundic, uterine, and esophageal and gastric cancers (reviewed by Hoffman). Pan-KRAS inhibitors have the potential to treat a broader patient population, including cancers with KRAS mutations, KRAS wild-type proliferation, and cancers with loss of the tumor suppressor NF1. In addition, pan-KRAS inhibitors may be used to treat cancers that have acquired resistance to allele-specific inhibitors such as KRAS G12C inhibitors.

[0005] Given the high frequency of KRAS mutations in various tumor types and the well-established role of KRAS as an oncogenic driver mutation in cancer, modulating KRAS activity is a highly attractive therapeutic goal and has been the subject of significant research efforts for over 30 years. However, directly influencing KRAS activity has proven extremely difficult, and research efforts have focused on other targets in the signaling cascade upstream or downstream of KRAS. Alternative approaches to inhibiting KRAS activity include affecting other points on the MAPK pathway (English et al., 2002; Adjei 2014; Chin et al., 2020), many of which have shown that MAPK pathway inhibition is clinically effective. Recently, a mutant KRAS G12C-selective inhibitor that covalently binds to the allosteric pocket has been reported (Kettle and Cassar 2020), which has advanced to clinical trials and shown efficacy in selected patients.

[0006] Compounds capable of modulating G12D mutant KRAS are described in WO2021 / 041671. Compounds capable of modulating multiple RAS isoforms and mutants have also been described (Kessler et al. 2019), but these compounds are considered to be of limited therapeutic benefit due to their poor selectivity for KRAS over HRAS and NRAS isoforms as well as insufficient potency.

[0007] It is an object of the present invention to provide alternative or improved compounds for inhibiting RAS proteins, for example, it is an object of the present invention to provide alternative or improved compounds for inhibiting KRAS proteins.

[0008] Furthermore, it is an object of certain embodiments of the present invention to provide novel compounds for use in the treatment of conditions regulated by RAS protein.For example, it is an object of certain embodiments of the present invention to provide compounds for use in the treatment of cancer.The compounds may be more selective for KRAS protein with G12D mutation than other KRAS proteins than the compounds of the prior art.Alternatively, the compounds may have broad spectrum activity over a range of KRAS proteins.

[0009] It is an object of certain embodiments of the present invention to provide new methods for the treatment of cancer. In particular, it is an object of certain embodiments of the present invention to provide compounds that have activity comparable to existing methods of treatment, and, where appropriate, they should have better activity.

[0010] It is an object of certain embodiments of this invention to provide compounds that exhibit reduced cytotoxicity compared to prior art compounds and existing therapies.

[0011] Another object of certain embodiments of the present invention is to provide compounds that have a suitable pharmacokinetic profile and a suitable duration of action after administration.A further object of certain embodiments of the present invention is to provide compounds whose post-absorption metabolic decomposition products or fragments of the drug are GRAS (Generally Regarded As Safe).

[0012] Certain embodiments of the present invention meet some or all of the above objectives. Summary of the Invention

[0013] In accordance with the present invention, a compound of formula (I): [ka] [In the formula, Z 1 are independently -O- and -NR 5 - Selected from; Z2 are independently absent or -O- and -NR 6 - Selected from; R 1 is C 0 -C 3 -Alkylene-R 1a and C 2 -C 6 -Alkylene-R 1b where R 1a is an oxygen-containing 4- to 7-membered heterocycloalkyl ring, a 4- to 7-membered heterocycloalkyl ring, and NR 7 R 8 C substituted with a group 3 -C 7 -cycloalkyl ring; said heterocycloalkyl ring or said cycloalkyl ring optionally contains 1 to 4 R 9 may be substituted with a group; R 1b are independently selected from the following: NR 7 R 8 , OR 8 , S.R. 8 , SOR 8 , S.O. 2 R 8 and SO(NH)R 8 ;or R 1 and R 5 Together with the nitrogen to which they are attached, they form 1-4 R 9 a monocyclic 4- to 7-membered heterocycloalkyl group optionally substituted with a group; and 1 to 4 R 9 forming a ring system selected from fused, spiro-fused or bridged bicyclic 6- to 11-membered heterocycloalkyl groups, optionally substituted with a group; R 2 is independently 1 -C 6 -Alkyl, C 1 -C 4 -Haloalkyl, C 0 -C 4 -Alkylene-R 2a , C 1 -C 4 -Alkylene-R 2b , C2 -C 4 -Alkylene-R 2c and; R 2a are independently selected from the group consisting of: a monocyclic 4- to 7-membered heterocycloalkyl group; a fused, spiro-fused or bridged bicyclic 6- to 11-membered heterocycloalkyl group; a 5-, 6-, 9- or 10-membered monocyclic or bicyclic heteroaryl group; phenyl; and C 3 -C 7 -cycloalkyl; where any heterocycloalkyl or cycloalkyl R 2a The group is 1 to 6 R 10 R is optionally substituted with any heteroaryl or phenyl group. 2a The group is 1 to 6 R 11 optionally substituted with a group; R 2b CONR 12 R 12 and CO 2 R 12 are independently selected from; R 2c is NR 12 R 13 and OR 12 are independently selected from; or R 2 and R 6 together with the nitrogen to which they are attached form a ring system selected from monocyclic 4- to 7-membered heterocycloalkyl groups; and fused, spiro-fused or bridged bicyclic 6- to 11-membered heterocycloalkyl groups; said heterocycloalkyl groups being selected from 1 to 6 R 10 optionally substituted with a group; R 3a , R 3b and R 3c are each independently selected from the following: H, halo, C 1 -C 4 -Alkyl, OC 1 -C 4 -Alkyl, C 1 -C 4 -Haloalkyl, OC 1 -C 4-haloalkyl, cyclopropyl, nitro and cyano; R 4 is phenyl (wherein the phenyl is optionally C 5 -C 7 -cycloalkyl ring); naphthyl; and 5-, 6-, 9-, or 10-membered monocyclic or bicyclic heteroaryl, where R 4 optionally, 1 to 4 R 14 optionally substituted with a group; R 5 , R 6 , R 8 and R 12 are each independently H, C 1 -C 4 -haloalkyl and C 1 -C 4 - alkyl; R 7 and R 13 are each independently H, C 1 -C 4 -Alkyl, C 1 -C 4 -haloalkyl and C(O)-C 1 -C 4 - alkyl; R 9 and R 10 each independently represents oxo, halo, cyano, NR 12 R 13 , OR 12 , CO 2 R 12 ,CONR 12 R 12 , C 1 -C 4 -Alkyl, NR 12 R 13 C replaced with 1 -C 4 -Alkyl, OR 12 C replaced with 1 -C 4 -Alkyl, cyano substituted C 1 -C 4 -Alkyl, C 2 -C 4 -Alkenyl, C 2 -C4 -Alkynyl, C 1 -C 4 - selected from haloalkyl and cyclopropyl; R 11 and R 14 are each independently halo, cyano, nitro, NR 12 R 13 , OR 12 , CO 2 R 12 ,CONR 12 R 12 , C 1 -C 4 -Alkyl, NR 12 R 13 C replaced with 1 -C 4 -Alkyl, OR 12 C replaced with 1 -C 4 -Alkyl, C 2 -C 4 -Alkenyl, C 2 -C 4 -Alkynyl, C 1 -C 4 -haloalkyl and cyclopropyl; any of the alkyl, alkylene or cyclopropyl groups may be optionally substituted, where chemically possible, with 1 to 5 substituents each independently selected from the group consisting of: 1 -C 4 -Alkyl, halo, nitro, cyano, NR a R b , OR a , S.R. a , CO 2 R a , C(O)R a and CONR a R a ;where R a are each independently H, C 1 -C 4 -Alkyl and C 1 -C 4 -haloalkyl; R b are each independently H, C 1 -C 4 -Alkyl, C(O)-C 1 -C4 -Alkyl and S(O) 2 -C 1 -C 4 -alkyl] or a pharma- ceutically acceptable salt thereof.

[0014] In one embodiment, the compound of formula (I) has the formula (Ia): [ka] [In the formula, R 1 is C 0 -C 3 -Alkylene-R 1a and C 2 -C 6 -Alkylene-R 1b where R 1a is a 4- to 7-membered heterocycloalkyl ring; 1 to 4 R 9 a fused or spiro-fused bicyclic 6- to 11-membered heterocycloalkyl group optionally substituted with a group; and C 3 -C 7 -cycloalkyl ring; said heterocycloalkyl ring or said cycloalkyl ring optionally contains 1 to 4 R 9 may be substituted with a group; R 1b are, independently, OR 8 , S.R. 8 , SOR 8 , S.O. 2 R 8 , SO(NH)R 8 , O.C.(O)R 8 and S.O. 2 NR 7 R 8 Select from: or R 1 and R 5 Together with the nitrogen to which they are attached, they form 1-4 R 9 a monocyclic 4- to 7-membered heterocycloalkyl group optionally substituted with a group; and 1 to 4 R 9fused, spirofused or bridged bicyclic 6- to 11-membered heterocycloalkyl groups, optionally substituted with R 1 and R 5 is NR 1 R 5 is selected to contain no more than one amine, said one amine may be a primary, secondary or tertiary amine; R 2 is independently 1 -C 6 -Alkyl, C 1 -C 4 -Haloalkyl, C 0 -C 4 -Alkylene-R 2a , C 1 -C 4 -Alkylene-R 2b , C 2 -C 4 -Alkylene-R 2c and; R 2a are monocyclic 4- to 7-membered heterocycloalkyl groups; fused, spiro-fused or bridged bicyclic 6- to 11-membered heterocycloalkyl groups; 5-, 6-, 9- or 10-membered monocyclic or bicyclic heteroaryl groups; phenyl; and C 3 -C 7 -cycloalkyl; where any heterocycloalkyl or cycloalkyl R 2a The group is 1 to 6 R 10 R is optionally substituted with any heteroaryl or phenyl group; 2a The group is 1 to 6 R 11 optionally substituted with a group; R 2b CONR 12 R 12 and CO 2 R 12 are independently selected from; R 2c is NR 12 R 13 and OR 12 are independently selected from; R 3a , R3b and R 3c H, halo, C 1 -C 4 -Alkyl, OC 1 -C 4 -Alkyl, C 1 -C 4 -Haloalkyl, OC 1 -C 4 - each independently selected from haloalkyl, cyclopropyl, nitro and cyano; R 4 is phenyl (wherein the phenyl is optionally C 5 -C 7 -cycloalkyl ring); naphthyl; and 5-, 6-, 9-, or 10-membered monocyclic or bicyclic heteroaryl, where R 4 optionally, 1 to 4 R 14 optionally substituted with a group; R 5 , R 8 and R 12 are each independently H, C 1 -C 4 -haloalkyl and C 1 -C 4 - alkyl; R 7 and R 13 are each independently H, C 1 -C 4 -Alkyl, C 1 -C 4 -haloalkyl and C(O)-C 1 -C 4 - alkyl; R 9 and R 10 each independently represents oxo, halo, cyano, NR 12 R 13 , OR 12 , CO 2 R 12 ,CONR 12 R 12 , C 1 -C 4 -Alkyl, NR 12 R 13 C replaced with 1 -C4 -Alkyl, OR 12 C replaced with 1 -C 4 -Alkyl, cyano substituted C 1 -C 4 -Alkyl, C 2 -C 4 -Alkenyl, C 2 -C 4 -Alkynyl, C 1 -C 4 - selected from haloalkyl and cyclopropyl; R 11 and R 14 are each independently halo, cyano, nitro, NR 12 R 13 , OR 12 , CO 2 R 12 ,CONR 12 R 12 , C 1 -C 4 -Alkyl, NR 12 R 13 C replaced with 1 -C 4 -Alkyl, OR 12 C replaced with 1 -C 4 -Alkyl, C 2 -C 4 -Alkenyl, C 2 -C 4 -Alkynyl, C 1 -C 4 - selected from haloalkyl and cyclopropyl; Any of the alkyl, alkylene or cyclopropyl groups may be, where chemically possible, 1 -C 4 -Alkyl, halo, nitro, cyano, NR a R b , OR a , S.R. a , CO 2 R a , C(O)R a ,CONR a R a wherein R is optionally substituted with 1 to 5 substituents each independently selected from the group consisting of a, H, C 1 -C 4 -Alkyl and C 1 -C 4 -haloalkyl; R b , H, C 1 -C 4 -Alkyl, C(O)-C 1 -C 4 -Alkyl and S(O) 2 -C 1 -C 4 -alkyl, It is a compound of the formula:

[0015] In one embodiment, the compound of formula (I) has the formula (II): [ka] [In the formula, R 1 , R 2 , R 3b , R 14 , Z 1 and Z 2 is as described above for compounds of formula (I); and x is independently selected from 0, 1, 2, 3, and 4. For the avoidance of doubt, throughout this specification, x R 14 The group may be attached to either ring of the naphthyl group.

[0016] In one embodiment, the compound of formula (I) has the formula (IIa): [ka] [In the formula, R 1 , R 2 , R 5 , R 3b , R 14 is as defined above for compounds of formula (Ia); and x is independently selected from 0, 1, 2, 3, and 4. For the avoidance of doubt, throughout this specification, x R 14 The group may be attached to either ring of the naphthyl group.

[0017] In an embodiment, the compound of formula (I) has formula (III): [ka] [In the formula, R 1 , R 3b , R 4 , R 10 , Z 1 and Z 2 is as described above for compounds of formula (I); R 15 H and C 1 -C 4 -alkyl; R 16 , H, C 1 -C 4 - independently selected from alkyl and cyclopropyl; or R 15 and R 16 together with the atoms to which they are attached, are one or two R 10 5- or 6-membered heterocycloalkyl ring optionally substituted with a 5- or 6-membered heterocycloalkyl group; and y is independently selected from 0, 1, 2, 3, and 4. It is a compound of the formula:

[0018] In one embodiment, the compound of formula (I) has the formula (IIIa): [ka] [In the formula, R 1 , R 3b , R 4 , R 5 and R 10 is as described above for compounds of formula (I); R 15 , H, C 1 -C 4 -alkyl; R 16 , H, C 1 -C 4 - independently selected from alkyl and cyclopropyl; or R 15 and R 16together with the atoms to which they are attached, are one or two R 10 5- or 6-membered heterocycloalkyl ring optionally substituted with a 5- or 6-membered heterocycloalkyl group; and y is independently selected from 0, 1, 2, 3, and 4. It is a compound of the formula:

[0019] In an embodiment, the compound of formula (I) has formula (IV): [ka] [In the formula, R 1 , R 3b , R 10 , R 14 , Z 1 and Z 2 is as described above for compounds of formula (I); 15 H and C 1 -C 4 -alkyl; R 16 , H, C 1 -C 4 -alkyl and cyclopropyl; or R 15 and R 16 together with the atoms to which they are attached, are one or two R 10 x is independently selected from 0, 1, 2, 3, and 4; and y is independently selected from 0, 1, 2, 3, and 4. It is a compound of the formula:

[0020] In an embodiment, the compound of formula (I) has the formula (IVa): [ka] [In the formula, R 1 , R 3b , R 5 , R 10 and R 14 is as described above for compounds of formula (I); R 15H and C 1 -C 4 -alkyl; R 16 , H, C 1 -C 4 -alkyl and cyclopropyl; or R 15 and R 16 together with the atoms to which they are attached, are one or two R 10 x is independently selected from 0, 1, 2, 3, and 4; and y is independently selected from 0, 1, 2, 3, and 4. It is a compound of the formula:

[0021] In an embodiment, the compound of formula (I) has the formula (V): [ka] [In the formula, R 1 , R 3b , R 4 , R 10 , Z 1 and Z 2 is as defined above for compounds of formula (I); and z is independently selected from 0, 1, 2, 3 and 4. For the avoidance of doubt, throughout this specification z R 10 The group may be attached to either ring of the pyrrolidinyl group.

[0022] In an embodiment, the compound of formula (I) has the formula (Va): [ka] [In the formula, R 1 , R 3 , R 3b , R 4 , R 5 and R 10 is as defined above for compounds of formula (I); and z is independently selected from 0, 1, 2, 3 and 4. For the avoidance of doubt, throughout this specification z R 10The group may be attached to either ring of the pyrrolidinyl group.

[0023] In an embodiment, the compound of formula (I) has the formula (VI): [ka] [In the formula, R 1 , R 3b , R 10 , R 14 , Z 1 and Z 2 is as described above for compounds of formula (I); x is independently selected from 0, 1, 2, 3, and 4; and z is independently selected from 0, 1, 2, 3, and 4.

[0024] In an embodiment, the compound of formula (I) has the formula (VIa): [ka] [In the formula, R 1 , R 3b , R 5 , R 10 and R 14 is as described above for compounds of formula (I); x is independently selected from 0, 1, 2, 3, and 4; and z is independently selected from 0, 1, 2, 3, and 4.

[0025] In an embodiment, the compound of formula (I) or (Ia) has the formula (VII): [ka] [In the formula, R 1 , R 2 , R 3b , R 3c , R 4 and R 5 is as described above for compounds of formula (I) or (Ia).

[0026] In an embodiment, the compound of formula (I) or (Ia) has formula (VIII): [ka] [In the formula, R 1 , R 2 , R 5 and R 14 is as defined above for compounds of formula (I) or (Ia); and x is independently selected from 0, 1, 2, 3 and 4. For the avoidance of doubt, throughout this specification, x R 14 The group may be attached to either ring of the naphthyl group.

[0027] In an embodiment, the compound of formula (I) or (Ia) has formula (IX): [ka] [In the formula, R 1 , R 4 , R 5 and R 10 is as described above for compounds of formula (I) or (Ia); R 15 H and C 1 -C 4 -alkyl; R 16 , H, C 1 -C 4 - independently selected from alkyl and cyclopropyl; or R 15 and R 16 together with the atoms to which they are attached, are one or two R 10 forming a 5- or 6-membered heterocycloalkyl ring optionally substituted with a group; and y is independently selected from 0, 1, 2, 3, and 4.

[0028] In an embodiment, the compound of formula (I) or (Ia) has the formula (X): [ka] [In the formula, R 1 , R 5 , R 10 and R 14 is as described above for compounds of formula (I) or (Ia); R 15 H and C 1 -C 4 -alkyl; R 16 , H, C 1 -C 4 -alkyl and cyclopropyl; or R 15 and R 16 together with the atoms to which they are attached, are one or two R 10 x is independently selected from 0, 1, 2, 3, and 4; and y is independently selected from 0, 1, 2, 3, and 4. It is a compound of the formula:

[0029] In an embodiment, the compound of formula (I) or (Ia) has the formula (XI): [ka] [In the formula, R 1 , R 4 , R 5 and R 10 is as defined above for compounds of formula (I) or (Ia); and z is independently selected from 0, 1, 2, 3 and 4. For the avoidance of doubt, throughout this specification z R 10 The group may be attached to either ring of the pyrrolidinyl group.

[0030] In an embodiment, the compound of formula (I) or (Ia) has formula (XII): [ka] [In the formula, R 1 , R 5 , R 10 and R14 is as described above for compounds of formula (I) or (Ia); x is independently selected from 0, 1, 2, 3, and 4; and z is independently selected from 0, 1, 2, 3, and 4.

[0031] The following embodiments apply to any compound of formula (I)-(XII). These embodiments are independent and interchangeable. Any embodiment can be combined with any other embodiment, if chemically permissible. In other words, any feature described in the following embodiments can be combined with features described in one or more other embodiments, if chemically permissible. In particular, if a compound is exemplified or illustrated herein, any two or more of the following listed embodiments, expressed at all general levels inclusive of that compound, can be combined to provide further embodiments forming part of the present disclosure.

[0032] Z 1 may be -O-. 1 -NR 5 -- may be.

[0033] Z 2 may be -O-. 2 -NR 6 -- may be.

[0034] R 1 is independently 0 -C 3 -Alkylene-R 1a Where R 1a is a 4- to 7-membered heterocycloalkyl ring; and NR 7 R 8 C substituted with a group 3 -C 7 -cycloalkyl ring; said heterocycloalkyl ring or said cycloalkyl ring optionally contains 1 to 4 R 9 It may be substituted with a group.

[0035] R1 is C 0 -C 3 -Alkylene-R 1a R 1 is C 0 -C 3 -Alkylene-R 1a R may be 1a is an oxygen-containing 4- to 7-membered heterocycloalkyl ring, a 4- to 7-membered heterocycloalkyl ring, and NR 7 R 8 C substituted with a group 3 -C 7 -cycloalkyl ring; said heterocycloalkyl ring or said cycloalkyl ring is independently selected from 1 to 4 R 9 R 1 is CH 2 -R 1a R may be 1a is a 4- to 7-membered heterocycloalkyl ring and NR 7 R 8 C substituted with a group 3 -C 7 -cycloalkyl ring; said heterocycloalkyl ring or said cycloalkyl ring is independently selected from 1 to 4 R 9 The group may be optionally substituted with a group.

[0036] R 1 is C 0 -C 3 -Alkylene-R 1a R may be 1a is an oxygen-containing 4- to 7-membered heterocycloalkyl ring, a nitrogen-containing 4- to 7-membered heterocycloalkyl ring, and NR 7 R 8 C substituted with a group 3 -C 7 -cycloalkyl ring; said heterocycloalkyl ring or said cycloalkyl ring is independently selected from 1 to 4 R 9 R 1 is CH 2 -R 1a R may be 1ais a nitrogen-containing 4- to 7-membered heterocycloalkyl ring and NR 7 R 8 C substituted with a group 3 -C 7 -cycloalkyl ring; said heterocycloalkyl ring or said cycloalkyl ring is independently selected from 1 to 4 R 9 The group may be optionally substituted with a group.

[0037] R 1 is R 1a R may be 1a is a 4- to 7-membered heterocycloalkyl ring; and NR 7 R 8 C substituted with a group 3 -C 7 -cycloalkyl ring; said heterocycloalkyl ring or said cycloalkyl ring is independently selected from 1 to 4 R 9 The group may be optionally substituted with a group.

[0038] R 1 is R 1a R may be 1a is a nitrogen-containing 4- to 7-membered heterocycloalkyl ring and NR 7 R 8 a C3-C7-cycloalkyl ring substituted with a heterocycloalkyl group; said heterocycloalkyl ring or said cycloalkyl ring is independently selected from 1 to 4 R 9 R 1 is R 1a R may be 1a is an oxygen-containing 4- to 7-membered heterocycloalkyl ring; said heterocycloalkyl ring is 9 R 1 is R 1a R may be 1a may be an oxygen-containing 4- to 7-membered heterocycloalkyl ring, such as a tetrahydropyranyl ring.

[0039] R 1 is C 0 -C 3 -Alkylene-R1a R may be 1a is a 4- to 7-membered heterocycloalkyl ring; said heterocycloalkyl ring is 9 R 1 is CH 2 -Alkylene-R 1a R may be 1a is a 4- to 7-membered heterocycloalkyl ring; said heterocycloalkyl ring is 9 The group may be optionally substituted with a group.

[0040] R 1 is C 0 -C 3 -Alkylene-R 1a R may be 1a is a nitrogen-containing 4- to 7-membered heterocycloalkyl ring; said heterocycloalkyl ring is 9 R 1 is CH 2 -Alkylene-R 1a R may be 1a is a nitrogen-containing 4- to 7-membered heterocycloalkyl ring; said heterocycloalkyl ring is 9 The group may be optionally substituted with a group.

[0041] R 1 is C 0 -C 3 -Alkylene-R 1a R may be 1a is a 4- to 7-membered heterocycloalkyl ring, the ring of which does not contain any nitrogen atoms; said heterocycloalkyl ring is a 4- to 7-membered heterocycloalkyl ring, the ring of which contains 1 to 4 R 9 R 1 is CH 2 -Alkylene-R 1a R may be 1a is a 4- to 7-membered heterocycloalkyl ring, the ring of which does not contain any nitrogen atoms; said heterocycloalkyl ring is a 4- to 7-membered heterocycloalkyl ring, the ring of which contains 1 to 4 R 9 The group may be optionally substituted with a group.

[0042] R 1 is R 1a R may be 1a is a 4- to 7-membered heterocycloalkyl ring; said heterocycloalkyl ring is 9 R 1 is R 1a R may be 1a is a nitrogen-containing 4- to 7-membered heterocycloalkyl ring; said heterocycloalkyl ring is 9 R 1 is R 1a R may be 1a is a 4- to 7-membered heterocycloalkyl ring; said heterocycloalkyl ring is 9 groups, and the ring does not contain any nitrogen atoms.

[0043] R 1 is C 0 -C 3 -Alkylene-R 1a R may be 1a is NR 7 R 8 C substituted with a group 3 -C 7 -cycloalkyl ring; said cycloalkyl ring is a cycloalkyl ring having 1 to 4 R 9 R 1 is CH 2 -Alkylene-R 1a where R may be 1a is NR 7 R 8 C substituted with a group 3 -C 7 -cycloalkyl ring; said cycloalkyl ring is a cycloalkyl ring having 1 to 4 R 9 The group may be optionally substituted with a group.

[0044] R 1 is R 1a R may be 1a is NR 7 R8 C substituted with a group 3 -C 7 -cycloalkyl ring; said cycloalkyl ring is a cycloalkyl ring having 1 to 4 R 9 The group may be optionally substituted with a group.

[0045] R 1 is C 2 -C 6 -Alkylene-R 1b R 1 is C 2 -C 3 -Alkylene-R 1b R 1 is C 3 -Alkylene-R 1b R 1b is NR 7 R 8 , OR 8 and S.R. 8 R 1b OR 8 R 1b SR 8 R 1b is NR 7 R 8 R 8 is C 1 -C 4 -alkyl, for example Me.

[0046] R 1 and R 5 is NR 1 R 5may be selected to contain no more than one amine, and said one amine may be a primary, secondary or tertiary amine. Compounds with only one amine at this position surprisingly show broad inhibition at comparable concentrations across a variety of mutant KRAS forms, as well as wild-type KRAS, rather than inhibition against specific KRAS G12C and G12D proteins. Compounds of the present invention show broad inhibition at comparable concentrations across KRAS mutants, including KRAS G12D, KRAS G12C, KRAS G12V, KRAS G12A, KRAS G13D and KRAS Q61H, as well as wild-type KRAS. Thus, these compounds are believed to be beneficial in treating cancers with KRAS mutations other than G12D and G12C, as well as cancers with wild-type KRAS.

[0047] R 1 and R 5 Together with the nitrogen to which they are attached, they form 1-4 R 9 a monocyclic 4- to 7-membered heterocycloalkyl group optionally substituted with a group; 9 a fused or spiro-fused bicyclic 6- to 11-membered heterocycloalkyl group optionally substituted with a group; and one to four R 9 R may form a ring system selected from the group consisting of bridged bicyclic 6- to 11-membered heterocycloalkyl groups, optionally substituted with a group; 1 and R 5 The nitrogen to which is attached is the only heteroatom in the ring system.

[0048] R 1 and R 5 Together with the nitrogen to which they are attached, they form 1-4 R 9 a monocyclic 4- to 7-membered heterocycloalkyl group optionally substituted with a group; 9 a fused or spiro-fused bicyclic 6- to 11-membered heterocycloalkyl group optionally substituted with a group; and one to four R 9R may form a ring system selected from the group consisting of bridged bicyclic 6- to 11-membered heterocycloalkyl groups, optionally substituted with a group; 1 and R 5 The nitrogen to which is attached is the only nitrogen in the ring system.

[0049] R 1 and R 5 is NR 1 R 5 The nitrogen of R may be selected to be the nitrogen of one amine. 1 and R 5 is NR 1 R 5 may be selected to be an amine. For the avoidance of doubt, the term "amine" as used herein includes primary amines, e.g., methylamine; secondary amines, e.g., dimethylamine; tertiary amines, e.g., trimethylamine; cyclic amines, e.g., piperidine. For the avoidance of doubt, the term "amine" as used herein excludes amides and lactams, e.g., piperazinonyl.

[0050] R 1 and R 5 may, together with the nitrogen to which they are attached, form a ring system having the structure: [ka] (In the formula, R 9c H and C 1 -C 4 -alkyl, and p5 and q5 are each selected from 0, 1, 2 and 3; with the proviso that the total number of p5 and q5 is 1 or greater than 1.

[0051] R 1 and R 5 may be taken together with the nitrogen to which they are attached to form a ring system having a structure selected from the following: [ka] wherein r6 is selected from 0, 1 and 2.

[0052] R 1 and R 5 Together with the nitrogen to which they are attached, they form 1-4 R 9 a monocyclic 4- to 7-membered heterocycloalkyl group optionally substituted with a group; 9 The ring system may be selected from fused, spiro-fused or bridged bicyclic 6- to 11-membered heterocycloalkyl groups, optionally substituted with groups.

[0053] R 1 and R 5 Together with the nitrogen to which they are attached, they form 1-4 R 9 a monocyclic 4- to 7-membered heterocycloalkyl group optionally substituted with a group; 9 a ring system selected from fused, spiro-fused or bridged bicyclic 6- to 11-membered heterocycloalkyl groups, optionally substituted with R 1 and R 5 It does not contain any nitrogen other than the nitrogen to which it is bonded.

[0054] R 1 and R 5 Together with the nitrogen to which they are attached, they form 1-4 R 9 a monocyclic 4- to 7-membered heterocycloalkyl group optionally substituted with a group; 9 a fused or spiro-fused bicyclic 6- to 11-membered heterocycloalkyl group optionally substituted with a group; and one to four R 9 The ring system may be selected from bridged bicyclic 6-11 membered heterocycloalkyl groups, optionally substituted with a group.

[0055] R 1 and R 5 Together with the nitrogen to which they are attached, they form 1-4 R 9 a monocyclic 4- to 7-membered heterocycloalkyl group optionally substituted with a group and 1 to 4 R9 The ring system may be selected from fused or spiro-fused bicyclic 6- to 11-membered heterocycloalkyl groups, optionally substituted with a group.

[0056] R 1 and R 5 Together with the nitrogen to which they are attached, they form 1-4 R 9 R may form a 6- or 7-membered heterocycloalkyl group, optionally substituted with a R group. 1 and R 5 Together with the nitrogen to which they are attached, they form 1-4 R 9 The total number of heteroatoms in the 6- or 7-membered heterocycloalkyl group may be 1 or 2. The total number of heteroatoms may be 2. 1 and R 5 together with the nitrogen to which they are attached form one R 9 The aryl group may form a 6- or 7-membered heterocycloalkyl group, which may be optionally substituted with a group.

[0057] R 1 and R 5 Together with the nitrogen to which they are attached, they form 1-4 R 9 R may form a monocyclic 4- to 7-membered heterocycloalkyl group which may be optionally substituted with a R group. 1 and R 5 may be joined together with the nitrogen to which they are attached to form an unsubstituted monocyclic 4- to 7-membered heterocycloalkyl group. 9 R may be present. 9 At least one of the groups is NR 12 R 13 and N.R. 12 R 13 C replaced with 1 -C 4 -alkyl. 1 and R 5may, together with the nitrogen to which they are attached, form a ring system having the structure: [ka] (In the formula, R 9a is NR 12 R 13 and N.R. 12 R 13 C replaced with 1 -C 4 -alkyl; p1 is selected from 0, 1, 2 and 3; q1 is selected from 0, 1 and 2; and r1 is selected from 0, 1, 2 and 3). r1 may be 0. R 9 may each independently be methyl. 9a NHR 12 and N.H.R. 12 C replaced with 1 -C 4 -alkyl.

[0058] R 1 and R 5 Together with the nitrogen to which they are attached, they form 1-4 R 9 The heterocycloalkyl group may form a monocyclic 4- to 7-membered heterocycloalkyl group (containing two nitrogen atoms in the ring) which may be optionally substituted by a group.

[0059] R 1 and R 5 may, together with the nitrogen to which they are attached, form a ring system having the structure: [ka] [In the formula, Z 6 is C(O)NR 9b , N.R. 9b , O, S, S(O) 2 , S(O), S(O)(NR 9b ) and S(O)(NH); R 9b H and C 1 -C 4-alkyl; p2 is selected from 2 and 3, q2 is 2; and r2 is selected from 0, 1, 2 and 3. 6 is NR 9b , O, S, S(O) 2 , S(O) and S(O)(NH). Z 6 is C(O)NR 9b , O, S, S(O) 2 , S(O), S(O)(NR 9b ) and S(O)(NH). Z 6 are O, S, and S(O) 2 , S(O) and S(O)(NH). Z 6 is NR 9b , O and S. 6 may be selected from O and S. Z6 may be O.

[0060] R 1 and R 5 may, together with the nitrogen to which they are attached, form a ring system having the structure: [ka] (In the formula, R 9b H and C 1 -C 4 -alkyl; p2 is selected from 2 and 3, q2 is 2; and r2 is selected from 0, 1, 2 and 3). r2 may be 0. R 9 may each independently be methyl. 9b may be H. 9b is C 1 -C 4 -alkyl.

[0061] R 1 and R 5 Together with the nitrogen to which they are attached, they form 1-4 R 9R may form a fused or spiro-fused bicyclic 6- to 11-membered heterocycloalkyl group, optionally substituted with a R group. 1 and R 5 Together with the nitrogen to which they are attached, they form 1-4 R 9 The heterocycloalkyl groups may form a fused or spiro-fused bicyclic 6- to 11-membered heterocycloalkyl group (containing two nitrogen atoms in said ring system) which may be optionally substituted with a group.

[0062] R 1 and R 5 Together with the nitrogen to which they are attached, they form 1-4 R 9 R may form a spiro-fused bicyclic 6- to 11-membered heterocycloalkyl group, optionally substituted with R 1 and R 5 Together with the nitrogen to which they are attached, they form 1-4 R 9 R may form a spiro-fused bicyclic 6- to 11-membered heterocycloalkyl group (containing two nitrogen atoms in the ring system) optionally substituted with a R group. 1 and R 5 may, together with the nitrogen to which they are attached, form a ring system having the structure: [ka] [In the formula, R 9b H and C 1 -C 4 -alkyl; p3, p4, q3 and q4 are each independently selected from 0, 1, 2 and 3; provided that the total number of p3, p4, q3 and q4 is 3 to 8, the total number of p3 and q3 is 2 or more, the total number of p4 and q4 is 2 or more; and r3 is selected from 0, 1, 2 and 3. 9 The group may be attached to either ring of the spiro-fused bicyclic ring system. r3 may be 0. R 9 may each independently be methyl. 9b may be H.

[0063] R 1 and R 5 Together with the nitrogen to which they are attached, they form 1-4 R 9 R may form a fused bicyclic 6- to 11-membered heterocycloalkyl group, which may be optionally substituted with a R group. 1 and R 5 Together with the nitrogen to which they are attached, they form 1-4 R 9 R may form a fused bicyclic 6- to 11-membered heterocycloalkyl group (containing two nitrogen atoms in the ring system) optionally substituted with a R group. 1 and R 5 may, together with the nitrogen to which they are attached, form a ring system having the structure: [ka] [In the formula, R 9b H and C 1 -C 4 p5, p6 and q5 are each selected from 0, 1, 2 and 3; provided that the total number of p3, p4, q3 and q4 is 2 to 7, the total number of p5 and q5 is 1 or more, the total number of p6 and q6 is 1 or more; and r5 is selected from 0, 1, 2 and 3. For the avoidance of doubt, throughout this specification, the term "R 9 The group may be attached to either ring of the fused bicyclic ring system. r5 may be 0. R 9 may each independently be methyl. 9b may be H.

[0064] R 1 and R 5 Together with the nitrogen to which they are attached, they form 1-4 R 9 The aryl group may form a bridged bicyclic 6- to 11-membered heterocycloalkyl group which may be optionally substituted with a group.

[0065] R 1 and R 5Together with the nitrogen to which they are attached, they form 1-4 R 9 The heterocycloalkyl group may form a bridged bicyclic 6- to 11-membered heterocycloalkyl group which may be optionally substituted with a group.

[0066] R 1 and R 5 may, together with the nitrogen to which they are attached, form a ring system having the structure: [ka] [In the formula, X 1 is C(O)NR 9d , O and NR 17 are independently selected from; Z 3 is CH 2 , C.H. 2 CH 2 , C.H. 2 -O-CH 2 CH 2 , C.H. 2 -O-CH 2 , C.H. 2 -NR 17 -CH 2 CH 2 and C.H. 2 -NR 17 -CH 2 are independently selected from; R 17 , H, C 1 -C 4 -haloalkyl and C 1 -C 4 -alkyl; R 9d H and C 1 -C 4 -alkyl; and n1 is an integer selected from 0, 1, 2, 3 and 4. For the avoidance of doubt, throughout this specification, n1 R 9 The group may be attached to either ring of the bridged bicyclic ring system. 3 is CH 2 , C.H. 2 CH 2 , C.H. 2 -O-CH 2 CH 2, C.H. 2 -O-CH 2 X 1 is O and NR 17 X may be independently selected from 1 is NR 17 X 1 may be NH. n1 may be 0. R 9 may each independently be methyl.

[0067] R 1 and R 5 may, together with the nitrogen to which they are attached, form a ring system having the structure: [ka] [In the formula, X 1 is C(O)NR 9d , O and NR 17 are independently selected from; Z 4 is CH 2 , C.H. 2 CH 2 , C.H. 2 -O-CH 2 CH 2 , C.H. 2 -O-CH 2 , C.H. 2 -NR 17 -CH 2 CH 2 and C.H. 2 -NR 17 -CH 2 are independently selected from; R 17 are each independently H, C 1 -C 4 -haloalkyl and C 1 -C 4 -alkyl; R 9d H and C 1 -C 4 -alkyl; and n2 is an integer selected from 0, 1, 2, 3 and 4. For the avoidance of doubt, in this specification, n2 R 9The group may be attached to either ring of the bridged bicyclic ring system. 4 is CH 2 , C.H. 2 CH 2 , C.H. 2 -O-CH 2 CH 2 , C.H. 2 -O-CH 2 X 1 is O and NR 17 X may be independently selected from 1 is NR 17 X 1 may be NH. n2 may be 0. R 9 may each independently be methyl. 1 is NR 17 X 1 may be NH. n2 may be 0. R 9 may each independently be methyl.

[0068] R 1 and R 5 may, together with the nitrogen to which they are attached, form a ring system having the structure: [ka] [In the formula, X 1 is C(O)NR 9d , O and NR 17 are independently selected from; Z 4 is CH 2 , C.H. 2 CH 2 , C.H. 2 -O-CH 2 CH 2 , C.H. 2 -O-CH 2 , C.H. 2 -NR 17 -CH 2 CH 2 and C.H. 2 -NR 17 -CH 2 are independently selected from; R17 , H, C 1 -C 4 -haloalkyl and C 1 -C 4 -alkyl; R 9d H and C 1 -C 4 -alkyl; and n3 is an integer selected from 0, 1, 2, 3 and 4. For the avoidance of doubt, throughout this specification, n3 R 9 The group may be attached to either ring of the bridged bicyclic ring system. 1 is O and NR 17 X may be independently selected from 1 is NR 17 X 1 may be NH. n3 may be 0. R 9 may each independently be methyl.

[0069] R 1 and R 5 may, together with the nitrogen to which they are attached, form a ring system having the structure: [ka] [In the formula, X 1 is C(O)NR 9d , O and NR 17 are independently selected from; Z 5 is CH 2 , C.H. 2 CH 2 , C.H. 2 -O-CH 2 CH 2 , C.H. 2 -O-CH 2 , C.H. 2 -NR 17 -CH 2 CH 2 and C.H. 2 -NR 17 -CH 2 are independently selected from; R 17 are each independently H, C 1 -C4 -haloalkyl and C 1 -C 4 -alkyl; R 9d H and C 1 -C 4 -alkyl; and n5 is an integer selected from 0, 1, 2, 3 and 4. For the avoidance of doubt, throughout this specification, n5 R 9 The group may be attached to either ring of the bridged bicyclic ring system. 5 are independently 2 , C.H. 2 CH 2 , C.H. 2 -O-CH 2 CH 2 , C.H. 2 -O-CH 2 Selected from: X 1 is O and NR 17 X may be independently selected from 1 is NR 17 X 1 may be NH. n5 may be 0. R 9 may each independently be methyl.

[0070] R 1 and R 5 may, together with the nitrogen to which they are attached, form a ring system having the structure: [ka] [In the formula, Z 6 is C(O)NR 9b , O, S, S(O) 2 , S(O), S(O)(NR 9b ), S(O)(NH) and NR 9b are independently selected from; R 9b are each independently H and C 1 -C 4 -alkyl; and n6 is an integer selected from 0, 1, 2, 3 and 4. 6 is NR 9b , O, S, S(O) 2, S(O), S(O)(NR 9b ) and S(O)(NH). Z 6 is C(O)NR 9b , O, S, S(O) 2 , S(O), and S(O)(NH). 6 are O, S, and S(O) 2 , S(O) and S(O)(NH). Z 6 is NR 9b , O and S. 6 may be selected from O and S. 6 may be O.

[0071] R 1 and R 5 may, together with the nitrogen to which they are attached, form a ring system having the structure: [ka] where n7 is an integer selected from 0, 1, 2 and 3.

[0072] R 1 and R 5 may, together with the nitrogen to which they are attached, form a ring system having the structure: [ka] where n7 is an integer selected from 0, 1, 2 and 3.

[0073] R 1 and R 5 together with the nitrogen to which they are attached form a ring system having the structure: [ka] where n8 is an integer selected from 0, 1, 2 and 3.

[0074] n7 may be 0.

[0075] R 2 is C 0 -C 4 -Alkylene-R 2a R 2 is CH 2 -R 2a R 2a may be selected from monocyclic 4- to 7-membered heterocycloalkyl groups; and fused, spiro-fused or bridged bicyclic 6- to 11-membered heterocycloalkyl groups; 2a The group is 1 to 6 R 10 R 2a R may contain at least one nitrogen in said ring system. 2a R may contain one nitrogen in said ring system. 2a may be selected from monocyclic 4- to 7-membered heterocycloalkyl groups; and fused, spiro-fused or bridged bicyclic 6- to 11-membered heterocycloalkyl groups; 2a The group is 1 to 6 R 10 group, where R 2a R contains at least one nitrogen in said ring system. 2a may be a monocyclic 4- to 7-membered heterocycloalkyl group; 2a The group is 1 to 6 R 10 group, where R 2a R contains at least one nitrogen in said ring system. 2a may be a fused, spiro-fused or bridged bicyclic 6- to 11-membered heterocycloalkyl group; 2a The group is 1 to 6 R 10 group, where R 2a contains at least one nitrogen in said ring system.

[0076] R 2 may have the structure: [ka] [In the formula, R 15 , H, C 1-C 4 -alkyl; where R 16 , H, C 1 -C 4 - independently selected from alkyl and cyclopropyl; or R 15 and R 16 together with the nitrogen to which they are attached, one or two R 10 and y is independently selected from 0, 1, 2, 3, and 4. y may be selected from 0 and 1. y may be 0. y may be 1. R 15 may be H. 16 is C 1 -C 4 -alkyl.

[0077] R 2 may have the structure: [ka] where z is independently selected from 0, 1, 2, 3, and 4. z may be selected from 0 and 1. z may be 0. z may be 1.

[0078] R 2 has the following structure: [ka] may have:

[0079] R 3a may be H.

[0080] R 3b Halo, C 1 -C 4 -Alkyl, OC 1 -C 4 -Alkyl, C 1 -C 4 -Haloalkyl, OC 1 -C 4-haloalkyl, cyclopropyl, nitro and cyano. 3b may be F. 3b is C 1 -C 4 -alkyl, for example Me.

[0081] R 3c Halo, C 1 -C 4 -Alkyl, OC 1 -C 4 -Alkyl, C 1 -C 4 -Haloalkyl, OC 1 -C 4 -haloalkyl, cyclopropyl, nitro and cyano. 3c may be F. 3c is C 1 -C 4 -alkyl, for example Me. 3c may be H.

[0082] R 3a and R 3c Both R and R may be H. 4 may be phenyl, said phenyl optionally being C 5 -C 7 -cycloalkyl ring, R 4 optionally, 1 to 4 R 14 R 4 is 1 to 4 R 14 It may be a phenyl optionally substituted with a group.

[0083] R 4 has the following structure: [ka] (In the formula, R 12a are independently H or C 1 -C 4 -alkyl; x1 is independently selected from 0, 1, 2 and 3. R 12a may be H.

[0084] R 4 is 1 to 4 R 14 R may be naphthyl optionally substituted with a R group. 4 may have the structure: [ka] where x is independently selected from 0, 1, 2, 3 and 4. For the avoidance of doubt, throughout this specification, x R 14 The group may be attached to either ring of the naphthyl group.

[0085] R 4 may have the structure: [ka] (In the formula, R 12a are independently H or C 1 -C 4 -alkyl; and x2 is independently selected from 0, 1, 2 and 3. For the avoidance of doubt, throughout this specification, x2 R 14 The R group may be attached to either ring of the naphthyl group. 12a may be H.

[0086] R 4 has the following structure: [ka] may have:

[0087] R 4 is 1 to 4 R 14 R may be a 5-, 6-, 9- or 10-membered monocyclic or bicyclic heteroaryl optionally substituted with a group. 4 is 1 to 4 R 14 The ring may be a 9- or 10-membered bicyclic heteroaryl optionally substituted with a group.

[0088] R 5 may be H. 5 is C 1 -C 4 -alkyl, for example methyl.

[0089] R 6 may be H. 6 is C 1 -C 4 -alkyl, for example methyl.

[0090] R 7 H and C 1 -C 4 -alkyl. 7 may be H. 7 is C 1 -C 4 -alkyl, for example methyl.

[0091] R 8 H and C 1 -C 4 -alkyl. 8 may be H. 8 is C 1 -C 4 -alkyl, for example methyl.

[0092] R 9 is oxo, fluoro, cyano, NR 12 R 13 , OR 12 , C 1 -C 4 -Alkyl, NR 12 R 13 C replaced with 1 -C 4 -Alkyl, OR 12 C replaced with 1 -C 4 -Alkyl and cyano substituted C 1 -C 4 -alkyl. 9is oxo, fluoro, NR 12 R 13 , OR 12 , C 1 -C 4 -Alkyl, NR 12 R 13 C replaced with 1 -C 4 -Alkyl and OR 12 C replaced with 1 -C 4 -alkyl.

[0093] R 9 is oxo, halo, cyano, NR 12 R 13 (However, R 12 But it's R, not H. 13 is not H), OR 12 , CO 2 R 12 ,CONR 12 R 12 , C 1 -C 4 -Alkyl, NR 12 R 13 C replaced with 1 -C 4 -alkyl (where R 12 But it's R, not H. 13 is not H), OR 12 C replaced with 1 -C 4 -Alkyl, cyano substituted C 1 -C 4 -Alkyl, C 2 -C 4 -Alkenyl, C 2 -C 4 -Alkynyl, C 1 -C 4 -haloalkyl and cyclopropyl.

[0094] R 10 is oxo, halo, cyano, NR 12 R 13 , OR 12 , CO 2 R 12 ,CONR12 R 12 , C 1 -C 4 -Alkyl, NR 12 R 13 C replaced with 1 -C 4 -Alkyl, OR 12 C replaced with 1 -C 4 -Alkyl, cyano substituted C 1 -C 4 -Alkyl, C 2 -C 4 -Alkenyl, C 2 -C 4 -Alkynyl, C 1 -C 4 -haloalkyl and cyclopropyl.

[0095] R 10 is oxo, fluoro, NR 12 R 13 , OR 12 , C 1 -C 4 -Alkyl, NR 12 R 13 C replaced with 1 -C 4 -Alkyl and OR 12 C replaced with 1 -C 4 -alkyl.

[0096] R 11 are halo, cyano, nitro, NR 12 R 13 , OR 12 , C 1 -C 4 -Alkyl, NR 12 R 13 C replaced with 1 -C 4 -Alkyl, OR 12 C replaced with 1 -C 4 -Alkyl, C 1 -C 4 -haloalkyl and cyclopropyl.11 OR 12 , C 1 -C 4 -Alkyl, C 1 -C 4 -haloalkyl and cyclopropyl.

[0097] R 12 H and C 1 -C 4 -alkyl.

[0098] R 13 H and C 1 -C 4 -alkyl.

[0099] R 14 are halo, cyano, nitro, NR 12 R 13 , OR 12 , C 1 -C 4 -Alkyl, NR 12 R 13 C replaced with 1 -C 4 -Alkyl, OR 12 C replaced with 1 -C 4 -Alkyl, C 1 -C 4 -haloalkyl and cyclopropyl. 14 OR 12 , C 1 -C 4 -Alkyl, C 1 -C 4 -haloalkyl and cyclopropyl.

[0100] The compound of formula (I) may be [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] may be selected from:

[0101] The compound of formula (I) is [ka] may be also possible.

[0102] The compounds of formula (I) are [ka] may be also possible.

[0103] The compound of formula (I) is [ka] may be also possible.

[0104] The present invention also encompasses the subject matter of the following items: 1. Formula (I): [ka] [In the formula, Z 1 -O- and -NR 5 - independently selected; Z 2 is independently absent or -O- and -NR 6 - Selected from; R 1 is C 0 -C 3 -Alkylene-R 1a and C 2 -C 6 -Alkylene-R 1b are independently selected from; where R 1a is a 4- to 7-membered heterocycloalkyl ring and NR 7 R 8 C substituted with a group 3 -C 7 -cycloalkyl ring; said heterocycloalkyl ring or said cycloalkyl ring optionally contains 1 to 4 R 9 may be substituted with a group; R 1b is NR 7 R 8 , OR 8 , S.R. 8 , SOR 8 , S.O. 2 R 8 and SO(NH)R 8 are independently selected from; or R 1 and R 5 Together with the nitrogen to which they are attached, they form 1-4 R 9 a monocyclic 4- to 7-membered heterocycloalkyl group optionally substituted with a group; and 1 to 4 R 9 forming a ring system selected from fused, spiro-fused or bridged bicyclic 6- to 11-membered heterocycloalkyl groups, optionally substituted with a group; R 2 is independently 1 -C 6 -Alkyl, C 1 -C 4 -Haloalkyl, C 0 -C 4 -Alkylene-R 2a , C 1 -C 4 -Alkylene-R 2b , C 2 -C 4 -Alkylene-R 2c and; R 2a are monocyclic 4- to 7-membered heterocycloalkyl groups; fused, spiro-fused or bridged bicyclic 6- to 11-membered heterocycloalkyl groups; 5-, 6-, 9- or 10-membered monocyclic or bicyclic heteroaryl groups; phenyl; and C 3 -C 7 -cycloalkyl; where R is any heterocycloalkyl or cycloalkyl. 2a The group is 1 to 6 R 10 R is optionally substituted with any heteroaryl or phenyl group; 2a The group is 1 to 6 R 11 optionally substituted with a group; R 2b CONR 12 R 12 and CO 2 R 12 are independently selected from; R 2c is NR 12 R 13 and OR 12 are independently selected from; or R 2 and R 6 together with the nitrogen to which they are attached form a ring system selected from monocyclic 4- to 7-membered heterocycloalkyl groups; and fused, spiro-fused or bridged bicyclic 6- to 11-membered heterocycloalkyl groups; said heterocycloalkyl groups being selected from 1 to 6 R 10 optionally substituted with a group; R3a , R 3b and R 3c H, halo, C 1 -C 4 -Alkyl, OC 1 -C 4 -Alkyl, C 1 -C 4 -Haloalkyl, OC 1 -C 4 - each independently selected from haloalkyl, cyclopropyl, nitro and cyano; R 4 is phenyl (wherein the phenyl is optionally C 5 -C 7 -cycloalkyl ring); naphthyl; and 5-, 6-, 9- or 10-membered monocyclic or bicyclic heteroaryl, where R 4 optionally, 1 to 4 R 14 optionally substituted with a group; R 5 , R 6 , R 8 and R 12 are each independently H, C 1 -C 4 -haloalkyl and C 1 -C 4 - alkyl; R 7 and R 13 are each independently H, C 1 -C 4 -Alkyl, C 1 -C 4 -haloalkyl and C(O)-C 1 -C 4 - alkyl; R 9 and R 10 each independently represents oxo, halo, cyano, NR 12 R 13 , OR 12 , CO 2 R 12 ,CONR 12 R 12 , C 1 -C 4 -Alkyl, NR 12 R13 C replaced with 1 -C 4 -Alkyl, OR 12 C replaced with 1 -C 4 -Alkyl, cyano substituted C 1 -C 4 -Alkyl, C 2 -C 4 -Alkenyl, C 2 -C 4 -Alkynyl, C 1 -C 4 - selected from haloalkyl and cyclopropyl; R 11 and R 14 are each independently halo, cyano, nitro, NR 12 R 13 , OR 12 , CO 2 R 12 ,CONR 12 R 12 , C 1 -C 4 -Alkyl, NR 12 R 13 C replaced with 1 -C 4 -Alkyl, OR 12 C replaced with 1 -C 4 -Alkyl, C 2 -C 4 -Alkenyl, C 2 -C 4 -Alkynyl, C 1 -C 4 - selected from haloalkyl and cyclopropyl; Any of the alkyl, alkylene or cyclopropyl groups may each independently be selected from the group consisting of C, where chemically possible. 1 -C 4 -Alkyl, halo, nitro, cyano, NR a R b , OR a , S.R. a , CO 2 R a , C(O)R a and CONR a R awherein R is optionally substituted with 1 to 5 substituents selected from the group consisting of a are each independently H, C 1 -C 4 -Alkyl and C 1 -C 4 -haloalkyl; and R b are each independently H, C 1 -C 4 -Alkyl, C(O)-C 1 -C 4 -Alkyl and S(O) 2 -C 1 -C 4 -alkyl] or a pharma- ceutically acceptable salt thereof. 2. Z 1 But -NR 5 The compound of item 1, 3. Z 2 The compound of item 1 or 2, wherein is -O-. 4. R 1 But, C 0 -C 3 -Alkylene-R 1a (In the formula, R 1a is a 4- to 7-membered heterocycloalkyl ring; and NR 7 R 8 C substituted with a group 3 -C 7 -cycloalkyl ring; said heterocycloalkyl ring or said cycloalkyl ring optionally contains 1 to 4 R 9 The compound according to any one of items 1 to 3, wherein the R 1 -R 2 -R 3 ... 5. R 1 and R 5 Together with the nitrogen to which they are attached, they form 1-4 R 9 a monocyclic 4- to 7-membered heterocycloalkyl group optionally substituted with a group; and 1 to 4 R 9 4. The compound according to any one of items 1 to 3, which forms a ring system selected from fused or spiro-fused bicyclic 6- to 11-membered heterocycloalkyl groups, optionally substituted with a group. 6. R1 and R 5 together with the nitrogen to which they are attached form the following structure: [ka] (In the formula, R 9a is NR 12 R 13 and N.R. 12 R 13 C replaced with 1 -C 4 -alkyl; p1 is selected from 0, 1, 2 and 3; q1 is selected from 0, 1 and 2; and r1 is selected from 0, 1, 2 and 3). The compound according to item 5, which forms a ring system having the formula: 7. R 1 and R 5 together with the nitrogen to which they are attached form the following structure: [ka] (In the formula, Z 6 is NR 9b , O, S, S(O) 2 , independently selected from S(O) and S(O)(NH); R 9b H and C 1 -C 4 -alkyl; p2 is selected from 2 and 3, q2 is 2; and r2 is selected from 0, 1, 2 and 3). The compound according to item 5, which forms a ring system having the formula: 8. R 1 and R 5 together with the nitrogen to which they are attached form the following structure: [ka] (In the formula, R 9b H and C 1 -C 4-alkyl; p3, p4, q3 and q4 are each independently selected from 0, 1, 2 and 3; provided that the total number of p3, p4, q3 and q4 is 3 to 8; the total number of p3 and q3 is 2 or greater; the total number of p4 and q4 is 2 or greater; and r3 is selected from 0, 1, 2 and 3). The compound according to item 5, which forms a ring system having the formula: 9. R 1 and R 5 together with the nitrogen to which they are attached form the following structure: [ka] (In the formula, R 9b H and C 1 -C 4 -alkyl; p5, p6, q5 and q5 are each selected from 0, 1, 2 and 3; provided that the total number of p3, p4, q3 and q4 is 2 to 7; the total number of p5 and q5 is 1 or more; the total number of p6 and q6 is 1 or more; and r5 is selected from 0, 1, 2 and 3). The compound according to item 5, which forms a ring system having the formula: 10. R 1 and R 5 Together with the nitrogen to which they are attached, they form 1-4 R 9 6. The compound according to item 5, wherein the compound forms a bridged bicyclic 6- to 11-membered heterocycloalkyl group, which may be optionally substituted with a group. 11. R 2 has the following structure: [ka] (In the formula, R 15 , H, C 1 -C 4 -alkyl; where R 16 , H, C 1 -C 4 -alkyl and cyclopropyl; or R 15 and R 16together with the nitrogen to which they are attached, one or two R 10 and y is independently selected from 0, 1, 2, 3, and 4. The compound according to any one of items 1 to 10, having the formula: 12. R 2 has the following structure: [ka] wherein z is independently selected from 0, 1, 2, 3, and 4; z may be selected from 0 and 1; z may be 0; z may be 1. Item 12. The compound according to item 11, having the formula: 13. R 3b is F. 14. R 3a and R 3c and n is H. 15. R 4 is phenyl, said phenyl optionally being C 5 -C 7 -cycloalkyl ring, R 4 optionally, 1 to 4 R 14 15. The compound according to any one of items 1 to 14, which may be substituted with a group. 16. R 4 has the following structure: [ka] wherein x is independently selected from 0, 1, 2, 3 and 4. 15. The compound according to any one of items 1 to 14, having the formula: 17. R 4 has the following structure: [ka] (In the formula, R12a are independently H or C 1 -C 4 -alkyl; and x2 is independently selected from 0, 1, 2 and 3. Item 17. The compound according to item 16, having the formula: 18. R 4 However, 1 to 4 R 14 15. The compound according to any one of items 1 to 14, which is a 5-, 6-, 9- or 10-membered monocyclic or bicyclic heteroaryl optionally substituted with a group. 19. A compound according to any one of items 1 to 18 for medical use. 20. A compound according to any one of items 1 to 18 for use in the treatment of cancer. 21. The compound for use according to item 20, wherein the cancer is selected from pancreatic cancer, colorectal cancer, rectal cancer, uterine cancer, non-small cell lung cancer, gastric cancer, ovarian cancer and small cell lung cancer. 22. The compound for use according to item 20 or 21, wherein the subject to be treated is suffering from a cancer having a KRAS G12D mutation. 23. A pharmaceutical composition comprising a compound according to any one of items 1 to 18 and a pharma- ceutical acceptable excipient.

[0105] In an aspect of the invention there is provided a compound of the invention for use as a medicament.

[0106] According to another aspect, the present invention provides a method for treating a condition that can be regulated by inhibition of a KRAS protein having a G12D mutation, said method comprising administering to a subject in need of treatment a therapeutically effective amount of a compound of the present invention.

[0107] According to another aspect, the present invention provides a pharmaceutical formulation comprising a compound of the present invention and a pharma- ceutically acceptable excipient.

[0108] In embodiments, the pharmaceutical composition may be a combination pharmaceutical comprising another pharma- ceutical active agent, which may be, for example, an anti-inflammatory agent, an anti-fibrotic agent, a chemotherapeutic agent, an anti-cancer agent, an immunosuppressant, an anti-tumor vaccine, a cytokine therapeutic agent, or a tyrosine kinase inhibitor.

[0109] In one aspect of the invention there is provided a compound of the invention for use in the treatment of cancer.

[0110] In one aspect of the invention, a method of treating cancer is provided, said method comprising administering to a subject in need of treatment a therapeutically effective amount of a compound of the invention.

[0111] In one aspect of the invention, there is provided a use of a compound of the invention for the manufacture of a medicament for treating cancer.

[0112] The cancer may be a solid or liquid tumor. The cancer may be a carcinoma.

[0113] The cancer may be selected from cervical cancer, uterine cancer, multiple myeloma, gastric cancer, bladder cancer, uterine cancer, esophageal squamous cell carcinoma, gastric cancer, glioblastoma, astrocytoma, retinoblastoma, osteosarcoma, chondrosarcoma, Ewing's sarcoma, rabies sarcoma, Wilm's tumor, basal cell carcinoma, non-retinoblastoma, osteosarcoma, chondrosarcoma, Ewing's sarcoma, rabies sarcoma, Wilm's tumor, basal cell carcinoma, non-small cell lung cancer, brain tumor, hormone refractory prostate cancer, prostate cancer, metastatic breast cancer, breast cancer, metastatic pancreatic cancer, pancreatic cancer, colorectal cancer, head and neck squamous cell carcinoma, head and neck cancer, appendix cancer, bile duct cancer, cancer of unknown primary site, ampulla of Vater cancer, ovarian cancer, acute myeloid leukemia, small cell lung cancer, germ cell tumor, small intestine cancer, malignant melanoma, soft tissue sarcoma, gastrointestinal stromal tumor, thyroid cancer, gastrointestinal neuroendocrine tumor, renal cell carcinoma, and histiocytosis.

[0114] The cancer may be selected from pancreatic cancer, colorectal cancer, colon cancer, endometrial cancer, non-small cell lung cancer, gastric cancer, ovarian cancer and small cell lung cancer.

[0115] The cancer may have wild type KRAS. The cancer may have KRAS mutation. The cancer may have KRAS mutation selected from KRAS G12D, KRAS G12C, KRAS G12V, KRAS G12A, KRAS G12S, KRAS G13D and KRAS Q61H. The cancer may have KRAS G12D mutation. The cancer may have KRAS G12D mutation, and the cancer is selected from pancreatic cancer, colorectal cancer, rectal cancer, endometrial cancer, non-small cell lung cancer, gastric cancer, ovarian cancer and small cell lung cancer.

[0116] The cancer may have a confirmed KRAS G12D mutation. The cancer may have a confirmed KRAS G12D mutation, and the cancer is selected from pancreatic cancer, colorectal cancer, rectal cancer, endometrial cancer, non-small cell lung cancer, gastric cancer, ovarian cancer, and small cell lung cancer.

[0117] The subject may be a human.

[0118] The subject may be suffering from a cancer with KRAS G12D mutation.The subject may have a cancer with KRAS G12D mutation, and the cancer is selected from pancreatic cancer, colorectal cancer, colon cancer, endometrial cancer, non-small cell lung cancer, gastric cancer, ovarian cancer and small cell lung cancer.

[0119] The subject may have a cancer with a confirmed KRAS G12D mutation.The subject may have a cancer with a confirmed KRAS G12D mutation, and the cancer is selected from pancreatic cancer, colorectal cancer, rectal cancer, endometrial cancer, non-small cell lung cancer, gastric cancer, ovarian cancer and small cell lung cancer.

[0120] The subject may have a confirmed G12D mutation in the tumor. To be confirmed, the test for the presence of G12D in the tumor must have an analytical specificity of more than 95% for detecting the mutation in the KRAS gene. Such validation detection tests include the tests already available on the market, namely Foundation One CDx and CARIS DNA sequencing.

[0121] As mentioned above, the present invention includes a method of treating cancer, the method comprising the steps of: a) identifying a subject as having a cancer with a G12D mutation; and b) administering to a subject in need of treatment a therapeutically effective amount of a compound of the invention.

[0122] The term "halo" refers to one of the halogens of Group 17 of the periodic table. Specifically, the term refers to fluorine, chlorine, bromine and iodine. Preferably, the term refers to fluorine or chlorine.

[0123] The term "alkyl" refers to a straight or branched hydrocarbon chain. For example, the term "C 1-6 Alkyl" or "C 1-4 "-Alkyl" refers to a straight or branched hydrocarbon chain containing 1, 2, 3, 4, 5 or 6 carbon atoms, such as, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl. 0-4When referred to as alkyl, it should be understood that this represents the possibility of no alkyl units or a length of 1, 2, 3 or 4 carbon atoms. Alkylene groups may similarly be linear or branched and may have two points of attachment to the remainder of the molecule. Furthermore, the alkylene group may correspond, for example, to one of the alkyl groups listed in this paragraph. The alkyl and alkylene groups may be unsubstituted or substituted with one or more substituents. Possible substituents are described below. Substituents for the alkyl groups include halogens, such as fluorine, chlorine, bromine and iodine, OH, C ... 1-6 It may be an alkoxy.

[0124] The term "alkoxy" refers to an alkyl group that is attached to a molecule through an oxygen. For example, the term "C 1-6 "Alkoxy" refers to an alkyl group attached to a molecule via an oxygen. It includes groups in which the alkyl portion may be linear or branched and may contain 1, 2, 3, 4, 5 or 6 carbon atoms, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl. Thus, alkoxy groups may be methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy and n-hexoxy. The alkyl portion of an alkoxy group may be unsubstituted or substituted with one or more substituents. Possible substituents are described below. Substituents for the alkyl group include halogens, such as fluorine, chlorine, bromine and iodine, OH, C, C, C-C ... 1-6 Examples of such radicals include alkoxy.

[0125] The term "haloalkyl" refers to a hydrocarbon chain substituted with at least one halogen atom, each independently selected, such as fluorine, chlorine, bromine, and iodine. For example, the term "C 1-6"Haloalkyl" refers to a straight or branched hydrocarbon chain containing 1, 2, 3, 4, 5, or 6 carbon atoms substituted with at least one halogen. The halogen atom may be located at any position on the hydrocarbon chain. For example, C 1-6 Haloalkyl refers to chloromethyl, fluoromethyl, trifluoromethyl, chloroethyl (e.g., 1-chloromethyl and 2-chloroethyl), trichloroethyl (e.g., 1,2,2-trichloroethyl, 2,2,2-trichloroethyl), fluoroethyl (e.g., 1-fluoromethyl and 2-fluoroethyl), trifluoroethyl (e.g., 1,2,2-trifluoroethyl and 2,2,2-trifluoroethyl), chloropropyl, trichloropropyl, fluoropropyl, trifluoropropyl.

[0126] The term "alkenyl" refers to a branched or straight-chain hydrocarbon chain containing at least one double bond. For example, "C 2-6 The term "alkenyl" refers to a branched or straight hydrocarbon chain containing at least one double bond and having 2, 3, 4, 5 or 6 carbon atoms. The double bond may be present as an E or Z isomer. The double bond may be in any possible position of the hydrocarbon chain. For example, "C 2-6 "Alkenyl" may be ethenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl and hexadienyl.

[0127] The term "alkynyl" refers to a branched or straight-chain hydrocarbon chain containing at least one triple bond. For example, 2-6 The term "alkynyl" refers to a branched or straight hydrocarbon chain containing at least one triple bond and having 2, 3, 4, 5 or 6 carbon atoms. The triple bond may be located at any available position on the hydrocarbon chain. For example, "C 2-6 "Alkynyl" may be ethynyl, propynyl, butynyl, pentynyl and hexynyl.

[0128] The term "heteroalkyl" refers to a branched or straight-chained hydrocarbon chain that contains at least one heteroatom selected from N, O, and S located between the carbons in the chain or at the end of the chain. For example, "C 1-6 The term "heteroalkyl" refers to a branched or straight-chained hydrocarbon chain containing 1, 2, 3, 4, 5, or 6 carbon atoms and at least one heteroatom selected from N, O, and S located between the carbons in the chain or at the end of the chain. For example, the hydrocarbon chain can contain 1 or 2 heteroatoms. 1-6 A heteroalkyl can be attached to the remainder of the molecule through a carbon or heteroatom. For example, "C 1-6 Heteroalkyl" is C 1-6 N-alkyl, C 1-6 N,N-alkyl or C 1-6 It can be an O-alkyl of the formula:

[0129] The term "cycloalkyl" refers to a saturated hydrocarbon ring system. 3-8 "Cycloalkyl" may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

[0130] The term "cycloalkenyl" refers to an unsaturated hydrocarbon ring system that is not aromatic. The ring may contain multiple double bonds, as long as the ring system is not aromatic. For example, "C 3-8 "Cycloalkyl" can be cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadiene, cyclooctenyl and cycloatadienyl.

[0131] The term "heterocycloalkyl" refers to a saturated hydrocarbon ring system containing carbon atoms and at least one heteroatom selected from N, O and S in the ring. For example, there may be 1, 2 or 3, optionally 1 or 2, heteroatoms. A "heterocycloalkyl" can be bonded to the remainder of the molecule via a carbon atom or a heteroatom. A "heterocycloalkyl" can have one or more, for example 1 or 2, bonds to the remainder of the molecule, and these bonds can be through any atom in the ring. For example, a "heterocycloalkyl" can be a "C 3-8 Heterocycloalkyl may also be used. 3-8 The term "heterocycloalkyl" refers to a saturated hydrocarbon ring system containing 3, 4, 5, 6, 7, or 8 carbon atoms and at least one heteroatom in the ring selected from N, O, and S. For example, there may be 1, 2, or 3 heteroatoms, optionally 1 or 2. 3-8 The "heterocycloalkyl" may be optionally attached to the remainder of the molecule through a carbon atom or a heteroatom. 3-8 A "heterocycloalkyl" may have one or more, e.g., one or two, bonds to the rest of the molecule; these bonds may be through any atom within the ring. For example, "C 3-8 Heterocycloalkyl" can be oxirane, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine and tetrahydropyran.

[0132] The term "heterocycloalkenyl" refers to a non-aromatic unsaturated hydrocarbon ring system containing carbon atoms and at least one heteroatom selected from N, O and S in the ring. For example, there can be 1, 2 or 3, optionally 1 or 2 heteroatoms. A "heterocycloalkenyl" can be bonded to the rest of the molecule through a carbon atom or a heteroatom. A "heterocycloalkenyl" can have one or more, for example 1 or 2, bonds to the rest of the molecule, and these bonds can be through any atom in the ring. For example, a "heterocycloalkenyl" can be a "heterocycloalkenyl" that is ... 3-8 "C" may be "heterocycloalkenyl". 3-8 The term "heterocycloalkenyl" refers to a saturated hydrocarbon ring system containing 3, 4, 5, 6, 7, or 8 atoms, in which at least one of the atoms in the ring is a heteroatom selected from N, O, and S. A "heterocycloalkenyl" can be tetrahydropyridine, dihydropyran, dihydrofuran, pyrroline.

[0133] The term "fused" refers to a bicyclic ring system in which two rings are joined through two atoms located adjacent to each other on each ring.

[0134] The term "spirofused" refers to a bicyclic ring system in which the two rings are joined through one atom.

[0135] The term "bridged" refers to a bicyclic ring system in which two rings are joined through two atoms that are not located adjacent to each other on either ring.

[0136] The term "aromatic" when applied to a substituent as a whole means a monocyclic or polycyclic ring system having 4n+2 electrons in a pi-conjugated system within the ring or ring system, with all atoms contributing to the pi-conjugated system lying in the same plane.

[0137] The term "aryl" refers to an aromatic hydrocarbon ring system. The ring system has 4n+2 electrons in a pi-conjugated system within the ring, with all atoms contributing to the pi-conjugated system lying in the same plane. For example, "aryl" can be phenyl and naphthyl. The aryl system can itself be substituted with other groups.

[0138] The term "heteroaryl" refers to an aromatic hydrocarbon ring system having at least one heteroatom selected from O, N and S in a single ring or in a fused ring system. The ring or ring system has 4n+2 electrons in a pi-conjugated system, and all atoms contributing to the pi-conjugated system are in the same plane. For example, a "heteroaryl" can be imidazole, thien, furan, thianthrene, pyrrole, benzimidazole, pyrazole, pyrazine, pyridine, pyrimidine and indole.

[0139] The term "halogen" as used herein means F, Cl, Br and I. The halogen may be Br. The halogen may be I.

[0140] [ka] A bond ending in represents that the bond is connected to another atom not shown in the structure. A bond that terminates within a ring structure and does not terminate at an atom of the ring structure represents that the bond may be connected to any atom of the ring structure if allowed by valences.

[0141] When a moiety is substituted, the substitution may be made at any position on the moiety that is chemically feasible and meets the valence requirements. The moiety may be substituted with one or more substituents, for example, 1, 2, 3 or 4 substituents, and optionally, there may be 1 or 2 substituents on a group. When there are more than one substituent, the substituents may be the same or different.

[0142] Substituents are present only at positions where they are chemically possible, and one skilled in the art can determine (experimentally or theoretically) whether a substitution is chemically possible or not without undue effort.

[0143] Ortho, meta and para substitution are terms well understood in the art. For the avoidance of doubt, "ortho" substitution is a substitution pattern in which adjacent carbons bear substituents, and is consistent with a simple group, such as the fluoro group in the following example: [ka] ,or [ka] The other portion of the molecule is indicated by a bond ending in .

[0144] A "meta" substitution is a substitution pattern in which two substituents are on carbons one carbon removed from each other, i.e., there is one carbon atom between the substituted carbons. In other words, the substituents are on the atom that is the second most distant from the atom with another substituent. For example, the following group is meta substituted: [ka]

[0145] "Para" substitution is a substitution pattern in which two substituents are on carbons two carbons removed from each other, i.e., there are two carbon atoms between the substituted carbons. In other words, the substituents are on the atom that is the third most distant from the atom with another substituent. For example, the following group is para substituted: [ka]

[0146] Throughout this specification, the disclosure of a compound also includes its pharma- ceutically acceptable salts, solvates, and stereoisomers. When a compound has a stereocenter, both the (R) and (S) stereoisomers are contemplated by the present invention, and mixtures of equal amounts of stereoisomers or racemic mixtures are encompassed by the present application. When a compound of the present invention has more than one stereocenter, any combination of the (R) and (S) stereoisomers is contemplated. The combination of the (R) and (S) stereoisomers may be a diastereomeric mixture or a single diastereomer. The compounds of the present invention may exist as a single stereoisomer, or may be a mixture of stereoisomers, such as a racemic mixture and other enantiomeric mixtures, as well as diastereomeric mixtures. When the mixture is a mixture of enantiomers, the enantiomeric excess may be any of those disclosed above. When the compound is a single stereoisomer, the compound may contain the other diastereomer or enantiomer as an impurity. Thus, a single stereoisomer need not necessarily have 100% enantiomeric excess (ee) or diastereomeric excess (de), but may have an ee or de of about 85% or more, about 60% or more, or less. For example, the ee or de may be 90% or more, 90% or more, 80% or more, 70% or more, 60% or more, 50% or more, 40% or more, 30% or more, 20% or more, or 10% or more.

[0147] The present invention contemplates pharma- ceutically acceptable salts of the compounds of the present invention. These may include acid addition salts and base salts of the compounds. These may be acid addition salts and base salts of the compounds. In addition, the present invention contemplates solvates of the compounds. These may be hydrates or other solvated forms of the compounds.

[0148] Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include acetate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronic acid, hexafluorophosphate, hybenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 1,5-naphthalenedisulfonate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, saccharate, stearate, succinate, tartrate, tosylate and trifluoroacetate.

[0149] Suitable base salts are formed from bases that form non-toxic salts. For example, aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine, and zinc salts are included. Hemisalts of acids and bases may also be formed, such as hemisulfate and hemicalcium salts. For a review of suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0150] Pharmaceutically acceptable salts of compounds of formula (I) can be prepared in three ways: (i) by reacting a compound of the invention with a desired acid or base; (ii) by removing an acid- or base-labile protecting group from a suitable precursor of a compound of the invention, or by ring-opening a suitable cyclic precursor, such as a lactone or lactam, with a desired acid or base; or (iii) by converting one salt of a compound of the invention into another salt by reaction with an appropriate acid or base or by means of a suitable ion exchange column; The composition may be produced by one or more of the following methods:

[0151] All three reactions are typically carried out in solution. The resulting salts are either precipitated and collected by filtration or recovered by evaporation of the solvent. The degree of ionization in the resulting salts may vary from completely ionized to almost non-ionized.

[0152] The compound of the present invention can exist in both nonsolvate and solvate form.The term "solvate" is used herein to refer to the molecular complex that comprises the compound of the present invention and one or more stoichiometric amounts of pharmaceutically acceptable solvent molecules, such as ethanol.The term "hydrate" is used when said solvent is water.

[0153] The scope of the present invention includes complexes such as clathrates, drug-host inclusion complexes, where, in contrast to the aforementioned solvates, the drug and host are present in stoichiometric or non-stoichiometric amounts. Also included are complexes of drugs that contain two or more organic and / or inorganic components, which may be in stoichiometric or non-stoichiometric amounts. The resulting complexes may be ionized, partially ionized, or non-ionized. For a review of such complexes, see J Pharm Sci, 64 (8), 1269-1288 by Haleblian (August 1975).

[0154] Hereinafter all references to compounds of any formula include references to salts, solvates and complexes thereof, as well as to solvates and complexes of salts thereof.

[0155] The compounds of the present invention include compounds of the various formulas defined herein, including all of their polymorphs and crystal habits, their prodrugs and isomers (including optical, geometric and tautomeric isomers) as defined below, and isotopically labeled compounds of the present invention.

[0156] The present invention also includes all pharma- ceutically acceptable isotopically labeled compounds of the present invention, in which one or more atoms are replaced by an atom having the same atomic number, but an atomic mass or mass number different from the most commonly found atomic mass or mass number in nature.

[0157] Suitable isotopes contained in the compounds of the present invention include, for example, 2 H and 3 Hydrogen isotopes such as H, 11 C. 13 C and 14 Carbon isotopes such as C, 36 Isotopes of chlorine such as Cl, 18 Fluorine isotopes such as F, 123 I and 125 Iodine isotopes such as I 13 N and 15 Nitrogen isotopes such as N 15 O. 17 O and 18 Oxygen isotopes such as O 32 Isotopes of phosphorus such as P 35 Examples include isotopes of sulfur such as S.

[0158] Certain isotopically labeled compounds, for example those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotope tritium, i.e. 3 H, and carbon 14, i.e. 14 C are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.

[0159] Deuterium, i.e. 2Substitution with heavier isotopes, such as H, may offer certain therapeutic advantages resulting from greater metabolic stability, such as increased half-life in vivo or reduced dosage requirements, and therefore may be preferable in some circumstances.

[0160] Before purification, the compounds of the present invention may exist as a mixture of enantiomers depending on the synthesis method used. Enantiomers can be separated by conventional techniques known in the art. Thus, the present invention includes individual enantiomers and their mixtures.

[0161] For some steps of the process for preparing the compounds of the present invention, it may be necessary to protect potentially reactive functional groups that are not to be reacted, and then to cleave said protecting groups. In such cases, compatible protecting groups can be used. In particular, the methods of protection and deprotection can be used, for example, those by TW GREENE (Protective Groups in Organic Synthesis, A. Wiley- Interscience Publication, 1981) or PJ K?ienski (Protecting groups, Georg Thieme Verlag, 1994). All the above reactions, and the preparation of new starting materials used in the above processes, are conventional, and the appropriate reagents and reaction conditions for their implementation or preparation, as well as the methods for isolating the desired products, will be well recognized by those skilled in the art, with reference to the prior art, the examples and preparations herein.

[0162] Additionally, the compounds of the present invention and intermediates therefor can be purified according to various well-known methods, such as, for example, crystallization or chromatography.

[0163] One or more of the compounds of the present invention may be combined with one or more agents (e.g., anti-inflammatory agents, anti-fibrotic agents, chemotherapeutic agents, anti-cancer agents, immunosuppressants, anti-tumor vaccines, cytokine therapy agents or tyrosine kinase inhibitors) for the treatment of diseases modulated by inhibition of RAS proteins (e.g., cancer, sarcoma, malignant melanoma, skin cancer, hematological tumors, lymphoma, carcinoma, and leukemia).

[0164] The compounds for the therapeutic method or use in the treatment of cancer, sarcoma, malignant melanoma, skin cancer, hematological tumors, lymphoma, carcinoma and leukemia as defined herein above may be applied as monotherapy or in combination therapy with additional active agents.

[0165] The therapeutic method or compound for use in the treatment of cancer, sarcoma, malignant melanoma, skin cancer, blood tumors, lymphoma, carcinoma and leukemia may include an additional active agent in addition to the compound of the present invention. The additional active agent may be one or more active agents used to treat the condition treated by the compound of the present invention and the additional active agent. The additional active agent may include one or more of the following active agents: (i) Steroids: For example, corticosteroids such as glucocorticoids and mineralocorticoids, for example, aclomethasone, aclomethasone dipropionate, aldosterone, ancinonide, beclomethasone, beclomethasone dipropionate, betamethasone dipropionate, betamethasone sodium phosphate, betamethasone valerate, budesonide, clobetasone, clobetasone butyrate, clobetasol propionate, cloprednol, cortisone, cortisone acetate, cortivazol, deoxycortone, desonide, desoximethasone, dexamethasone, dexamethasone sodium phosphate, dexamethasone isonicotinate, difluorocortolone, fluclorolone, flumethasone, flunisolide, fluocinolone, fluocinolone acetonide, fluocinonide, fluocinonide, rutin butyl, fluorocortisone, fluorocortolone, fluocortolone caproate, fluocortolone pivalate, fluorometholone, fluprednidene, fluprednidene acetate, flurandrenolone, fluticasone, fluticasone propionate, halcinonide, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone aceponate, hydrocortisone buteprate, hydrocortisone valerate, icomethasone, icomethasone embutate, meprednisone, methylprednisolone, mometasone, paramethasone, mometasone furoate monohydrate, prednicarbate, prednisolone, prednisone, tixocortol, tixocortol pivalate, triamcinolone, triamcinolone acetonide, triamcinolone alcohol, and pharma- ceutical acceptable derivatives thereof. Combinations of steroids may also be used, for example, combinations of two or more of the steroids mentioned in this paragraph; (ii) TNF inhibitors: e.g., etanercept; monoclonal antibodies (e.g., infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia), golimumab (Simponi)); fusion proteins (e.g., etanercept (Enbrel)); and 5-HT 2Aagonists (e.g., 2,5-dimethoxy-4-iodoamphetamine, TCB-2, lysergic acid diethylamide (LSD), lysergic acid dimethylazetidide); (iii) Anti-inflammatory drugs: e.g., non-steroidal anti-inflammatory drugs; (iv) Dihydrofolate reductase inhibitors / antifolates: e.g., methotrexate, trimethoprim, brodimoprim, tetroxoprim, iclaprim, pemetrexed, ralitrexed and pralatrexate; and (v) Immunosuppressants: for example, cyclosporine, tacrolimus, sirolimus, pimecrolimus, angiotensin II inhibitors (e.g., valsartan, telmisartan, losartan, irbesatan, azilsartan, olmesartan, candesartan, eprosartan) and ACE inhibitors, such as sulfhydryl-containing agents (e.g., captopril, zofenopril), dicarboxylate-containing agents (e.g., enalapril, ramipril, quinapril, perindopril, lisinopril, benazepril, imidapril, zofenopril, trandolapril), phosphate-containing agents (e.g., fosinopril), casokinins, lactokines, lactotripeptides. (vi) Antifibrotic agents: for example, pirfenidone, nintedanib, anti-IL-13 monoclonal antibodies (e.g., tralokinumab, QAX576, lebrikizumab), simtuzumab, FG-3019, lysophosphatidic acid receptor antagonists (e.g., BMS-986020, AM966), LOXL2 inhibitors, BET bromodomain inhibitors (e.g., JQ1), HDAC inhibitors (e.g., vorinostat), thrombin inhibitors (e.g., dabigatran), factor Xa inhibitors (e.g., apixaban, rivaroxaban), 15PGDH inhibitors, anti-αvβ6 monoclonal antibodies (e.g., BG00011), anti-CTGF monoclonal antibodies (e.g., FG-3019), PAR1 inhibitors, Nox4 inhibitors and PAI-1 inhibitors. (vii) CNS therapeutics: for example: levodopa, dopamine agonists, apomorphine, glutamate antagonists, anticholinergics, COMT inhibitors, MAO-B inhibitors, riluzole (Rilutek), tetrabenazine (Xenazine), haloperidol (Haldol), chlorpromazine, risperidone (Risperdal), quetiapine (Seroquel), amantadine, levetiracetam (Keppra), clonazepam (Klonopin), donepezil (Aliplex), Ceptor), galantamine (Razadyne), rivastigmine (Exelon), memantine (Ebixa, Axula), aducanumab, ocrelizumab, interferon beta-1a (Avonex, Rebif), peginterferon beta-1a (Pregridy), teriflunomide (Aubagio), fingolimod (Gilenya), mitoxantrone (Novantrone), dimethyl fumarate (Tecfidera), and natalizumab (Tysabri).

[0166] Methods of treating or compounds for treating cancer, sarcoma, malignant melanoma, skin cancer, hematological tumors, lymphoma, carcinoma, leukemia and central nervous system disorders may include, in addition to the compounds of the present invention, conventional surgery or radiation therapy or chemotherapy. Such chemotherapy may include one or more of the following categories of anti-tumor agents: (i) Antiproliferative / Antineoplastic Agents and Combinations thereof: For example, alkylating agents (e.g., cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, uracil mustard, bendamustine, melphalan, chlorambucil, chlormethine, busulfan, temozolamide, nitrosoureas, ifosamide, melphalan, pipobroman, triethylene-melamine, triethylenethiophosphoramine, carmustine, lomustine, stroptozocin, and dacarbazine; antimetabolites (e.g., gemcitabine, and folate antagonists, e.g., fluoropyrimidines such as 5-fluorouracil and tegafur, raltitrexed, methotrexate, pemetrexed, cytosine arabinoside, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatin, gemcitabine, and hydroxyurea); antibiotics (e.g., adriamycin, bleomycin, doxorubicin, daunomycin, ethambutol, anthracyclines, such as pirubicin, idarubicin, mitomycin-C, dactinomycin, and mithramycin; mitotic inhibitors (e.g., vinca alkaloids, such as vincristine, vinblastine, vindesine, and vinorelbine, and taxoids, such as taxol and taxotere, and polo kinase inhibitors); proteasome inhibitors, such as carfilzomib and bortezomib; interferon therapeutics; and topoisomerase inhibitors (e.g., etoposide, epipodophyllotoxins such as tetanusside and teniposide, amsacrine, topotecan, mitoxantrone and camptothecin; bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, ara-C, paclitaxel (Taxol™), nab-paclitaxel, docetaxel, mithramycin, deoxycoformycin, mitomycin-C, L-asparaginase, interferons (especially IFN-a), etoposide and teniposide; (ii) Cytostatics: for example, antiestrogens (e.g., tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene, iodoxyfene), antiandrogens (e.g., bicalutamide, flutamide, nilutamide, and cyproterone acetate), LHRH antagonists or agonists (e.g., goserelin, leuprorelin, buserelin), progestogens (e.g., megestrol acetate), aromatase inhibitors (e.g., anastrozole, letrozole, borazole, and exemestane), and 5α-reductase inhibitors, such as finasteride; navelbene, CPT-II, anastrazole, letrazole, capecitabine, reloxafume, cyclophosphamide, ifosamide, and droloxafine; (iii) anti-invasive agents: for example, dasatinib and bosutinib (SKI-606), as well as metalloprotease inhibitors, inhibitors of urokinase-type plasminogen activator receptor function, or antibodies against heparanase; (iv) Growth factor function inhibitors: For example, such inhibitors include growth factor antibodies and growth factor receptor antibodies, such as the anti-erbB2 antibody trastuzumab [Herceptin®], the anti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab, tyrosine kinase inhibitors, such as inhibitors of the epidermal growth factor family (e.g., EGFR family tyrosine kinase inhibitors, such as gefitinib, erlotinib, 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine (CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib), antibodies against costimulatory molecules such as CTLA-4, 4-IBB and PD-1, or antibodies against cytokines (IL-I0, TGF-β); inhibitors of the hepatocyte growth factor family; inhibitors of the insulin growth factor family; modulators of protein regulators of cell apoptosis (e.g. Bcl-2 inhibitors); inhibitors of the platelet-derived growth factor family such as imatinib and / or nilotinib (AMN107); inhibitors of serine / threonine kinases (e.g. farnesinib, tyrosine kinase inhibitors, e.g. Ras / Raf signaling inhibitors such as sorafenib, tipifarnib and lonafarnib), inhibitors of cell signaling via MEK and / or AKT kinases, c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1R kinase inhibitors, IGF receptor kinase inhibitors; cyclin dependent kinase inhibitors such as Aurora kinase inhibitors and CDK2 and / or CDK4 inhibitors; and CCR2, CCR4 or CCR6 modulators; (v) Antiangiogenic agents: for example, those that inhibit the action of vascular endothelial growth factor, such as the anti-vascular endothelial growth factor antibody bevacizumab (Avastin™); thalidomide; lenalidomide; and VEGF receptor tyrosine kinase inhibitors, such as vandetanib, vatalanib, sunitinib, axitinib, and pazopanib; (vi) gene therapy approaches: for example, approaches that replace abnormal genes such as p53 abnormalities or BRCA1 or BRCA2 abnormalities; (vii) Immunotherapeutic approaches: for example, antibody therapies such as alemtuzumab, rituximab, ibritumomab, uxetan (Zevalin™) and ofatumumab; interferons such as interferon alpha; interleukins such as IL-2 (aldesleukin); interleukin inhibitors, for example, IRAK4 inhibitors; cancer vaccines, including prophylactic and therapeutic vaccines such as HPV vaccines, for example, Gardasil, Cervarix, Oncophage and Sipuleucel-T (Provenge); gp100; dendritic cell-based vaccines (such as Ad.p53 DC); Toll-like receptor modulators, for example, TLR-7 or TLR-9 agonists; and (viii) Cytotoxic drugs: for example, fludaribine (Fludara), cladribine, pentostatin (Nipent™); (ix) Steroids: For example, corticosteroids such as glucocorticoids and mineralocorticoids, for example, aclomethasone, aclomethasone dipropionate, aldosterone, amcinonide, beclomethasone, beclomethasone dipropionate, betamethasone dipropionate, betamethasone sodium phosphate, betamethasone valerate, budesonide, clobetasone, clobetasone butyrate, clobetasol propionate, cloprednol, cortisone, cortisone acetate, cortivazol, deoxycortone, desonide, desoxymethasone, dexamethasone, dexamethasone sodium phosphate, dexamethasone isonicotinate, difluorocortolone, fluclorolone, flumethasone, flunisolide, fluocinolone, fluocinolone acetonide, fluocinonide, fluocinonide, rutin butyl, fluorocortisone, fluorocortolone, fluocortolone caproate, fluocortolone pivalate, fluorometholone, fluprednidene, fluprednidene acetate, flurandrenolone, fluticasone, fluticasone propionate, halcinonide, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone aceponate, hydrocortisone buteprate, hydrocortisone valerate, icomethasone, icomethasone embutate, meprednisone, methylprednisolone, mometasone, paramethasone, mometasone furoate monohydrate, prednicarbate, prednisolone, prednisone, tixocortol, tixocortol pivalate, triamcinolone, triamcinolone acetonide, triamcinolone alcohol, and pharma- ceutical acceptable derivatives thereof. Combinations of steroids may also be used, for example, combinations of two or more of the steroids mentioned in this paragraph; (x) Targeted therapeutics: for example, PI3Kd inhibitors, such as idelalisib and perifosine; PD-1, PD-L1, PD-L2 and CTL4-A modulators, antibodies and vaccines; other IDO inhibitors (such as indoximod); anti-PD-1 monoclonal antibodies (such as MK-3475 and nivolumab); anti-PD-L1 monoclonal antibodies (such as MEDI-4736 and RG-7446); anti-PD-L2 monoclonal antibodies; and anti-CTLA-4 antibodies (such as ipilimumab); (xii) Chimeric antigen receptors, anticancer vaccines and arginase inhibitors.

[0167] Such combination therapy may be accomplished by simultaneous, sequential or separate administration of the individual therapeutic components. Such combinations employ the compounds of this invention within the therapeutically effective dosage ranges described herein and the other pharmacologic active agent(s) within their approved dosage ranges.

[0168] The compounds of the present invention may exist in a single crystal form or a mixture of crystal forms, or they may be amorphous.Therefore, the compounds of the present invention intended for pharmaceutical use may be administered as crystalline or amorphous products.They may be obtained as solid plugs, powders or films by methods such as precipitation, crystallization, freeze-drying, spray-drying or evaporative drying.For this purpose, microwave or radio frequency drying may be used.

[0169] For the above compounds of the present invention, the dosage administered will of course vary depending on the compound used, the administration method, the therapeutic purpose and the applicable disease.For example, when the compound of the present invention is administered orally, the daily dosage of the compound of the present invention can range from 0.01 microgram per kilogram of body weight (μg / kg) to 100 milligram per kilogram of body weight (mg / kg).

[0170] The compound of the present invention or its pharmaceutically acceptable salt may be used by itself, but is usually administered in the form of a pharmaceutical composition in which the compound of the present invention or its pharmaceutically acceptable salt is combined with a pharmaceutically acceptable auxiliary, diluent or carrier. Conventional techniques for the selection and preparation of suitable pharmaceutical preparations are described, for example, in "Pharmaceuticals - The Science of Dosage Form Designs", ME Aulton, Churchill Livingstone, 1988.

[0171] Depending on the method of administration of the compound of the present invention, the pharmaceutical composition used to administer the compound of the present invention preferably contains 0.05 to 99 wt % of the compound of the present invention, more preferably 0.05 to 80 wt % of the compound of the present invention, even more preferably 0.10 to 70 wt % of the compound of the present invention, and even more preferably 0.10 to 50 wt % of the compound of the present invention, all weight percentages being based on the total weight of the composition.

[0172] The pharmaceutical compositions can be administered topically (e.g., to the skin), for example, in the form of creams, gels, lotions, solutions, suspensions, or systemically, for example, by oral administration, for example, in the form of tablets, capsules, syrups, powders or granules; or parenterally, in the form of sterile solutions, suspensions or emulsions for injection (such as intravenous, subcutaneous, intramuscular, intravascular or infusion); rectally, in the form of a suppository; or by inhalation in the form of an aerosol.

[0173] For oral administration, the compounds of the present invention may be mixed with auxiliary agents or carriers such as lactose, saccharose, sorbitol, mannitol; starches such as potato starch, corn starch or amylopectin; cellulose derivatives; binders such as gelatin or polyvinylpyrrolidone; and / or lubricants such as magnesium stearate, calcium stearate, polyethylene glycol, wax, paraffin, etc., and compressed into tablets. If coated tablets are required, the cores prepared as described above may be coated with a concentrated sugar solution that may contain, for example, gum arabic, gelatin, talcum and titanium dioxide. Alternatively, the tablets may be coated with a suitable polymer dissolved in a readily volatile organic solvent.

[0174] For the preparation of soft gelatin capsules, the compound of the present invention may be mixed with, for example, vegetable oil or polyethylene glycol. Hard gelatin capsules may contain granules of the compound using any of the excipients for tablets mentioned above. Liquid or semi-solid preparations of the compound of the present invention may also be filled into hard gelatin capsules. Liquid preparations for oral administration may be in the form of syrups or suspensions, for example, solutions containing the compound of the present invention and, as the balance, sugar, and a mixture of ethanol, water, glycerol and propylene glycol. Optionally, such liquid preparations may contain coloring agents, flavoring agents, sweetening agents (such as saccharin), carboxymethylcellulose as a preservative and / or thickening agent, or other excipients known to those skilled in the art.

[0175] For intravenous (parenteral) administration, the compounds of the present invention may be administered in the form of a sterile aqueous or oily solution.

[0176] The size of a dose of the compounds of the invention for therapeutic purposes will naturally vary according to the nature and severity of the disease, the age and sex of the animal or patient and the route of administration, in accordance with well-known principles of medicine.

[0177] Dosage levels, frequency of administration and duration of treatment of the compounds of the invention will, of course, vary depending on the formulation and the clinical indications, age and co-morbidities of the patient.

[0178] Throughout the description and claims, the words "comprise" and "contain" and variations thereof mean "including, but not limited to," and are not intended to (and do not) exclude other moieties, additives, ingredients, integers, or steps. Throughout the description and claims, the singular encompasses the plural, unless the context dictates otherwise. In particular, where the indefinite article is used, the specification is understood to contemplate the plural as well as the singular, unless the context dictates otherwise.

[0179] It is to be understood that features, integers, properties, compounds, chemical moieties or groups described in connection with a particular aspect, embodiment or example of the invention are applicable to other aspects, embodiments or examples described herein, unless incompatible. All features and / or steps of the disclosed methods or processes disclosed herein (including the accompanying claims, abstract and drawings) may be combined in any combination, except at least some combinations in which such features and / or steps are mutually exclusive. The invention is not limited to the details of the foregoing embodiments. The invention extends to any novel feature or combination of novel features of the features disclosed herein (including the accompanying claims, abstract and drawings) or to any novel or combination of steps of the disclosed methods or processes.

[0180] The reader's attention is directed to all articles and documents filed contemporaneously or previously hereto in connection with this application and publicly disclosed herein, the contents of all such articles and documents being incorporated herein by reference. EXAMPLES

[0181] The following terms are used herein with the following meanings: "Boc" means tert-butoxycarbonyl; "Cbz" means carboxybenzyl; "dba" means dibenzylideneacetone; "DCM" means dichloromethane; "DIPEA" means N,N-diisopropylethylamine; "DMA" means dimethylacetamide; "DMF" means N,N-dimethylformamide; "DMSO" means dimethylsulfoxide; "dppf" means 1,1'-bis(diphenylphosphino)ferrocene; "EtOAc" means ethyl acetate; "EtOH" means ethanol; "Et 2 "O" means diethyl ether; "IPA" means isopropyl alcohol; "LiHMDS" means lithium bis(trimethylsilyl)amide; "mCPBA" means meta-chloroperbenzoic acid; "MeCN" means acetonitrile; "MeOH" means methanol; "min" means minute; "NMR" means nuclear magnetic resonance; "PhMe" means toluene; "pTsOH" means p-toluenesulfonic acid; "py" means pyridine; "rt" means room temperature; "SCX" means strong cation exchange resin; "T3P" means propylphosphonic anhydride; "Tf 2 "O" means trifluoromethanesulfonic anhydride; "THF" means tetrahydrofuran; "THP" means 2-tetrahydropyranyl; "(UP)LC-MS" means (high performance) liquid chromatography / mass spectrometry.

[0182] Solvents, reagents and starting materials were commercially available and used as received unless otherwise indicated. All reactions were performed at room temperature unless otherwise indicated. Compound identity and purity were confirmed by LCMS UV using a Waters Acquity SQ Detector 2 (ACQ-SQD2#LCA081). The wavelength of the diode array detector was 254 nm and the MS was in positive and negative electrospray mode (m / z: 150-800). Aliquots of 2 μl were sequentially injected into a guard column (0.2 μm x 2 mm filter) and a UPLC column (C18, 50 x 2.1 mm, <2 μm) maintained at 40°C. Samples were eluted at a flow rate of 0.6 mL / min using a mobile phase system consisting of A (0.1% (v / v) formic acid in water) and B (0.1% (v / v) formic acid in acetonitrile) according to the gradient outlined in Table 1 below. Retention times RT are reported in minutes. The following methods were also used where described in the experimental section and the gradients are listed in Table 1. For method 3, a Shimadzu 2020 series spectrometer equipped with a binary pump and a diode array detector (capture wavelengths 214 nm and 254 nm) was used and MS was performed in positive and negative electrospray mode (m / z: 100-900). Aliquots of 2 μL were injected onto an Agilent Poroshell 120 EC-C18 column (2.7 μm, 4.6 × 50 mm) maintained at 35 °C and eluted at 1.0 ml / min with the following mobile phases: A: 0.05% formic acid in water (v / v) and B: 0.05% formic acid in ACN (v / v). For method 4, an Agilent Technologies 1290 series spectrometer equipped with a binary pump and a diode array detector (capture wavelengths 214 nm and 254 nm) was used, and MS was performed in positive electrospray mode (m / z: 70-1000). Aliquots of 2 μL were injected onto an Agilent Eclipse Plus RRHD C18, (1.8 μm, 3.0 × 50 mm) column, held at 40 °C and eluted at 0.8 ml / min: A: 0.05% formic acid / water (v / v) and B: 0.05% formic acid / ACN (v / v). [Table 1]

[0183] NMR was also used to characterize the final compounds. NMR spectra were obtained using a Bruker AVIII 400 Nanobay with a 5 mm BBFO probe. Where appropriate, Rf values ​​of compounds were measured on silica thin layer chromatography (TLC) plates.

[0184] Purification of compounds was performed by flash column chromatography on silica or preparative LCMS. LCMS purification was performed using a Waters 3100 mass detector and a Waters 2489 UV / Vis detector in positive and negative electrospray mode (m / z: 150-800). Samples were eluted using an XBridgeTM prep C18 5μM OBD 19x100mm column with a mobile phase system containing A (0.1% (v / v) formic acid in water) and B (0.1% (v / v) formic acid in acetonitrile) at a flow rate of 20mL / min according to the gradient outlined in Table 2 below. [Table 2]

[0185] General reaction scheme Certain compounds of the invention can be prepared using the following general reaction schemes: Certain compounds of the invention can be prepared according to or analogously to the synthetic examples described below.

[0186] [ka] Compounds described by formula (I) can be prepared according to Scheme 1. In step A, compound 1, where X represents a suitable leaving group such as a halogen or sulfonate ester, is reacted with a suitable nucleophile HZ. 1 R 1Then, in step C, the appropriate boronic acid or R 4 Cross-coupling reaction with esters of R, e.g., using the Suzuki reaction 4 Under basic or acidic conditions, the appropriate HZ 2 R 2 In step C, Z is obtained by nucleophilic displacement of the chloride with a reagent. 2 R 2 Step D may or may not be necessary, and step D may include R 4 , Z 1 R 1 and Z 2 R 2 Alternatively, as depicted in Scheme 2, prior to the nucleophilic substitution steps (A and B), R 4 can also be introduced to obtain compound 5. Compound 4 can be produced in the same manner as in Scheme 1, via steps A and B, and then, if necessary, via deprotection step C.

[0187] [ka] Certain example compounds were prepared according to Scheme 3 starting from commercially available compound 7. Step D involved the introduction of the methoxymethyl protecting group and Z in intermediate 12. 1 R 1 This was necessary as a final step to remove any acid labile protecting groups present on the substituents.

[0188] [ka]

[0189] Intermediate 12: 2-[3-(methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] Step A, 3-(methoxymethoxy)naphthalene: To a suspension of 4-bromonaphthalen-2-ol (3 g, 13.45 mmol) and N,N-diisopropylethylamine (7.03 mL, 40.35 mmol) in DCM (30 mL) was added chloromethyl methyl ether (1.53 mL, 20.17 mmol) at 0° C. The resulting mixture was stirred for 30 min. The reaction mixture was diluted with distilled water and extracted with DCM (x2), the combined organics were washed with brine (x2) and concentrated with Na 2 SO 4 The mixture was dried over ice, filtered and the filtrate was evaporated in vacuo to give a red / pink oil which was purified by flash column chromatography (40 g SiO 2 , dry loaded with DCM). The desired fractions were combined and evaporated in vacuo to give a pink oil which was analyzed as 1-bromo-3-(methoxymethoxy)naphthalene (3.2 g, 11.9 mmol, 89% yield). UPLC-MS (ES + , short acidic): 2.06 min, m / z 266.9, 268.9 [M+H] + 1 H NMR (400MHz, CDCl 3 ) δ / ppm:8.19-8.15 (1H, m), 7.77-7.73 (1H, m), 7.60 (1H, d, J = 2.4Hz), 7.53-7.46 (2H, m), 7.42-7.40 (1H, m), 5.31 (2H, s), 3.55 (3H, s).

[0190] Step B, 2-[3-(methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane: To a nitrogen purged suspension of 1-bromo-3-(methoxymethoxy)naphthalene (5.2 g, 19.4 mmol), bis(pinacolato)diboron (9.9 g, 38.9 mmol) and potassium acetate (6.7 g, 68 mmol) in toluene (50 mL) was added [1,1'bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.4 g, 1.9 mmol). The mixture was stirred at 110° C. for 2.5 h. The reaction mixture was filtered over Celite, washed with EtOAc and the filtrate evaporated in vacuo to give a black oil. This was taken up in distilled water and EtOAc and extracted with water (x2) along with EtOAc and the combined organics were washed with brine and sodium chloride. 2 SO 4 The extract was dried over ice, filtered and evaporated in vacuo to give a black oil which was purified by flash column chromatography (40 g SiO 2 ) eluting with 0-20% EtOAc / petroleum ether. 2 The crude product was purified by elution with hexane (dry loaded with DCM) and the desired fractions were combined and evaporated in vacuo to give a waxy, colourless residue which was analysed as 2-[3-(methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6 g, 98% yield). UPLC-MS (ES + , short acidic): 2.16 min, m / z 315 [M+H] + 1 H NMR (400MHz, D 6 -DMSO) δ / ppm:8.56-8.59 (1H, d, J=7.1Hz), 7.86-7.89 (1H, d, J=7.1Hz), 7.63-7.65 (1H, d, J=2.4Hz), 7.58-7.60 (1H, d, J=2.4Hz), 7.40-7.50 (2H, m), 5.31 (2H, s), 3.55 (3H, s), 1.2 (s, 12H).

[0191] Intermediate 11: 1,2,3,5,6,7-Hexahydropyrrolidin-8-ylmethanol [ka] Step A: O1-tert-Butyl O2-methyl 2-(3-chloropropyl)pyrrolidine-1,2-dicarboxylate: A 1M solution of lithium bis(trimethylsilyl)amide (43.6 mL, 43.6 mmol) in THF was added to a solution of N-boc-proline methyl ester (10 g, 43.6 mmol) in THF (100 mL) at -78°C. The mixture was then stirred at that temperature for 30 min. 3-Chloropropyl iodide (5.6 mL, 52.3 mmol) was added and the reaction mixture was allowed to warm gradually to 0°C. After 2 h in an ice bath, TLC (3:1 petroleum ether: EtOAc) showed complete consumption of the starting material (I 2 (Visualized by .) The reaction mixture was quenched with a saturated solution of aqueous ammonium chloride (50 mL) and partitioned between ethyl acetate (100 mL) and water (50 mL). The organic layer was separated. The aqueous layer was extracted with ethyl acetate (100 mL) and the organic extracts were combined, washed with a saturated solution of brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a pale yellow oil analyzed as O1-tert-butyl O2-methyl 2-(3-chloropropyl)pyrrolidine-1,2-dicarboxylate (13 g, 42.5 mmol, 97% yield). 1 H NMR (400MHz, CDCl 3 ) δ / ppm:3.50-3.62 (4H, m), 3.35-3.45 (2H, m), 3.19-3.23 (1H, m), 2.11-2.20 m, 1H), 1.50-2.05 (m, 6H), 1.25-1.29 (9H, d).

[0192] Step B: Methyl 2-(3-chloropropyl)pyrrolidin-1-ium-2-carboxylate; 2,2,2-trifluoroacetate Trifluoroacetic acid (10 mL, 130.2 mmol) was added to a solution of O1-tert-butyl O2-methyl 2-(3-chloropropyl)pyrrolidine-1,2-dicarboxylate (13 g, 42.5 mmol) in DCM (22 mL). The resulting solution was stirred at room temperature overnight. All volatiles were removed under reduced pressure and the dark oil was redissolved in DCM and re-evaporated to remove TFA. The resulting dark oil was analyzed as methyl 2-(3-chloropropyl)pyrrolidin-1-ium-2-carboxylate; trifluoroacetate salt (19 g, 59.4 mmol, 140% yield). NMR indicated the product was the TFA salt with approximately 1 equivalent of TFA remaining and was used without further purification. 1 H NMR (400MHz, CDCl 3 ) δ / ppm:10.20-10.45 (1H, bs), 7.70-8-02 (1H, bs), 3.91 (s, 3H), 3.45-3.70 (m, 4H), 2.45-2.55 (1H, m), 2.26-2.31 (1H, m), 2.15-2.25 (3H, m), 1.95-2.04 (2H, m), 1.55-1.65 (1H, m).

[0193] Step C: Methyl 1,2,3,5,6,7-hexahydropyrrolidine-8-carboxylate: Potassium carbonate (27 g, 195.4 mmol) was added to a mixture of potassium iodide (1 g, 6.02 mmol) and methyl 2-(3-chloropropyl)pyrrolidin-1-ium-2-carboxylate; 2,2,2-trifluoroacetate (13.5 g, 42.2 mmol) in methanol (200 mL). The mixture was stirred at 35° C. for 90 min and then concentrated under reduced pressure. The reaction mixture was then partitioned between DCM (150 mL) and water (150 mL) layers. The organic layer was separated. The aqueous layer was extracted with DCM (100 mL). The organic extracts were combined, washed with brine (100 mL), dried (Na 2 SO 4), filtered and concentrated under reduced pressure to give methyl 1,2,3,5,6,7-hexahydropyrrolidine-8-carboxylate (6.5 g, 38.4 mmol, 91% yield) as a clear oil. 1 H NMR (400MHz, CDCl 3 ) δ / ppm:3.73 (3H, s), 3.12-3.20 (2H, m), 2.62-2.70 (2H, m), 2.25-2.31 (2H, m), 1.78-1.85 (4H, m), 1.62-1.74 (2H, m).

[0194] Step D: 1,2,3,5,6,7-Hexahydropyrrolidin-8-ylmethanol: At 0 °C, N 2 A 1M solution of lithium aluminum hydride (19.5 mL, 19.5 mmol) in THF was added dropwise under atmospheric pressure to a solution of methyl 1,2,3,5,6,7-hexahydropyrrolidine-8-carboxylate (1.1 g, 6.5 mmol) in THF (10 mL). The mixture was stirred at that temperature for 30 minutes. At a temperature of 0° C., maintaining an inert atmosphere and under vigorous stirring, water (0.7 mL) was added dropwise, followed by 15% aqueous NaOH (0.7 mL), and then water (2 mL) to quench the reaction. The mixture was stirred until the precipitated salts were dispersed in a free-moving suspension, warmed to room temperature, filtered, and the filter cake was washed with THF (2 x 10 mL). The filtrate was collected and concentrated under reduced pressure to give 1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethanol (1.0 g, 7.1 mmol, 100% yield) as a yellow oil. 1 H NMR (400MHz, CDCl 3 ) δ / ppm:3.75-3.79 (1H, m), 3.30 (2H, s), 2.98-3.03 (2H, m), 2.59-2.65 (2H, m), 1.51-1.92 (8H, m).

[0195] Intermediate 13: rac-[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methanol [ka] Process A : Ethyl 6-methylene-3-oxo-1,2,5,7-tetrahydropyrrolidine-8-carboxylate LiHMDS (1.34 L, 1.34 mol, 2.1 eq) was added dropwise to a solution of ethyl 5-oxo-2-pyrrolidinecarboxylate (100 g, 637 mmol, 1.0 eq) and 3-chloro-2-chloromethyl-1-propene (239 g, 1.91 mol, 3.0 eq) in THF (2000 mL) at -40°C. The mixture was allowed to warm to room temperature and stirred overnight. The mixture was cooled to -60°C, adjusted to pH 7 with 2M HCl, poured into water (10 L), extracted with EtOAc (2 L x 3), washed with brine (5 L) and concentrated with Na 2 SO 4 The filtered mixture was concentrated and purified on a silica gel column (5:1 petroleum ether / EtOAc to 3:1 petroleum ether / EtOAc) to give ethyl 6-methylene-3-oxo-1,2,5,7-tetrahydropyrrolidine-8-carboxylate (40 g, 30% yield) as a colorless oil. 1 H NMR (400MHz, CDCl 3 ) δ / ppm:5.01-5.06 (2H, d), 4.16-4.30 (3H, m), 3.69-3.73 (1H, d), 3.02-3.06 (1H, d), 2.30-2.75 (4H, m), 2.07-2.16 (1H, m), 1.23-1.27 (3H, t).

[0196] Process B :Ethyl 3,6-dioxo-1,2,5,7-tetrahydropyrrolidine-8-carboxylate To a solution of ethyl 6-methylene-3-oxo-1,2,5,7-tetrahydropyrrolidine-8-carboxylate (115.1 g, 550 mmol, 1.0 eq) in DCM (1 L) and MeOH (100 mL) at -78 °C, add O 2Then, ozone was bubbled through the solution while stirring at -78 °C until the solution turned blue. Then, O was bubbled through the solution while stirring at -78 °C for another 30 min at the same temperature. 2 was bubbled through the solution. Dimethylsulfide (68.35g, 1.1mol, 2.0eq) was added at -78°C and the solution was allowed to warm to room temperature and stirred overnight. The mixture was concentrated and purified on a silica gel column (5:1 petroleum ether / EtOAc to 3:1 petroleum ether / EtOAc) to give ethyl 3,6-dioxo-1,2,5,7-tetrahydropyrrolidine-8-carboxylate (108g, 93% yield) as a colorless oil. 1 H NMR (400MHz, CDCl 3 ) δ / ppm:4.20-4.24 (2H, q), 4.08-4.14 (1H, d), 3.52-3.56 (1H, d), 2.95-3.00 (2H, m), 2.81-2.86 (1H, m), 2.39-2.48 (2H, m), 2.19-2.24 (1H, m), 1.26-1.29 (3H, t).

[0197] Process C :rac-Ethyl (2S,8S)-2-hydroxy-5-oxo-2,3,6,7-tetrahydro-1H-pyrrolidine-8-carboxylate At 0 °C, NaBH 4 (5.81 g, 153 mmol, 0.3 eq) was added to a solution of ethyl 3,6-dioxo-1,2,5,7-tetrahydropyrrolidine-8-carboxylate (108 g, 512 mmol, 1.0 eq) in EtOH (550 mL) and stirred for 10 min. The mixture was diluted with aqueous NH 4 Cl (50 mL) was added and stirred for an additional 20 min at 0° C. The mixture was concentrated in vacuo and the crude product was purified on a silica gel column (30:1 DCM / MeOH) to give rac-ethyl (2S,8S)-2-hydroxy-5-oxo-2,3,6,7-tetrahydro-1H-pyrrolidine-8-carboxylate (88 g, 81% yield) as a yellow oil with a distinct stereoisomeric mixture. LC-MS (ES +, Method 4):0.40min, 214.10 [M+H] + .

[0198] Process D rac-Ethyl (2R,8S)-2-fluoro-5-oxo-2,3,6,7-tetrahydro-1H-pyrrolidine-8-carboxylate DAST (99.8 g, 619 mmol, 1.5 eq) was added dropwise to a solution of rac-ethyl (2S,8S)-2-hydroxy-5-oxo-2,3,6,7-tetrahydro-1H-pyrrolidine-8-carboxylate (88 g, 413 mmol, 1.0 eq) in DCM (1.5 L) at -78°C and stirred at room temperature overnight. The mixture was cooled to 0°C, then MeOH (60 mL) was added and diluted with brine (2000 mL). The phases were separated and the organics were washed with Na 2 SO 4 After drying, filtering and concentrating under reduced pressure, the crude product was purified on a silica gel column (8:1→5:1 petroleum ether / EtOAc) to give ethyl rac-(2R,8S)-2-fluoro-5-oxo-2,3,6,7-tetrahydro-1H-pyrrolidine-8-carboxylate (42 g, 47% yield) as a yellow oil. 1 H NMR (400MHz, CDCl 3 ) δ / ppm:5.21-5.36 (1H, d), 4.20-4.47 (3H, m), 3.19-3.41 (1H, dd), 2.10-2.60 (6H, m), 1.24-1.28 (3H, t).

[0199] Process E rac-(6R,8S)-6-Fluoro-8-(hydroxymethyl)-2,5,6,7-tetrahydro-1H-pyrrolidin-3-one At 0°C, LiBH 4(81 mL, 163 mmol, 1.0 eq) was added dropwise to ethyl (2R,8S)-2-fluoro-5-oxo-2,3,6,7-tetrahydro-1H-pyrrolidine-8-carboxylate (35 g, 163 mmol, 1.0 eq) in THF (350 mL) and stirred at room temperature for 2 h. The mixture was cooled to 0° C. and then diluted with NH 4 Aqueous Cl (100 mL) was added and stirred at 0° C. for 30 min. The mixture was concentrated and the crude product was purified on a silica gel column (30:1 DCM / MeOH) to give rac-(6R,8S)-6-fluoro-8-(hydroxymethyl)-2,5,6,7-tetrahydro-1H-pyrrolidin-3-one (28 g, 99% yield). 1 H NMR (400MHz, CDCl 3 ) δ / ppm:5.21-5.35 (1H, d), 4.05-4.16 (1H, m), 3.51-3.55 (1H, d), 3.42-3.46 (1H, d) 2.52-3.11 (3H, m), 1.94-2.41 (5H, m).

[0200] Process F rac-[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methanol At 0℃, BH 3 DMS (10M, 75.1mL, 751mmol, 5.0eq) was added dropwise to rac-(6R,8S)-6-fluoro-8-(hydroxymethyl)-2,5,6,7-tetrahydro-1H-pyrrolidin-3-one (26g, 150mmol,1.0eq) in THF (1300mL) and stirred at room temperature overnight. The mixture was cooled to 0°C, MeOH (300mL) was added and stirring was continued at 0°C for 1h. The mixture was concentrated and the crude product was dissolved in MeOH (300mL) and stirred at 50°C overnight. The mixture was concentrated to give rac-[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methanol (21g, 87.9% yield), intermediate 21, as a colorless oil. 1 H NMR (400MHz, CDCl 3) δ / ppm:5.11-525 (1H, d), 2.80-3.31 (6H, m), 1.74-2.11 (6H, m).

[0201] Intermediate 14: 4-[7-bromo-2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-8-methyl-quinazolin-4-yl]-1,4-oxazepane and Intermediate 15: 4-[2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-8-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl]-1,4-oxazepane [ka] Step A, 4-(7-bromo-2-chloro-8-methyl-quinazolin-4-yl)-1,4-oxazepane: To a solution of 7-bromo-2,4-dichloro-8-methylquinazoline (200 mg, 0.69 mmol) and [1,4]-oxazepane (139 mg, 1.37 mmol) in DCM (7 mL) at 0 °C was added n,n-diisopropylethylamine (0.6 mL, 3.43 mmol) and the mixture was stirred at 0 °C for 2 h. The reaction mixture was dry loaded onto silica and the crude product was purified by column chromatography eluting with 0-50% ethyl acetate / petroleum ether. The desired fractions were concentrated in vacuo to give 4-(7-bromo-2-chloro-8-methyl-quinazolin-4-yl)-1,4-oxazepane (206 mg, 0.58 mmol, 84% yield) as a white solid. UPLC-MS (ES + , short acidity): 2.22 min, m / z 358.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6) δ / ppm:7.88 (d, J=8.7 Hz, 1H), 7.64 (d, J=9.1 Hz, 1H), 4.04-4.00 (m, 4H), 3.88-3.86 (m, 2H), 3.72-3.69 (m ,2H), 2.62 (s, 3H), 2.07-2.01(m, 2H).

[0202] Step B, 4-[7-bromo-2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-8-methyl-quinazolin-4-yl]-1,4-oxazepane: Sodium hydride (69 mg, 1.73 mmol) dispersed 60% in mineral oil was added to 1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethanol (163 mg, 1.16 mmol) in dry THF (6 mL) under nitrogen at 0° C. and the reaction mixture was stirred at 0° C. for 30 min. 4-(7-Bromo-2-chloro-8-methyl-quinazolin-4-yl)-1,4-oxazepane (206 mg, 0.58 mmol) was added and the vial was sealed. The reaction mixture was heated to 60° C. and stirred overnight. Water (10 mL) was added and the reaction mixture was extracted with ethyl acetate (10 mL). The organics were washed with NaHCO 3 Wash with Na 2 SO 4 It was dried over water and concentrated in vacuo to give 4-[7-bromo-2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-8-methyl-quinazolin-4-yl]-1,4-oxazepane (245 mg, 0.53 mmol, 92% yield) as a pink solid. UPLC-MS (ES + , short acidic): 1.38 min, m / z 463.1 [M+H] + 1 H NMR (400 MHz, DMSO-d 6) δ / ppm:7.66 (d, J=9.0 Hz, 1H), 7.42 (d, J=9,1 Hz, 1H), 4.04 (s, 2H), 3.99-3.96 (m, 4H), 3.87-3.85 (m,2H), 3.71 (t, J=5.3 Hz, 2H), 2.96-2.91 (m, 2H), 2.61 (s, 3H), 2.57 -2.54 (m, 1H), 2.07-2.01 (m, 2H), 1.93-1.70 (m, 7H), 1.60-1.53 ​​(m, 2H).

[0203] Step C, 15 4-[2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-8-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl]-1,4-oxazepane To a degassed suspension of 4-[7-bromo-2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-8-methyl-quinazolin-4-yl]-1,4-oxazepane (500 mg, 1.08 mmol), bis(pinacolato)diboron (550. 37 mg, 2.17 mmol) and potassium acetate (372 mg, 3.79 mmol) in toluene (12 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium II (79.29 mg, 0.11 mmol). The mixture was stirred at 110°C for 2 h, then diluted with EtOAc and filtered. The filtrate was evaporated in vacuo to give an orange oil. The product was purified by flash column chromatography (KP Amino D 11g) eluting with 0-100% EtOAc / petroleum ether. The desired fractions were combined and concentrated in vacuo to give 4-[2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-8-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl]-1,4-oxazepane (380 mg, 69%) as a crude brown oil which was used without further purification. UPLC-MS (ES +, short acidity): 1.63 min, m / z 509.3 [M+H] +

[0204] Intermediate 16 [ka] 7-Bromo-2,4-dichloro-8-fluoro-quinazoline [ka] Step A, 2-amino-4-bromo-3-fluoro-benzamide To a solution of 2-amino-4-bromo-3-fluorobenzoic acid (7 g, 29.9 mmol) in DMF (70 mL), DIEA (38.6 g, 299.1 mmol), HATU (22.7 g, 59.824 mmol), NH 4 Cl (9.5 g, 179.472 mmol) was added. The mixture was stirred at room temperature for 2 h. The mixture was diluted with MTBE (1000 mL) and washed with 1 M hydrochloric acid (500 mL) and brine (500 mL), and then washed with Na 2 SO 4 After drying over and concentrating in vacuo, trituration with DCM afforded 2-amino-4-bromo-3-fluoro-benzamide (5g, 70%) as a pale red solid. UPLC-MS (ES + , Method 4): 1.2 min, m / z 233.0 and 235.0 [M+H] + 1 H NMR (400 MHz, DMSO-d 6 ) δ / ppm:7.91 (bs. 1H), 7.37-7.35 (m, 2H), 6.78-6.74 (m, 3H).

[0205] Step B, 7-bromo-8-fluoro-quinazoline-2,4-diol To a solution of 2-amino-4-bromo-3-fluorobenzamide (9 g, 38.6 mmol) in DMF (150 mL) was added NaH (3.86 g, 96 mmol, 60% in oil) at 0° C. and stirred for 30 min at 0° C. CDI (15.6 g, 96.5 mmol) was added and the mixture was stirred for 30 min at 60° C. The mixture was quenched with water, adjusted to pH 2 with 1 M hydrochloric acid, filtered and washed with water to give 7-bromo-8-fluoro-quinazoline-2,4-diol (11.5 g) as a pale yellow solid. UPLC-MS (ES + , Method 4): 1.0 min, m / z 256.9 and 259.0 [MH] + 1 H NMR (400 MHz, DMSO-d 6 ) δ / ppm:11.51 - 11.46 (m, 2H), 7.64 - 7.61 (m, 1H), 7.44-7.41 (m, 1H).

[0206] Step C, 7-bromo-2,4-dichloro-8-fluoro-quinazoline 7-Bromo-8-fluoro-quinazoline-2,4-diol (200 mg, 0.77 mmol), DIEA (499 mg, 3.86 mmol) and POCl 3 (2.1 g, 13.9 mmol) was stirred at 100° C. for 0.5 h. The reaction mixture was concentrated in vacuo and saturated NaHCO 3 The aqueous layer was extracted with DCM (5 ml) and washed with brine (2×10 ml). The organic layer was diluted with Na 2 SO 4 Drying on and concentration in vacuo afforded crude 7-bromo-2,4-dichloro-8-fluoro-quinazoline (188 mg, 82%) which was used without further purification. 1 H NMR (400 MHz, DMSO-d 6 ) δ / ppm:7.65 - 7.62 (m, 1H), 7.46 - 7.42 (m, 1H).

[0207] Example Compounds Example 1 [ka] 4-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-8-methyl-quinazolin-7-yl]naphthalen-2-ol [ka] Step A, tert-butyl 3-(7-bromo-2-chloro-8-methyl-quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate: A solution of tert-butyl 3-(7-bromo-2-chloro-8-methyl-quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (80 mg, 0.17 mmol) in NMP (1.5 mL) was added to 1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethanol (45 mg, 0.32 mmol). The reaction mixture was heated to 140° C. under microwave irradiation for 2 h. The mixture was partitioned between EtOAc and water and the layers were separated. The organic layer was washed with water (x3), NH 4 Cl (x2) and brine (x3), then dried (Na 2 SO 4 The solution was concentrated in vacuo to give tert-butyl 3-(7-bromo-2-chloro-8-methyl-quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate as a brown oil in quantitative yield. UPLC-MS (ES + , short acidic): 2.36 min, m / z 469.1 [M+H] + 1 H NMR (400 MHz, CDCl 3 ) δ / ppm:7.54-7.48 (m, 2H), 4.38-4.28 (m, 2H),3.68-3.47 (m, 2H), 3.11-2.97 (m. 1H), 2.75 (s, 3H), 2.53 -1.41 (m, 1H), 1.98-1.88 (m, 2H), 1.80-1.70 (m, 2H), 1.02 (s, 9H)

[0208] Step B, tert-butyl 3-[2-chloro-7-[3-(methoxymethoxy)-1-naphthyl]-8-methyl-quinazolin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate: A stirred solution of tert-butyl 3-(7-bromo-2-chloro-8-methyl-quinazolin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (145.03 mg, 0.3100 mmol), 2-[3-(methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (107 mg, 0.34 mmol) and cesium carbonate (202 mg, 0.62 mmol) in 1,4-dioxane (3 mL) and water (0.5 mL) was diluted with N 2 The mixture was degassed at rt for 10 min. Tris(dibenzylideneacetone)dipalladium(0) (28 mg, 0.0300 mmol) was added and the reaction mixture was stirred at 100 °C overnight. The reaction mixture was filtered through Celite and washed with MeOH. The product was purified by flash chromatography (12 g SiO 2 The crude product was purified by elution with 0-40% EtOAc / petroleum ether (0-40% EtOAc / petroleum ether). The desired fractions were concentrated in vacuo to give tert-butyl 3-[2-chloro-7-[3-(methoxymethoxy)-1-naphthyl]-8-methyl-quinazolin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (116 mg, 0.20 mmol, 65% yield) as a colorless oil. UPLC-MS (ES + , short acidic): 2.43 min, m / z 576.3 [M+H] 1 H NMR (400 MHz, CDCl 3) δ / ppm 7.83 (d, J=8.2 Hz, 1H), 7.75 (d, J=9.0 Hz, 1H), 7.49-7.44 (m, 2H), 7.32-7.29 (m, 2H), 7.25-7.24 (m, 1H), 7.10 (d, J=2.6 Hz, 1H), 5.36-5.32 (m, 2H), 4.48-4.43 (m, 2H), 3.56 (s, 3H), 2.38 (s, 3H), 2.01-1.85 (m, 4H), 1.52 (s, 9H), 1.32-1.24 (m, 4H).

[0209] Step C, tert-butyl 3-[2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-7-[3-(methoxymethoxy)-1-naphthyl]-8-methyl-quinazolin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate: To a stirred solution of 1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethanol (23 mg, 0.16 mmol) in THF (1 mL) at 0° C. was added sodium hydride (60% dispersion in mineral oil) (10 mg, 0.26 mmol). The solution was stirred at 0° C. for 30 min. The ice bath was removed and tert-butyl 3-[2-chloro-7-[3-(methoxymethoxy)-1-naphthyl]-8-methyl-quinazolin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (50 mg, 0.09 mmol) was added. The vial was sealed and heated to 60° C. for 4 h. The reaction mixture was cooled to room temperature, concentrated in vacuo, and partitioned between EtOAc and water. The layers were separated and the organic layer was washed with water (×3). The organics were passed through a phase separator and concentrated in vacuo to give tert-butyl 3-[2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-7-[3-(methoxymethoxy)-1-naphthyl]-8-methyl-quinazolin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (60 mg, 0.09 mmol, 100% yield) as an orange solid. UPLC-MS (ES +, short acidic): 1.95 min, m / z 680.8 [M+H] + (84%)

[0210] Step D, 4-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-8-methyl-quinazolin-7-yl]naphthalen-2-ol: Triethylsilane (0.11 mL, 0.69 mmol) was added to a solution of tert-butyl 3-[2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-7-[3-(methoxymethoxy)-1-naphthyl]-8-methyl-quinazolin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (47 mg, 0.07 mmol) in DCM (0.7 mL) at 0°C. Trifluoroacetic acid (1 mL, 13.75 mmol) was added and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure and dry loaded onto Celite. The product was purified by reverse phase chromatography (4 g C-18 silica, 15-100% MeCN in water) and the desired fractions were concentrated under vacuum. The product was further purified by SCX (1 g cartridge) eluting with MeOH (x2 volumes) followed by 1M NH 3 Elution with (x3 vol) / MeOH afforded 4-[4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-8-methyl-quinazolin-7-yl]naphthalen-2-ol (14 mg, 0.026 mmol, 38% yield) as a white solid. UPLC-MS (ES + , Long acidity): 2.48 min, m / z 536.4 [M+H] + 1 H NMR (400 MHz, DMSO-d 6) δ / ppm:9.89 (s, 1H), 7.85 (d, J=8.6 Hz, 1H), 7.78 (d, J=8.5 Hz, 1H), 7.44-7.38 (m, 1H), 7.21 (d, J=2.5 Hz, 1H), 7.19-7.17 (m, 2H), 7.10 (d, J=8.9 Hz, 1H), 6.95 (d, J=2.4 Hz, 1H), 4.24 (t, J=10.0 Hz, 2H), 4.05 (s, 2H), 3.50 (s, 2H), 3.43 (q, J=6.3 Hz, 2H), 2.94 (dq, J=5.3, 5.1 Hz, 2H), 2.17 (s, 3H), 1.96-1.89 (m, 3H), 1.85-1.72 (m, 6H), 1.70-1.64 (m, 2H), 1.62-1.54 (m, 3H).

[0211] Example 2 [ka] 4-[2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-8-methyl-4-(1,4-oxazepan-4-yl)quinazolin-7-yl]naphthalen-2-ol [ka] Step A, 4-(7-bromo-2-chloro-8-methyl-quinazolin-4-yl)-1,4-oxazepane: To a solution of 7-bromo-2,4-dichloro-8-methylquinazoline (200 mg, 0.69 mmol) and [1,4]-oxazepane (139 mg, 1.37 mmol) in DCM (7 mL) at 0° C., N,N-diisopropylethylamine (0.6 mL, 3.43 mmol) was added and the mixture was stirred at 0° C. for 2 h. The reaction mixture was dry loaded onto silica and the crude product was purified by column chromatography eluting with 0-50% ethyl acetate / petroleum ether. The desired fractions were concentrated in vacuo to give 4-(7-bromo-2-chloro-8-methyl-quinazolin-4-yl)-1,4-oxazepane (206 mg, 0.58 mmol, 84% yield) as a white solid. UPLC-MS (ES + , short acidity): 2.22 min, m / z 358.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ / ppm:7.88 (d, J=8.7 Hz, 1H), 7.64 (d, J=9.1 Hz, 1H), 4.04-4.00 (m, 4H), 3.88-3.86 (m, 2H), 3.72-3.69 (m ,2H), 2.62 (s, 3H), 2.07-2.01(m, 2H).

[0212] Step B, 4-[7-bromo-2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-8-methyl-quinazolin-4-yl]-1,4-oxazepane Sodium hydride (69 mg, 1.73 mmol) (60% dispersion in mineral oil) was added to 1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethanol (163 mg, 1.16 mmol) in dry THF (6 mL) under nitrogen at 0° C. and the reaction mixture was stirred at 0° C. for 30 min. 4-(7-Bromo-2-chloro-8-methyl-quinazolin-4-yl)-1,4-oxazepane (206 mg, 0.58 mmol) was added and the vial was sealed. The reaction mixture was heated to 60° C. and stirred overnight. Water (10 mL) was added and the reaction mixture was extracted with ethyl acetate (10 mL). The organics were washed with NaHCO 3 Wash with Na 2 SO 4 Drying over and concentration in vacuo afforded 4-[7-bromo-2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-8-methyl-quinazolin-4-yl]-1,4-oxazepane (245 mg, 0.53 mmol, 92% yield) as a pink solid. UPLC-MS (ES + , short acidic): 1.38 min, m / z 463.1 [M+H] + 1 H NMR (400 MHz, DMSO-d 6 ) δ / ppm:7.66 (d, J=9.0 Hz, 1H), 7.42 (d, J=9,1 Hz, 1H), 4.04 (s, 2H), 3.99-3.96 (m, 4H), 3.87-3.85 (m,2H), 3.71 (t, J=5.3 Hz, 2H), 2.96-2.91 (m, 2H), 2.61 (s, 3H), 2.57 -2.54 (m, 1H), 2.07-2.01 (m, 2H), 1.93-1.70 (m, 7H), 1.60-1.53 ​​(m, 2H).

[0213] Step C, 4-[2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-7-[3-(methoxymethoxy)-1-naphthyl]-8-methyl-quinazolin-4-yl]-1,4-oxazepane 4-[7-bromo-2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-8-methyl-quinazolin-4-yl]-1,4-oxazepane (245 mg, 0.53 mmol), Cs 2 CO 3 (519 mg, 1.59 mmol) and 2-(3-(2-methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (200 mg, 0.64 mmol) in 1,4-dioxane (3 mL) and water (1 mL) were degassed in a microwave vial for 30 min. [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium II (78 mg, 0.11 mmol) was added and the reaction mixture was stirred at 95 °C overnight. The mixture was concentrated in vacuo and the crude product was purified by elution with 70% ethyl acetate / petroleum ether followed by 0-12% 1N NH 3 Purification by column chromatography eluting with MeOH / DCM was performed. The desired fractions were concentrated in vacuo to give 4-[2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-7-[3-(methoxymethoxy)-1-naphthyl]-8-methyl-quinazolin-4-yl]-1,4-oxazepane (181 mg, 0.32 mmol, 60% yield) as a brown oil. UPLC-MS (ES + , short acidic): 1.49 min, m / z 569.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6) δ / ppm:7.92 (d, J=8.2 Hz, 1H), 7.88 (d, J=8.5 Hz, 1H), 7.55 (s, 1H), 7.51-7.48 (m, 1H), 7.24 (d, J=7.5 Hz, 1H), 7.20 (d, J=8.5 Hz, 1H), 7.14 (s, 1H), 5.39-5.35 (m, 2H), 4.10 (br s, 2H), 3.86-3.80 (m, 2H), 3.72-3.70 (m, 2H), 3.66-3.62 (m, 2H), 3.46 (s, 3H), 2.99-2.94 (m, 2H), 2.60-2.56 (m, 2H), 2.21 (s, 3H), 1.97-1.89 (m, 2H), 1.83-1.57 (m, 18H).

[0214] Step D, 4-[2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-8-methyl-4-(1,4-oxazepan-4-yl)quinazolin-7-yl]naphthalen-2-ol Triethylsilane (0.5 mL, 3.18 mmol) and 4-[2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-7-[3-(methoxymethoxy)-1-naphthyl]-8-methyl-quinazolin-4-yl]-1,4-oxazepane (181 mg, 0.32 mmol) were combined in DCM (3 mL) at 0 °C. Trifluoroacetic acid (2.4 mL, 31.83 mmol) was added and the reaction mixture was stirred at 25 °C for 1 h. The mixture was concentrated in vacuo. The crude product was purified by elution with 0-50% MeCN (containing 0.1% formic acid) / H 2 Purification was performed by reverse phase column chromatography eluting with 20 mL of MeOH. The desired fraction was taken up in a minimal amount of MeOH and loaded onto an SCX column. After passing MeOH (20 ml) through the column, the product was purified by 1M NH 3Rinsing with 100 ml / MeOH and concentration in vacuo afforded 4-[2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-8-methyl-4-(1,4-oxazepan-4-yl)quinazolin-7-yl]naphthalen-2-ol (110 mg, 0.21 mmol, 66% yield) as a white solid. UPLC-MS (ES + , Long acidity): 2.85 min, m / z 525.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ / ppm:9.90 (s, 1H), 7.95 (d, J=8.6 Hz, 1H), 7.79 (d, J=8.3 Hz, 1H), 7.43-7.39 (m, 1H), 7.21-7.18 (m, 3H), 7.10 (d, J=8.6 Hz, 1H), 6.95 (s, 1H), 4.07-4.04 (m, 6H), 3.92-3.90 (m, 2H), 3.77-3.74 (m, 2H), 2.97-2.92 (m, 2H), 2.58-2.56 (m, 1H), 2.18 (s, 3H), 2.12-2.06 (m, 2H), 1.96-1.90 (m, 2H), 1.85-1.73 (m, 4H), 1.61-1.55 (m, 2H) (2H, buried below the solvent peak).

[0215] Example 3 [ka] 4-[2-(1,2,3,5,6,7-Hexahydropyrrolidin-8-ylmethoxy)-8-methyl-4-thiomorpholino-quinazolin-7-yl]naphthalen-2-ol [ka] Step A, 4-(7-bromo-2-chloro-8-methyl-quinazolin-4-yl)thiomorpholine Thiomorpholine (0.14 mL, 1.37 mmol) was added to a stirred solution of 7-bromo-2,4-dichloro-8-methylquinazoline (200 mg, 0.69 mmol) in DCM (7 mL) at 0 °C and the reaction mixture was stirred at 0 °C for 3 h. The mixture was dry loaded onto silica and the product was purified by flash column chromatography eluting with 0-80% EtOAc / petroleum ether. The desired fractions were combined and concentrated under reduced pressure to give 4-(7-bromo-2-chloro-8-methyl-quinazolin-4-yl)thiomorpholine (220 mg, 0.61 mmol, 89% yield) as a pale yellow solid. UPLC-MS (ES + , short acidity): 2.28 min, m / z 360.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ / ppm:7.75-7.67 (m, 2H), 4.04-3.99 (m, 4H), 2.87-2.83 (m, 4H), 2.63 (s, 3H).

[0216] Step B, 4-[7-bromo-2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-8-methyl-quinazolin-4-yl]thiomorpholine Sodium hydride (74 mg, 1.84 mmol) (60% dispersed in mineral oil) was added to a stirred solution of tetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (173 mg, 1.23 mmol) in dry THF (6 mL) at 0° C. and the reaction mixture was stirred at 0° C. for 30 min. 4-(7-Bromo-2-chloro-8-methyl-quinazolin-4-yl)thiomorpholine (220 mg, 0.61 mmol) was added and the reaction mixture was heated to 60° C. and stirred overnight. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was taken up in a mixture of EtOAc (100 mL) and water (100 mL). The organic phase was collected and the aqueous phase was washed with EtOAc (3 x 100 mL). The combined organics were washed with water (100 mL) and saturated sodium bicarbonate (100 mL). The organic layer was diluted with Na2 SO 4 It was dried over, filtered and concentrated in vacuo to give 4-[7-bromo-2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-8-methyl-quinazolin-4-yl]thiomorpholine (275 mg, 0.59 mmol, 97% yield) as an amber solid. UPLC-MS (ES + , short acidic): 1.55 min, m / z 465.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ / ppm:7.62 (d, J = 9.0 Hz, 1H), 7.47 (d, J = 8.9 Hz, 1H), 4.05 (s, 2H), 3.93-3.88 (m, 4H), 2.97-2.90 (m, 2H), 2.86-2.80 (m, 4H), 2.62 (s, 3H), 1.94-1.69 (m, 7H), 1.61-1.52 (m, 2H), 0.89-0.71 (m, 2H).

[0217] Step C, 4-[2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-7-[3-(methoxymethoxy)-1-naphthyl]-8-methyl-quinazolin-4-yl]thiomorpholine 4-[7-bromo-2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-8-methyl-quinazolin-4-yl]thiomorpholine (78 mg, 0.17 mmol), 2-(3-(2-methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (79 mg, 0.25 mmol) and Cs in a mixture of 1,4-dioxane (1.3 mL) and water (0.4 mL). 2 CO 3A suspension of (110 mg, 0.34 mmol) was degassed with nitrogen for 15 min. [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (22 mg, 0.03 mmol) was added and the reaction mixture was heated to 95° C. and stirred for 2 h. The reaction mixture was cooled to room temperature and the solvent removed in vacuo. The residue was taken up in DCM and dry loaded onto silica. The product was purified by flash column chromatography on silica gel eluting with 0-60% (20% 1M ammonia / MeOH) in DCM. The desired fractions were combined and concentrated in vacuo to give 4-[2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-7-[3-(methoxymethoxy)-1-naphthyl]-8-methyl-quinazolin-4-yl]thiomorpholine (39 mg, 0.07 mmol, 41% yield) as a light brown solid. UPLC-MS (ES + , short acidic): 1.86 min, m / z 571.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ / ppm:7.92 (d, J = 8.3 Hz, 1H), 7.83 (d, J = 8.5 Hz, 1H), 7.54 (d, J = 2.4 Hz, 1H), 7.52-7.47 (m, 1H), 7.32-7.27 (m, 1H), 7.24-7.18 (m, 2H), 7.13 (d, J = 2.3 Hz, 1H), 5.40-5.34 (m, 2H),4.20 (br s, 2H), 4.03-3.94 (m, 4H), 3.46-3.45 (m, 3H), 3.21-2.95 (br s, 2H), 2.93-2.84 (m, 4H), 2.21 (s, 3H), 2.10-1.54 (m, 9H), 1.17 (d, J = 13.5 Hz, 1H).

[0218] Step D, 4-[2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-8-methyl-4-thiomorpholino-quinazolin-7-yl]naphthalen-2-ol To a solution of 4-[2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-7-[3-(methoxymethoxy)-1-naphthyl]-8-methyl-quinazolin-4-yl]thiomorpholine (39 mg, 0.07 mmol) in DCM (0.7 mL) was added triethylsilane (0.11 mL, 0.69 mmol) at 0 °C. Trifluoroacetic acid (0.53 mL, 6.9 mmol) was added and the reaction mixture was stirred at room temperature for 1 h. The mixture was dry loaded onto silica and purified by reverse phase chromatography eluting with 5-50% MeCN (0.1% formic acid) / water (0.1% formic acid) and the product containing fractions were purified by SCX (methanol wash (x2) followed by 1M NH 3 (x2) / MeOH) The filtrate was concentrated in vacuo to give 4-[2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-8-methyl-4-thiomorpholino-quinazolin-7-yl]naphthalen-2-ol (34 mg, 0.06 mmol, 92% yield) as a yellow solid. UPLC-MS (ES + , Long acidity): 3.31 min, m / z 527.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ / ppm: 9.90 (s, 1H), 7.83-7.76 (m, 2H), 7.43-7.38 (m, 1H), 7.21 (d, J = 2.4 Hz, 1H), 7.18-7.15 (m, 3H), 6.95 (d, J = 2.4 Hz, 1H), 4.07 (s, 2H), 4.00-3.93 (m, 4H), 2.97-2.85 (m, 6H), 2.19 (s, 3H), 2.03-1.87 (m, 3H), 1.86-1.69 (m, 5H), 1.63-1.53 ​​(m, 2H).

[0219] Example 4 [ka] 4-[2-(1,2,3,5,6,7-Hexahydropyrrolidin-8-ylmethoxy)-7-(3-hydroxy-1-naphthyl)-8-methyl-quinazolin-4-yl]-1,4-oxazepan-5-one [ka] Step A, 4-(7-bromo-2-chloro-8-methyl-quinazolin-4-yl)-1,4-oxazepan-5-one Lithium bis(trimethylsilyl)amide (1.71 mL, 1.71 mmol) was added dropwise to a stirred solution of [1,4]-oxazepan-5-one (197.17 mg, 1.71 mmol) in dry THF (18 mL) at 0° C. and the reaction mixture was stirred at this temperature for 30 min. 7-Bromo-2,4-dichloro-8-methylquinazoline (500 mg, 1.71 mmol) was added and the reaction mixture was continued to stir at 0° C. for 3 h. The reaction mixture was concentrated to dryness. The residue was redissolved in DCM and dry loaded onto silica. The product was purified by flash column chromatography on silica gel (40 g) eluting with 0-100% EtOAc / petroleum ether. The desired fraction was concentrated to dryness to give 4-(7-bromo-2-chloro-8-methyl-quinazolin-4-yl)-1,4-oxazepan-5-one (357.4 mg, 0.96 mmol, 56.3% yield) as a powdery white solid. UPLC-MS (ES + , short acidic): 1.88 min, m / z 372.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ / ppm:7.90 (d, J = 9.0 Hz, 1H), 7.81 (dd, J = 9.0, 0.6 Hz, 1H), 4.16-4.11 (m, 2H), 3.96-3.88 (m, 4H), 3.03-2.98 (m, 2H), 2.74 (s, 3H).

[0220] Step B, 4-[2-chloro-7-[3-(methoxymethoxy)-1-naphthyl]-8-methyl-quinazolin-4-yl]-1,4-oxazepan-5-one A suspension of 4-(7-bromo-2-chloro-8-methyl-quinazolin-4-yl)-1,4-oxazepan-5-one (357.4 mg, 0.96 mmol), 2-(3-(2-methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (363.56 mg, 1.16 mmol) and potassium carbonate (266.55 mg, 1.93 mmol) in a mixture of 1,4-dioxane (8.85 mL) and water (0.89 mL) was degassed with nitrogen for 10 min. [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (125.7 mg, 0.19 mmol) was added and the reaction mixture was heated to 80° C. and then stirred at this temperature for 1 h 45 min. The reaction mixture was cooled to room temperature and silica was added for dry loading. The product was purified by flash column chromatography on silica gel (40 g) eluting with 30-85% EtOAc / petroleum ether. The desired fractions were combined and concentrated in vacuo to give 4-[2-chloro-7-[3-(methoxymethoxy)-1-naphthyl]-8-methyl-quinazolin-4-yl]-1,4-oxazepan-5-one (148 mg, 0.31 mmol, 32.1 yield) as a translucent oily residue. 1 H NMR (400 MHz, DMSO-d 6 ) δ / ppm:8.00 (dd, J =8.6, 0.6 Hz, 1H), 7.95 (d, J = 8.2 Hz, 1H), 7.62-7.58 (m, 2H), 7.54-7.49 (m, 1H), 7.34-7.29 (m, 1H), 7.21-7.17 (m, 2H), 5.41-5.36 (m, 2H), 4.21-4.16 (m, 2H), 3.99-3.93 (m, 4H), 3.46 (s, 3H), 3.06-3.01 (m, 2H), 2.34 (s, 3H).

[0221] Step C, 4-[2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-7-[3-(methoxymethoxy)-1-naphthyl]-8-methyl-quinazolin-4-yl]-1,4-oxazepan-5-one A suspension of 4-[2-chloro-7-[3-(methoxymethoxy)-1-naphthyl]-8-methyl-quinazolin-4-yl]-1,4-oxazepan-5-one (148.mg, 0.31 mmol), 1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethanol (218.mg, 1.55 mmol), cesium carbonate (201.95 mg, 0.62 mmol) and 4,6-bis(diphenylphosphino)-10H-phenoxazine (68.32 mg, 0.12 mmol) in dry 1,4-dioxane (3 mL) was degassed with nitrogen for 10 min. Palladium(II) acetate (13.9 mg, 0.06 mmol) was added. The reaction mixture was heated to 110° C. and stirred at this temperature for 3 h. The reaction mixture was cooled to room temperature and silica was added for dry loading. The product was purified by flash column chromatography on silica gel (40 g) eluting with 25-100% MeOH / DCM. The desired fractions were combined and concentrated in vacuo to give 4-[2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-7-[3-(methoxymethoxy)-1-naphthyl]-8-methyl-quinazolin-4-yl]-1,4-oxazepan-5-one (53.5 mg, 0.0918 mmol, 29.65% yield) as a translucent residue. UPLC-MS (ES + , short acidic): 1.70 min, m / z 583.3 [M+H] +

[0222] Step D, 4-[2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-7-(3-hydroxy-1-naphthyl)-8-methyl-quinazolin-4-yl]-1,4-oxazepan-5-one 4-[2-(1,2,3,5,6,7-Hexahydropyrrolidin-8-ylmethoxy)-7-[3-(methoxymethoxy)-1-naphthyl]-8-methyl-quinazolin-4-yl]-1,4-oxazepan-5-one (53.5 mg, 0.09 mmol) was dissolved in DCM (2 mL) and the reaction solution was cooled to 0° C. Triethylsilane (0.15 mL, 0.92 mmol) was added, followed by the slow addition of trifluoroacetic acid (0.21 mL, 2.75 mmol). The reaction mixture was stirred at 0° C. for 5 minutes, after which the reaction mixture was allowed to warm to room temperature. The reaction mixture was stirred at 25° C. for 45 minutes. Celite was added to the reaction mixture and it was concentrated to dryness. The product was purified by reverse phase chromatography (25 g) eluting with 0-40% MeCN (0.1% formic acid) / water (0.1% formic acid) and fractions containing the product were purified by SCX (methanol wash (x2) followed by 1M NH 3 (x2)) The filtrate was concentrated under reduced pressure to give 4-[2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-7-(3-hydroxy-1-naphthyl)-8-methyl-quinazolin-4-yl]-1,4-oxazepan-5-one (11.8 mg, 0.02 mmol, yield 23.8) as a pale yellow solid. UPLC-MS (ES + , Long acidity,): 3.11 min, m / z 539.8 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6) δ / ppm:9.95 (s, 1H), 7.85 (dd, J = 8.6, 0.6 Hz, 1H), 7.80 (d, J = 8.3 Hz, 1H), 7.44-7.39 (m, 1H), 7.32 (d, J = 8.6 Hz, 1H), 7.23 (d, J = 2.4 Hz, 1H), 7.21-7.16 (m, 1H), 7.15-7.11 (m, 1H), 6.97 (d, J = 2.4 Hz, 1H), 4.20-4.14 (m, 2H), 4.14-4.09 (m, 2H), 3.98-3.91 (m, 4H), 3.03-2.91 (m, 2H), 2.29 (s, 3H), 1.99-1.89 (m, 3H), 1.89-1.68 (m, 6H), 1.66-1.57 (m, 3H).

[0223] Example 5 [ka] 4-[2-(1,2,3,5,6,7-Hexahydropyrrolidin-8-ylmethoxy)-7-(3-hydroxy-1-naphthyl)-8-methyl-quinazolin-4-yl]-1,4-oxazepan-3-one [ka] Step A, 4-(7-bromo-2-chloro-8-methyl-quinazolin-4-yl)-1,4-oxazepan-3-one Lithium bis(trimethylsilyl)amide (1.71 mL, 1.71 mmol) was added dropwise to a stirred solution of [1,4]-oxazepan-3-one (197.17 mg, 1.71 mmol) in dry THF (18 mL) at 0° C. and the reaction mixture was stirred at this temperature for 30 min. 7-Bromo-2,4-dichloro-8-methylquinazoline (500 mg, 1.71 mmol) was added and the reaction mixture was continued to stir at 0° C. for 3 h. The reaction mixture was concentrated to dryness. The residue was redissolved in DCM and dry loaded onto silica. The product was purified by flash column chromatography on silica gel (40 g) eluting with 0-100% EtOAc / petroleum ether. The desired fractions were concentrated to dryness to give 4-(7-bromo-2-chloro-8-methyl-quinazolin-4-yl)-1,4-oxazepan-3-one (273.8 mg, 0.7387 mmol, 43.1% yield) as a powdery white solid. UPLC-MS (ES + , short acidity): 1.93 min, m / z 372.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ / ppm:7.95 (d, J = 9.0 Hz, 1H), 7.68 (dd, J = 9.1, 0.6 Hz, 1H), 4.46 (s, 2H), 4.20.4.15 (m, 2H), 4.00-3.94 (m, 2H), 2.74 (s, 3H), 2.06-1.99 (m, 2H).

[0224] Step B, 4-[2-chloro-7-[3-(methoxymethoxy)-1-naphthyl]-8-methyl-quinazolin-4-yl]-1,4-oxazepan-3-one A suspension of 4-(7-bromo-2-chloro-8-methyl-quinazolin-4-yl)-1,4-oxazepan-3-one (673.6mg, 1.82mmol), 2-(3-(2-methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (685.21mg, 2.18mmol) and potassium carbonate (502.38mg, 3.63mmol) in a mixture of 1,4-dioxane (16.7mL) and water (1.67mL) was degassed with nitrogen for 20 minutes. [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (236.9mg, 0.36mmol) was added and the reaction mixture was heated to 80°C and then stirred at this temperature for 2h 10min. The reaction mixture was cooled to room temperature and silica was added for dry loading. The product was purified by flash column chromatography on silica gel (40 g) eluting with 30-85% EtOAc / petroleum ether. The desired fractions were combined and concentrated in vacuo to give 4-[2-chloro-7-[3-(methoxymethoxy)-1-naphthyl]-8-methyl-quinazolin-4-yl]-1,4-oxazepan-3-one (351.3 mg, 0.73 mmol, 40.4 yield) as a clear oily residue. UPLC-MS (ES + , short acidic): 2.17 min, m / z 478.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6) δ / ppm:7.95 (d, J = 8.4 Hz,1H), 7.88 (dd, J = 8.6, 0.6 Hz, 1H), 7.65 (d, J = 8.6 Hz, 1H), 7.59 (d, J = 2.5 Hz,1H), 7.54-7.49 (m, 1H), 7.34-7.29 (m, 1H), 7.21-7.17 (m, 2H), 5.41-5.35 (m, 2H), 4.49 (s, 2H), 4.25-4.19 (m, 2H), 4.02-3.97 (m, 2H), 3.46 (s, 3H), 2.35-2.31 (m, 3H), 2.12-2.03 (m, 2H).

[0225] Step C, 4-[2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-7-[3-(methoxymethoxy)-1-naphthyl]-8-methyl-quinazolin-4-yl]-1,4-oxazepan-3-one A suspension of 4-[2-chloro-7-[3-(methoxymethoxy)-1-naphthyl]-8-methyl-quinazolin-4-yl]-1,4-oxazepan-3-one (351.3mg, 0.74mmol), 1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethanol (518.97mg, 3.68mmol), cesium carbonate (479.36mg, 1.47mmol) and 4,6-bis(diphenylphosphino)-10H-phenoxazine (162.16mg, 0.29mmol) in dry 1,4-dioxane (7.5mL) was degassed with nitrogen for 10 minutes. Palladium(II) acetate (33mg, 0.1500mmol) was added. The reaction mixture was heated to 110°C and stirred at this temperature for 3 hours. The reaction mixture was cooled to room temperature and silica was added for dry loading. The product was purified by flash column chromatography on silica gel (40 g), eluting first with 20-100% EtOAc / petroleum ether, then with 0-20% (1M ammonia / MeOH) / DCM. The desired fractions were combined and concentrated in vacuo to give 4-[2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-7-[3-(methoxymethoxy)-1-naphthyl]-8-methyl-quinazolin-4-yl]-1,4-oxazepan-3-one (37.1 mg, 0.064 mmol, 8.6 yield) as a translucent residue. UPLC-MS (ES + , short acidity,): 1.67 min, m / z 583.6 [M+H] + .

[0226] Step D, 4-[2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-7-(3-hydroxy-1-naphthyl)-8-methyl-quinazolin-4-yl]-1,4-oxazepan-3-one 4-[2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-7-[3-(methoxymethoxy)-1-naphthyl]-8-methyl-quinazolin-4-yl]-1,4-oxazepan-3-one (37.1 mg, 0.06 mmol) was dissolved in DCM (2.5 mL) and the reaction mixture was cooled to 0° C. Triethylsilane (0.1 mL, 0.64 mmol) was added, followed by slow addition of trifluoroacetic acid (0.15 mL, 1.91 mmol). The reaction mixture was stirred at 0° C. for 5 minutes, after which the reaction mixture was allowed to warm to room temperature. The reaction mixture was stirred at 25° C. for 2 hours and 40 minutes. Celite was added to the reaction mixture and it was concentrated to dryness. The product was purified by reverse phase chromatography (12 g) eluting with 0-40% MeCN (0.1% formic acid) / water (0.1% formic acid) and fractions containing the product were purified by SCX (methanol wash (x2) followed by 1M NH 3 (x2) / MeOH) The filtrate was concentrated to dryness to give 4-[2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-7-(3-hydroxy-1-naphthyl)-8-methyl-quinazolin-4-yl]-1,4-oxazepan-3-one (8.1 mg, 0.015 mmol, 23.6 yield) as a pale yellow powdery solid. UPLC-MS (ES + , Long acidity): 3.23 min, m / z 539.7 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6) δ / ppm:9.95 (s, 1H), 7.80 (d, J = 8.3 Hz, 1H), 7.75 (dd, J = 8.5, 0.5 Hz, 1H), 7.44-7.39 (m, 1H), 7.35 (d, J = 8.6 Hz, 1H), 7.23 (d, J = 2.4 Hz, 1H), 7.21-7.16 (m, 1H), 7.15-7.11 (m, 1H), 6.97 (d, J = 2.4 Hz, 1H), 4.46 (s, 2H), 4.19-4.12 (m, 4H), 4.02-3.96 (m, 2H), 2.99-2.92 (m, 2H), 2.29 (s, 3H), 2.11 (m, 2H), 2.00-1.89 (m, 3H), 1.89-1.72 (m, 5H), 1.66-1.57 (m, 2H).

[0227] Example 6 [ka] rac-5-ethynyl-6-fluoro-4-[2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-8-methyl-4-(1,4-oxazepan-4-yl)quinazolin-7-yl]naphthalen-2-ol [ka] The 2-[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthyl]ethynyl-triisopropyl-silane used in step C was prepared according to the procedure published in The Journal of Medicinal Chemistry: https: / / doi.org / 10.1021 / acs.jmedchem.1c01688.

[0228] Step A, 4-(7-bromo-2-chloro-8-methyl-quinazolin-4-yl)-1,4-oxazepane This procedure is described in Example 2 (Step A). Step B, rac-4-[7-bromo-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-8-methyl-quinazolin-4-yl]-1,4-oxazepane To a stirred solution of rac-[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methanol (78.56 mg, 0.4900 mmol) in dry THF (6 mL) was added sodium hydride (60% dispersion in mineral oil) (29.61 mg, 0.74 mmol) at 0° C. and the reaction mixture was stirred at 0° C. for 30 minutes. 4-(7-Bromo-2-chloro-8-methyl-quinazolin-4-yl)-1,4-oxazepane (88.mg, 0.25 mmol) was added and the reaction mixture was heated to 60° C. and then stirred overnight. The reaction mixture was cooled to room temperature and concentrated to dryness. The residue was dissolved in a mixture of DCM and MeOH and silica was added for dry loading. The product was purified by flash column chromatography on silica gel (25 g), eluting first with 0–100% EtOAc / petroleum ether, then with 0–20% MeOH (1M NH 3 ) / DCM. The desired fractions were combined and concentrated in vacuo to give rac-4-[7-bromo-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-8-methyl-quinazolin-4-yl]-1,4-oxazepane (99.4 mg, 0.2073 mmol, 84.048 yield) as a brown residue. UPLC-MS (ES + , short acidic,): 1.46 min, m / z 481.1 [M+H] + .

[0229] Step C, rac-2-[2-fluoro-8-[2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-8-methyl-4-(1,4-oxazepan-4-yl)quinazolin-7-yl]-6-(methoxymethoxy)-1-naphthyl]ethynyl-triisopropyl-silane A suspension of 2-[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthyl]ethynyl-triisopropyl-silane (337.26mg, 0.66mmol), rac-4-[7-bromo-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-8-methyl-quinazolin-4-yl]-1,4-oxazepane (210.3 mg, 0.44 mmol) and cesium carbonate (285.86 mg, 0.88mmol) in a mixture of 1,4-dioxane (8.23 mL) and water (2.7438 mL) was degassed with nitrogen for 15 min. [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (28.59 mg, 0.04 mmol) was added and the reaction mixture was heated to 90°C. The reaction mixture was stirred overnight. The reaction mixture was cooled to room temperature and filtered through a plug of Celite (washed twice with MeOH). The filtrate was concentrated to dryness. The resulting residue was taken up in a mixture of MeOH and DCM and silica was added for dry loading. The product was purified by flash column chromatography on silica gel (40 g) eluting with 0-20% (1M ammonia / MeOH) / DCM. The desired fractions were combined and concentrated under reduced pressure to give rac-2-[2-fluoro-8-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-8-methyl-4-(1,4-oxazepan-4-yl)quinazolin-7-yl]-6-(methoxymethoxy)-1-naphthyl]ethynyl-triisopropylsilane (258.8 mg, 0.32 mmol, 75.1 yield) as a brown residue. UPLC-MS (ES +, short acidic): 2.20 min, m / z 785.5 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ / ppm:8.09 (m, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 2.7 Hz, 1H), 7.52 (t, J = 8.9 Hz, 1H), 7.10 (d, J = 8.7 Hz, 1H), 7.03 (d, J = 2.6 Hz, 1H), 5.37-5.32 (m, 2H), 4.18-3.95 (m, 6H), 3.92 (s, 3H), 3.83-3.71 (m, 2H), 3.43 (s, 3H), 3.18-2.97 (m, 3H), 2.90-2.79 (m, 1H), 2.56-2.44 (m, 2H), 2.22 (d, J = 3.5 Hz, 3H), 2.19-1.97 (m, 6H), 1.92-1.68 (m, 3H), 0.83-0.77 (m, 18H), 0.50-0.39 (m, 3H)

[0230] Step D, rac-4-[7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-8-methyl-quinazolin-4-yl]-1,4-oxazepane A stirred solution of 1.0M tetrabutylammonium fluoride (0.35 mL, 0.35 mmol) in THF was added to a stirred solution of rac-2-[2-fluoro-8-[2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-8-methyl-4-(1,4-oxazepan-4-yl)quinazolin-7-yl]-6-(methoxymethoxy)-1-naphthyl]ethynyl-triisopropylsilane (249.8 mg, 0.32 mmol) in THF (6 mL) at 0°C. The reaction mixture was allowed to warm to room temperature and then stirred for 45 min. Silica was added for dry loading. The product was dissolved in 0-20% MeOH (1M NH3 The crude product was purified by flash column chromatography on silica gel (25 g) eluting with 1,2-dimethyl-2,3-dihydro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-8-methyl-quinazolin-4-yl]-1,4-oxazepane (194.5 mg, 0.31 mmol, 97.2% yield) as a brown waxy residue. UPLC-MS (ES + , short acidity): 1.59 min, m / z 629.3 [M+H] + 1 H NMR (400 MHz, DMSO-d 6 ) δ / ppm:8.08-8.02 (m, 1H), 7.81 (d, J = 8.7 Hz, 1H), 7.64 (d, J = 2.6 Hz, 1H), 7.49 (t, J = 9.0 Hz, 1H), 7.12-7.07 (m, 2H), 5.37-5.32 (m, 2H), 4.24-4.13 (m, 1H), 4.12-3.84 (m, 8H), 3.80-3.76 (m, 4H), 3.65 (s, 1H), 3.45 (s, 3H), 3.25-2.99 (m, 2H), 2.95-2.80 (m, 1H), 2.15 (s, 3H), 2.13-2.00 (m, 4H), 1.95-1.74 (m, 3H).

[0231] Process E , rac-5-ethynyl-6-fluoro-4-[2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-8-methyl-4-(1,4-oxazepan-4-yl)quinazolin-7-yl]naphthalen-2-ol Hydrogen chloride (5. mL, 5 mmol) in dioxane (1M) was slowly added to a solution of rac-4-[7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-2-[[(2R,8S)-2-fluoro-1,2,3,5,6.7-hexahydropyrrolidin-8-yl]methoxy]-8-methyl-quinazolin-4-yl]-1,4-oxazepane (70 mg, 0.11 mmol) in dry 1,4-dioxane (5 mL) and stirred at room temperature for 15 min. The reaction mixture was concentrated to dryness and the resulting residue was taken up in DCM. Celite was added for dry loading. The product was purified by reverse phase chromatography eluting with 0-80% MeCN (0.1% ammonium carbonate) / water (0.1% ammonium carbonate). The product was purified by SCX (methanol wash (x2) followed by 1M NH 3 The desired fractions were isolated by SCX (methanol washes (x2), followed by 1 M NH in MeOH (x2)) and the solvent was evaporated under reduced pressure to give a pale yellow residue. The product was purified by preparative HPLC. The product was isolated from the desired fractions by SCX (methanol washes (x2), followed by 1 M NH in MeOH (x2)). 3 (x2)) and the solvent evaporated under reduced pressure to give rac-5-ethynyl-6-fluoro-4-[2-[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-8-methyl-4-(1,4-oxazepan-4-yl)quinazolin-7-yl]naphthalen-2-ol (8.4 mg, 0.014 mmol, 12.9 yield) as a powdery white solid which was analyzed as a mixture of atropisomers. UPLC-MS (ES + , Long acidity): 3.17 min, m / z 585.3 [M+H] + , 3.18 min, m / z 585.3 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ / ppm: 10.04 (s, 1H), 7.96-7.91 (m, 1H), 7.80 (d, J = 8.6 Hz, 1H), 7.45-7.39 (m, 1H), 7.30 (d, J = 2.6 Hz, 1H), 7.06 (d, J = 8.6 Hz, 1H), 6.92 (d, J = 2.5 Hz, 1H), 5.37-5.19 (m, 1H), 4.16-4.09 (m, 1H), 4.09-3.94 (m, 6H), 3.93-3.88 (m, 2H), 3.79-3.73 (m, 2H), 3.72-3.70 (m, 1H), 3.15-2.99 (m, 3H), 2.88-2.78 (m, 1H), 2.17-2.00 (m, 7H), 1.89-1.71 (m, 3H).

[0232] The following example compounds in Table 3 were prepared using the same sequence of synthetic steps as in Example 2, replacing the 1,4-oxazepane in Step A with the corresponding building block as described in Table 3. [Table 3] [Table 4]

[0233] Example 12 [ka] 4-[2-(1,2,3,5,6,7-Hexahydropyrrolidin-8-ylmethoxy)-8-methyl-4-(1,4-oxazepan-4-yl)quinazolin-7-yl]quinazoline-6-carbonitrile [ka] To a degassed suspension of 4-[2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-8-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl]-1,4-oxazepane (120 mg, 0.24 mmol), 4-chloro-6-quinazolinecarbonitrile (67.12 mg, 0.35 mmol) and cesium carbonate (230.69 mg, 0.71 mmol) in 1,4-dioxane (3 mL) and water (0.3 mL) was added [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (15.38 mg, 0.02 mmol). The mixture was stirred at 95° C. overnight. The crude product was diluted with EtOAc, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (5 g, KP-Amino D) eluting with 10-100% EtOAc / petroleum ether followed by 0-20% MeOH / DCM. The product was further purified by preparative HPLC. Collected fractions were purified by SCX column (1M NH 3 The concentrated solution of the product was dried under vacuum to give 4-[2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-8-methyl-4-(1,4-oxazepan-4-yl)quinazolin-7-yl]quinazoline-6-carbonitrile (15 mg, 10%) as a yellow crystalline solid. UPLC-MS (ES + , Method 1):2.68 min, m / z 536.3 [M+H] + 1 H NMR (400 MHz, DMSO-d 6) δ / ppm 9.59 (s, 1H), 8.37 (dd, J=1.7, 8.8 Hz, 1H), 8.31 (d, J=8.7 Hz, 1H), 8.22-8.20 (m, 1H), 8.07-8.02 (m, 1H), 7.28-7.23 (m, 1H), 4.27 (s, 1H), 4.09 (s, 2H), 3.94-3.89 (m, 6H), 3.77-3.74 (m, 2H), 2.98-2.92 (m, 2H), 2.27-2.23 (m, 3H), 2.13-2.07 (m, 3H), 1.97-1.74 (m, 6H), 1.63-1.55 (m, 2H).

[0234] Example 13 [ka] 4-[2-(1,2,3,5,6,7-Hexahydropyrrolidin-8-ylmethoxy)-8-methyl-4-(1,4-oxazepan-4-yl)quinazolin-7-yl]-1,3-benzothiazol-2-amine [ka] Step A, tert-butyl N-[4-[2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-8-methyl-4-(1,4-oxazepan-4-yl)quinazolin-7-yl]-1,3-benzothiazol-2-yl]carbamate To a degassed suspension of 4-[7-bromo-2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-8-methyl-quinazolin-4-yl]-1,4-oxazepane (50 mg, 0.11 mmol), tert-butyl N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzothiazol-2-yl]carbamate (61.16 mg, 0.16 mmol) and cesium carbonate (105.9 mg, 0.33 mmol) in 1,4-dioxane (2 mL) and water (0.2 mL) was added [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (7.06 mg, 0.01 mmol). The mixture was stirred at 95° C. overnight. The reaction mixture was diluted with EtOAc, filtered, and concentrated in vacuo to give a black oil. The crude product was purified by flash column chromatography (5 g KP NH modified column) eluting with 10%-100% EtOAc / petroleum ether followed by filtration with 20% MeOH / DCM. The product containing fractions were combined and concentrated in vacuo to give tert-butyl N-[4-[2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-8-methyl-4-(1,4-oxazepan-4-yl)quinazolin-7-yl]-1,3-benzothiazol-2-yl]carbamate (10 mg, 15%) as a yellow oil. UPLC-MS (ES + , Method 2):1.9 min, m / z 631.3 [M+H] +

[0235] Step B, 4-[2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-8-methyl-4-(1,4-oxazepan-4yl)quinazolin-7-yl]-1,3-benzothiazol-2-amine To a solution of tert-butyl N-[4-[2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-8-methyl-4-(1,4-oxazepan-4-yl)quinazolin-7-yl]-1,3-benzothiazol-2-yl]carbamate (10 mg, 0.02 mmol) in DCM (1 mL) was added trifluoroacetic acid (0.01 mL, 0.16 mmol) at room temperature and stirred for 30 min. The crude product was concentrated and purified by flash column chromatography eluting with 100% DCM to 20% MeOH / DCM. The desired fraction was concentrated to dryness to give 4-[2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-8-methyl-4-(1,4-oxazepan-4-yl)quinazolin-7-yl]-1,3-benzothiazol-2-amine (7 mg, 80%) as a white solid. UPLC-MS (ES + , Method 1):2.7 min, m / z 531.3 [M+H] + 1 H NMR (400 MHz, DMSO-d 6 ) δ / ppm 7.84 (d, J=8.8 Hz, 1H), 7.72 (dd, J=2.4, 6.7 Hz, 1H), 7.51 (s, 2H), 7.13-7.10 (m, 3H), 4.06-3.99 (m, 6H), 3.91-3.87 (m, 2H), 3.76-3.71 (m, 2H), 2.97-2.91 (m, 1H), 2.53 (d, J=1.8 Hz, 1H), 2.46-2.44 (m, 1H), 2.34-2.27 (m, 3H), 2.10-2.05 (m, 3H), 1.95-1.72 (m, 6H), 1.61-1.53 ​​(m, 2H).

[0236] Example 14 [ka] 4-[2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-8-methyl-7-(2-methylquinazolin-4-yl)quinazolin-4-yl]-1,4-oxazepane Following a procedure similar to that of Example 12, substituting 4-chloro-2-methylquinazoline for 4-chloro-6-quinazolinecarbonitrile, 4-[2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-8-methyl-7-(2-methylquinazolin-4-yl)quinazolin-4-yl]-1,4-oxazepane was prepared. UPLC-MS (ES + , Method 1):2.6 min, m / z 525.3 [M+H] + 1 H NMR (400 MHz, DMSO-d 6 ) δ / ppm 8.05-7.98 (m, 3H), 7.63-7.53 (m, 2H), 7.21 (d, J=8.6 Hz, 1H), 4.10-4.03 (m, 6H), 3.92 (dd, J=4.5, 4.5 Hz, 2H), 3.75 (dd, J=5.3, 5.3 Hz, 2H), 2.97-2.91 (m, 2H), 2.84 (s, 3H), 2.55-2.52 (m, 2H), 2.23, 2.21 (s, 3H), 2.12-2.06 (m, 2H), 1.96-1.72 (m, 6H), 1.62-1.54 (m, 2H).

[0237] Example 15 [ka] 4-[2-(1,2,3,5,6,7-Hexahydropyrrolidin-8-ylmethoxy)-7-[2-methoxy-5-(trifluoromethyl)phenyl]-8-methyl-quinazolin-4-yl]-1,4-oxazepane 4-[2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-7-[2-methoxy-5-(trifluoromethyl)phenyl]-8-methyl-quinazolin-4-yl]-1,4-oxazepane was prepared in a similar manner to Step A of Example 13, except that tert-butyl N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzothiazol-2-yl]carbamate was replaced with 2-methoxy-5-(trifluoromethyl)phenylboronic acid. UPLC-MS (ES + , Method 1):3.2 min, m / z 557.4 [M+H] + 1 H NMR (400 MHz, DMSO-d 6 ) δ / ppm 7.87 (d, J=8.7 Hz, 1H), 7.80 (dd, J=1.8, 8.7 Hz, 1H), 7.47 (d, J=2.2 Hz, 1H), 7.35 (d, J=8.7 Hz, 1H), 7.05 (d, J=8.6 Hz, 1H), 4.07-3.98 (m, 6H), 3.82 (m, 5H), 3.73 (dd, J=4.8, 5.8 Hz, 2H), 2.98 - 2.90 (m, 2H), 2.58 - 2.52 (m, 2H), 2.25 (s, 3H), 2.11 - 2.03 (m, 2H), 1.95 - 1.71 (m, 6H), 1.61 - 1.52 (m, 2H).

[0238] Example 16 [ka] 4-[7-(5-chloro-2-methoxy-phenyl)-2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-8-methyl-quinazolin-4-yl]-1,4-oxazepane 4-[7-(5-chloro-2-methoxy-phenyl)-2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-8-methyl-quinazolin-4-yl]-1,4-oxazepane was prepared in a similar manner to Step A of Example 13, except that tert-butyl N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzothiazol-2-yl]carbamate was replaced with 5-chloro-2-methoxyphenylboronic acid. UPLC-MS (ES + , Method 1):3.2 min, m / z 523.3 [M+H] + 1 H NMR (400 MHz, DMSO-d 6 ) δ / ppm 7.84 (d, J=8.7 Hz, 1H), 7.46 (d, J=2.2 Hz, 1H), 7.20-7.15 (m, 2H), 7.05 (d, J=8.6 Hz, 1H), 4.07-3.98 (m, 6H), 3.82 (m, 5H), 3.73 (dd, J=4.8, 5.8 Hz, 2H), 2.98 - 2.90 (m, 2H), 2.58 - 2.52 (m, 2H), 2.25 (s, 3H), 2.11 - 2.03 (m, 2H), 1.95 - 1.71 (m, 6H), 1.61 - 1.52 (m, 2H).

[0239] Example 17 [ka] 4-[2-(1,2,3,5,6,7-Hexahydropyrrolidin-8-ylmethoxy)-8-methyl-7-[3-(trifluoromethyl)-1H-pyrazol-4-yl]quinazolin-4-yl]-1,4-oxazepane 4-[2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-8-methyl-7-[3-(trifluoromethyl)-1H-pyrazol-4-yl]quinazolin-4-yl]-1,4-oxazepane was prepared in a similar manner to step A of Example 13, except that tert-butyl N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-benzothiazol-2-yl]carbamate was replaced with 3-trifluoromethyl-1H-pyrazole-4-boronic acid pinacol ester. UPLC-MS (ES + , Method 1):2.6 min, m / z 517.2 [M+H] + 1 H NMR (400 MHz, DMSO-d 6 ) δ / ppm 13.87-13.83 (bs, 1H), 8.08 (d, J=0.6 Hz, 1H), 7.85 (d, J=8.7 Hz, 1H), 7.06 (d, J=8.7 Hz, 1H), 4.05-3.73 (m, 10H), 2.97-2.90 (m, 2H), 2.53 (m, 2H), 2.47 (d, J=1.8 Hz, 3H), 2.35 (s, 1H), 2.34 (s, 3H), 2.09 - 1.52 (m, 10H).

[0240] Example 18 [ka] 4-[2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-8-methyl-7-(5-methyl-1H-indazol-4-yl)quinazolin-4-yl]-1,4-oxazepane [ka] Step A, 4-[2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-8-methyl-7-(5-methyl-1-tetrahydropyran-2-yl-indazol-4-yl)quinazolin-4-yl]-1,4-oxazepane A suspension of 5-methyl-1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazole (215.2 mg, 0.63 mmol), 4-[7-bromo-2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-8-methyl-quinazolin-4-yl]-1,4-oxazepane (241.7 mg, 0.52 mmol) and cesium carbonate (512.1 mg, 1.57 mmol) in a mixture of 1,4-dioxane (4 mL) and water (1.38 mL) was degassed with nitrogen for 15 minutes. [1,1'-Bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane complex (85.58 mg, 0.1 mmol) was added and the reaction mixture was stirred at 95°C overnight. The reaction mixture was cooled to room temperature and filtered through Celite. The filtrate was concentrated to dryness and the resulting residue was redissolved in DCM and dry loaded onto silica. The product was purified by flash column chromatography on silica gel (40 g) eluting with 0-60% (20% 1M ammonia / MeOH) / DCM. The desired fractions were combined and concentrated in vacuo to give 4-[2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-8-methyl-7-(5-methyl-1-tetrahydropyran-2-yl-indazol-4-yl)quinazolin-4-yl]-1,4-oxazepane (37.3 mg, 12% yield) as a brown flaky solid. UPLC-MS (ES + , Method 2):1.6 min, m / z 597.3 [M+H] + 1 H NMR (400 MHz, DMSO-d 6) δ / ppm 8.00-7.93 (m, 1H), 7.69 (d, J = 8.7 Hz, 1H), 7.43-7.40 (m, 2H), 7.09-7.02 (m, 1H), 5.89-5.83 (m, 1H), 4.10-4.00 (m, 5H), 3.94-3.86 (m, 3H), 3.78-3.72 (m, 3H), 2.53-2.46 (m, 3H), 2.44-2.36 (m, 2H), 2.17 (d, J = 8.6 Hz, 3H), 2.11 (s, 3H) 2.09-1.93 (m, 7H), 1.93-1.68 (m, 6H), 1.63-1.54 (m, 3H).

[0241] Step B, 4-[2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-8-methyl-7-(5-methyl-1H-indazol-4-yl)quinazolin-4-yl]-1,4-oxazepane 4-[2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-8-methyl-7-(5-methyl-1-tetrahydropyran-2-yl-indazol-4-yl)quinazolin-4-yl]-1,4-oxazepane (36.3 mg, 0.06 mmol) was dissolved in a mixture of DCM (0.6 mL) and methanol (0.01 mL) and the reaction mixture was cooled to 0° C. Triethylsilane (0.1 mL, 0.61 mmol) was added followed by trifluoroacetic acid (0.47 mL, 6.08 mmol). The reaction mixture was stirred at 0° C. for 5 minutes and then the reaction mixture was allowed to warm to room temperature. The reaction mixture was stirred at 25° C. for 2.5 hours. Celite was added to the reaction mixture and it was concentrated to dryness. The product was purified by reverse phase chromatography eluting with 2-50% MeCN (0.1% formic acid) / water (0.1% formic acid) and fractions containing the product were purified by SCX (methanol wash (x2) followed by 1M NH 3The filtrate was concentrated in vacuo to give 4-[2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-8-methyl-7-(5-methyl-1 H-indazol-4-yl)quinazolin-4-yl]-1,4-oxazepane (29.5 mg, 94.6%) as an off-white powder. UPLC-MS (ES + , Method 1):2.6 min, m / z 513.4 [M+H] + 1 H NMR (400 MHz, DMSO-d 6 ) δ / ppm 13.08 (s, 1H), 7.94 (d, J = 8.7 Hz, 1H),7.49 (d, J = 8.6 Hz, 1H), 7.39 (s, 1H), 7.34 (d, J= 8.6 Hz, 1H), 7.05 (d, J = 8.6 Hz, 1H), 4.07-4.01 (m, 6H), 3.92-3.88 (m, 2H), 3.77-3.72 (m, 2H), 2.97-2.89 (m, 2H), 2.57-2.46 (m, 2H), 2.16 (s, 3H), 2.12-2.06 (m, 5H), 1.96-1.88 (m, 2H), 1.85-1.71 (m, 4H), 1.61-1.52 (m, 2H).

[0242] Example 19 [ka] 4-[2-(1,2,3,5,6,7-Hexahydropyrrolidin-8-ylmethoxy)-7-(1H-indazol-4-yl)-8-methyl-quinazolin-4-yl]-1,4-oxazepane In a similar manner to Example 18, 5-methyl-1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazole in step A was replaced with 1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indazole to produce 4-[2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-7-(1H-indazol-4-yl)-8-methyl-quinazolin-4-yl]-1,4-oxazepane. UPLC-MS (ES + , Method 1):2.7 min, m / z 499.3 [M+H] + 1 H NMR (400 MHz, DMSO-d 6 ) δ / ppm 13.25 (s, 1H), 7.94 (d, J=8.7 Hz, 1H), 7.72 (s, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.47 (dd, J=7.0, 8.3 Hz, 1H), 7.22 (d, J=8.7 Hz, 1H), 7.07 (dd, J=0.7, 7.0 Hz, 1H), 4.09-4.01 (m, 6H), 3.92-3.88 (m, 2H), 3.75 (dd, J=4.8, 5.8 Hz, 2H), 2.99-2.92 (m, 2H), 2.60-2.52 (m, 3H), 2.36 (s, 3H), 2.12-2.05 (m, 2H), 1.98-1.73 (m, 6H), 1.63-1.55 (m, 2H).

[0243] Example 20 [ka] 4-[2-(1,2,3,5,6,7-Hexahydropyrrolidin-8-ylmethoxy)-7-(1H-indazol-3-yl)-8-methyl-quinazolin-4-yl]-1,4-oxazepane [ka] Step A, 4-[2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-8-methyl-7-(1-tetrahydropyran-2-yl indazol-3-yl)quinazolin-4-yl]-1,4-oxazepane To a degassed suspension of 4-[2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-8-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazolin-4-yl]-1,4-oxazepane (150 mg, 0.3 mmol), 3-bromo-1-tetrahydropyran-2-yl-indazole (124.41 mg, 0.44 mmol) and cesium carbonate (288.4 mg, 0.89 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was added [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (19.23 mg, 0.03 mmol). The mixture was stirred at 95° C. overnight. The reaction mixture was diluted with EtOAc, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (5 g KP NH modified column) eluted with 10%-100% EtOAc / petroleum ether followed by 20% MeOH / DCM. Fractions containing the product were combined and concentrated to give 4-[2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-8-methyl-7-(1-tetrahydropyran-2-ylindazol-3-yl)quinazolin-4-yl]-1,4-oxazepane (81 mg, 47%) as a brown oil. UPLC-MS (ES + , Method 2):1.7 min, m / z 583.3 [M+H] +

[0244] Step B, 4-[2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-7-(1H-indazol-3-yl)-8-methyl-quinazolin-4-yl]-1,4-oxazepane A solution of 4-[2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-8-methyl-7-(1-tetrahydropyran-2-ylindazol-3-yl)quinazolin-4-yl]-1,4-oxazepane (80 mg, 0.14 mmol) in a mixture of DCM (2 mL), methanol (2 mL) and trifluoroacetic acid (0.11 mL, 1.37 mmol) was added at room temperature and stirred overnight. The reaction solution was warmed to 40° C. and 4N hydrochloric acid (0.34 mL, 1.37 mmol) in dioxane was added to the reaction solution. This was stirred at room temperature over the weekend. The crude product was purified by flash column chromatography eluting with 10%-100% EtOAc / petroleum ether followed by 20% MeOH / DCM. The desired fractions were concentrated to give 4-[2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-7-(1H-indazol-3-yl)-8-methyl-quinazolin-4-yl]-1,4-oxazepane (4 mg, 6%) as a white solid. UPLC-MS (ES + , Method 1):2.7 min, m / z 499.3 [M+H] + 1 H NMR (400 MHz, DMSO-d 6 ) δ / ppm 3.35 (s, 1H), 7.96 (d, J=8.7 Hz, 1H), 7.65-7.60 (m, 2H), 7.45-7.38 (m, 2H), 7.20-7.16 (m, 1H), 4.09-4.01 (m, 6H), 3.92-3.88 (m, 2H), 3.75 (dd, J=4.8, 5.8 Hz, 2H), 2.99-2.92 (m, 2H), 2.60-2.52 (m, 3H), 2.36 (s, 3H), 2.12-2.05 (m, 2H), 1.98-1.73 (m, 6H), 1.63-1.55 (m, 2H).

[0245] Example 21 [ka] 4-[2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-8-methyl-7-(1-methylindazol-7-yl)quinazolin-4-yl]-1,4-oxazepane 4-[2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-8-methyl-7-(1-methylindazol-7-yl)quinazolin-4-yl]-1,4-oxazepane was prepared by a method similar to that described in Example 12, substituting 7-bromo-1-methyl-1H-indazole for 4-chloro-6-quinazolinecarbonitrile. UPLC-MS (ES + , Method 1):2.9 min, m / z 513.4 [M+H] + 1 H NMR (400 MHz, DMSO-d 6 ) δ / ppm 8.15 (s, 1H), 7.95 (d, J=8.7 Hz, 1H), 7.84 (dd, J=1.1, 7.9 Hz, 1H), 7.26-7.16 (m, 3H), 4.07-4.02 (m, 6H), 3.93-3.88 (m, 2H), 3.78 -3.73 (m, 2H), 3.43 (s, 3H), 2.97-2.90 (m, 2H), 2.56-2.52 (m, 2H), 2.22 (s, 3H), 2.12-2.05 (m, 2H), 1.96-1.71 (m, 6H), 1.61-1.53 ​​(m, 2H).

[0246] Example 22 [ka] 2-Amino-4-[2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-8-methyl-4-(1,4-oxazepan-4-yl)quinazolin-7-yl]benzothiophene-3-carbonitrile [ka] Step A, tert-butyl N-[3-cyano-4-[2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-8-methyl-4-(1,4-oxazepan-4-yl)quinazolin-7-yl]benzothiophen-2-yl]carbamate To a degassed suspension of 4-[7-bromo-2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-8-methyl-quinazolin-4-yl]-1,4-oxazepane (50 mg, 0.11 mmol), tert-butyl N-[3-cyano-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzothiophen-2-yl]carbamate (173.52 mg, 0.43 mmol) and cesium carbonate (105.9 mg, 0.33 mmol) in 1,4-dioxane (2.5 mL) and water (0.25 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium II (15.9 mg, 0.02 mmol). The mixture was stirred at 95° C. overnight. The reaction was diluted with 20% MeOH / DCM, filtered and concentrated to give a black solid. The crude product was purified by flash column chromatography (5 g KP NH modified column) eluting with 0-100% EtOAc / petroleum ether followed by 20% MeOH / DCM. The desired fractions were combined and concentrated in vacuo to give tert-butyl N-[3-cyano-4-[2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-8-methyl-4-(1,4-oxazepan-4-yl)quinazolin-7-yl]benzothiophen-2-yl]carbamate (30 mg, 43%) as a yellow oil. UPLC-MS (ES + , Method 2):1.9 min, m / z 655.5 [M+H] +

[0247] Step B, 2-amino-4-[2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-8-methyl-4-(1,4-oxazepan-4-yl)quinazolin-7-yl]benzothiophene-3-carbonitrile To a solution of tert-butyl N-[3-cyano-4-[2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-8-methyl-4-(1,4-oxazepan-4-yl)quinazolin-7-yl]benzothiophen-2-yl]carbamate (30 mg, 0.05 mmol) in DCM (1 mL) was added trifluoroacetic acid (0.04 mL, 0.46 mmol) at room temperature and stirred for 30 min. The mixture was concentrated and the crude product was purified by flash chromatography eluting with 10%-100% EtOAc / petroleum ether followed by 20% MeOH / DCM. The desired fractions were combined, dried and concentrated to give an off-white residue. This was dissolved in DCM (1 ml) and purified by HPLC on a SXC column (NH 3 / MeOH) and the solvent removed from the product-containing fractions to give 2-amino-4-[2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-8-methyl-4-(1,4-oxazepan-4-yl)quinazolin-7-yl]benzothiophene-3-carbonitrile (4 mg, 15%) as an off-white solid. UPLC-MS (ES + , Method 1):2.9 min, m / z 555.3 [M+H] + 1 H NMR (400 MHz, DMSO-d 6 ) δ / ppm 7.85 (d, J=8.4 Hz, 1H), 7.72 (dd, J=1.1, 7.9 Hz, 1H), 7.67 (s, 2H), 7.20 (dd, J=7.6, 7.6 Hz, 1H), 7.09-7.04 (m, 2H), 4.09-3.99 (m, 6H), 3.92-3.88 (m, 2H), 3.77-3.72 (m, 2H), 3.05-2.94 (m, 2H), 2.55 -2.50 (m, 2H), 2.23 (s, 3H), 2.07 -2.06 (m, 2H), 1.91 (s, 2H), 1.84-1.78 (m, 4H), 1.71-1.60 (m, 2H).

[0248] Example 23 [ka] 1-[2-(1,2,3,5,6,7-Hexahydropyrrolidin-8-ylmethoxy)-8-methyl-4-(1,4-oxazepan-4-yl)quinazolin-7-yl]isoquinolin-3-amine 1-[2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-8-methyl-4-(1,4-oxazepan-4-yl)quinazolin-7-yl]isoquinolin-3-amine was prepared in a similar manner to Example 12, substituting 3-amino-1-bromoisoquinoline for 4-chloro-6-quinazolinecarbonitrile. UPLC-MS (ES + , Method 1):2.6 min, m / z 525.3 [M+H] + 1 H NMR (400 MHz, DMSO-d 6 ) δ / ppm 7.96-7.93 (m, 1H), 7.62-7.60 (m, 1H), 7.46-7.40 (m, 1H), 7.20 - 7.03 (m, 3H), 6.69 (s, 1H), 6.09-6.01 (bs, 2H), 4.10-4.03 (m, 6H), 3.92 (dd, J=4.5, 4.5 Hz, 2H), 3.75 (dd, J=5.3, 5.3 Hz, 2H), 2.97-2.91 (m, 2H), 2.55-2.52 (m, 2H), 2.23, 2.21 (s, 3H), 2.12-2.06 (m, 2H), 1.96-1.72 (m, 6H), 1.62-1.54 (m, 2H).

[0249] Example 24 [ka] 4-[7-(8-ethynyl-7-fluoro-3-hydroxy-1-naphthyl)-2-[[rac-(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-8-methyl-quinazolin-4-yl]-1,4-diazepan-2-one [ka] Step A, 4-(7-bromo-2-chloro-8-methyl-quinazolin-4-yl)-1,4-diazepan-2-one 1,4-Diazepan-2-one (234.59 mg, 2.06 mmol) was added to a stirred solution of 7-bromo-2,4-dichloro-8-methylquinazoline (300 mg, 1.03 mmol) and N,N-diisopropylethylamine (0.6 mL, 3.43 mmol) in DCM (7 mL) at 0° C. and the reaction mixture was allowed to stand for 2 h. The reaction mixture was dry loaded directly onto silica. The product was purified by flash column chromatography (12 g SiO 2 ) and eluted first with 20-100% EtOAc / petroleum ether, then with 0-20% MeOH / DCM. The desired fractions were combined and concentrated in vacuo to give 4-(7-bromo-2-chloro-8-methyl-quinazolin-4-yl)-1,4-diazepan-2-one (382.5 mg, 100% yield) as a powdery white solid. UPLC-MS (ES + , Method 2):1.7 min, m / z 371.0 [M+H] +

[0250] Step B, 4-(7-bromo-8-methyl-2-methylsulfanyl-quinazolin-4-yl)-1,4-diazepan-2-one Sodium methanethiolate (135.54 mg, 1.93 mmol) was added to a solution of 4-(7-bromo-2-chloro-8-methyl-quinazolin-4-yl)-1,4-diazepan-2-one (357.4 mg, 0.97 mmol) in dry DMF (10 mL) and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated to dryness. The residue was taken up in EtOAc (30 mL) and silica was added for dry loading. The product was purified by flash column chromatography on silica gel (12 g) eluting first with 20-100% EtOAc / petroleum ether, then 0-20% MeOH / DCM. The desired fractions were combined and concentrated under reduced pressure to give 4-(7-bromo-8-methyl-2-methylsulfanyl-quinazolin-4-yl)-1,4-diazepan-2-one (312.4 mg, 0.81 mmol, yield 84) as a pale yellow powder. UPLC-MS (ES + , Method 2):1.8 min, m / z 382.4 [M+H] + 1 H NMR (400 MHz, DMSO-d 6 ) δ / ppm 7.87 (d, J = 9.1 Hz, 1H), 7.77-7.71 (m, 1H), 7.53 (d, J = 9.0 Hz, 1H), 4.29 (s, 2H), 3.99-3.92 (m, 2H), 3.09-3.01 (m, 2H), 2.64 (s, 3H) 2.53 (s, 3H), 2.08-1.98 (m, 2H).

[0251] Step C, 4-[7-bromo-8-methyl-2-[[rac-(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]quinazolin-4-yl]-1,4-diazepan-2-one To a stirred solution of 4-(7-bromo-8-methyl-2-methylsulfanyl-quinazolin-4-yl)-1,4-diazepan-2-one (312.4 mg, 0.82 mmol) in DCM (25 mL) was added m-chloroperbenzoic acid (m-CPBA) (565.56 mg, 3.28 mmol) at 0° C. The reaction mixture was stirred for 2.5 h. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was concentrated to dryness. The resulting residue was dissolved in dry THF (30 mL) and [rac-(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methanol (391.31 mg, 2.46 mmol) was added. Sodium tert-butoxide (1.23 mL, 2.46 mmol) (2 M in THF) was added dropwise and the reaction mixture was stirred for 2.5 h. The reaction mixture was concentrated to dryness. The resulting residue was redissolved in DCM (5 mL) and THF (5 mL). Silica was added for dry loading. The product was purified by flash column chromatography on silica gel (25 g) eluting with 0-20% (1M ammonia in MeOH) / DCM. The desired fractions were combined and concentrated to dryness to give 4-[7-bromo-8-methyl-2-[[rac-(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]quinazolin-4-yl]-1,4-diazepan-2-one (304.3 mg, 0.618 mmol, 75% yield) as a translucent yellow gum. UPLC-MS (ES + , Method 2):1.4 min, m / z 494.0 [M+H] +

[0252] Step D, 4-[7-[7-fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1-naphthyl]-8-methyl-2-[[rac-(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]quinazolin-4-yl]-1,4-diazepan-2-one A suspension of 2-[2-fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-naphthyl]ethynyl-triisopropyl-silane (237.65 mg, 0.46 mmol), 4-[7-bromo-8-methyl-2-[[rac-(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]quinazolin-4-yl]-1,4-diazepan-2-one (152.2 mg, 0.31 mmol) and cesium carbonate (201.43 mg, 0.62 mmol) in a mixture of 1,4-dioxane (5 mL) and water (2 mL) was degassed with nitrogen for 15 minutes. [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (40.29 mg, 0.06 mmol) was added and the reaction mixture was heated to 90°C. The reaction mixture was stirred overnight. The reaction mixture was cooled to room temperature and filtered through a plug of Celite (washed twice with MeOH). The filtrate was concentrated to dryness. The resulting residue was taken up in a mixture of MeOH and DCM and silica was added for dry loading. The product was purified by flash column chromatography on silica gel (12 g) eluting with 0-20% (1M ammonia in MeOH) / DCM. The desired fractions were combined and concentrated under reduced pressure to give 4-[7-fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1-naphthyl]-8-methyl-2-[[rac-(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]quinazolin-4-yl]-1,4-diazepan-2-one (32.7 mg, 13% yield) as a brown residue. UPLC-MS (ES + , Method 2):1.92 min, m / z 798.7 [M+H] +

[0253] Step E, 4-[7-(8-ethynyl-7-fluoro-3-hydroxy-1-naphthyl)-2-[[rac-(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-8-methyl-quinazolin-4-yl]-1,4-diazepan-2-one A solution of 4-[2-[[rac-(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7-[7-fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1-naphthyl]-8-methyl-quinazolin-4-yl]-1,4-diazepan-2-one (32.7 mg, 0.04 mmol) in dry THF (2 mL) was cooled to 0° C. 1.0 M tetrabutylammonium fluoride in THF (0.08 mL, 0.08 mmol) was added and the reaction mixture was allowed to warm to room temperature and stirred for 30 minutes. The reaction mixture was concentrated to dryness. The residue was taken up in dry 1,4-dioxane (2 mL). Hydrogen chloride (0.51 mL, 2.05 mmol) (4M in 1,4-dioxane) was added and the reaction mixture was stirred for 50 min. Silica was added and the reaction mixture was concentrated to dryness. The product was purified by flash column chromatography on silica gel (4 g) eluting with 0-20% (1M ammonia / MeOH) / DCM. The desired fractions were combined and concentrated to dryness to give 4-[7-(8-ethynyl-7-fluoro-3-hydroxy-1-naphthyl)-2-[[rac-(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-8-methyl-quinazolin-4-yl]-1,4-diazepan-2-one (11.5 mg, 47% yield) as a brown solid. UPLC-MS (ES + , Method 1):2.9 min, m / z 598.3 [M+H] + 1 H NMR (400 MHz, DMSO-d 6) δ / ppm 10.05 (s, 1H), 7.97-7.92 (m, 1H), 7.90 (d, J = 8.6 Hz, 1H), 7.83-7.78 (m, 1H), 7.43 (t, J = 9.0 Hz, 1H), 7.32 (d, J = 2.6 Hz, 1H), 7.11 (d, J = 8.6 Hz, 1H), 6.94 (d, J = 2.5 Hz, 1H), 4.37 (d, J = 4.7 Hz, 2H), 4.26-3.90 (m, 2H), 3.73 (s, 1H), 3.24-3.13 (m, 4H), 2.87 (s, 1H), 2.18-2.00 (m, 8H), 1.96-1.71 (m, 4H), 1.63-1.52 (m, 1H), 1.37-1.28 (m, 1H), 0.94 (t, J = 7.3 Hz, 1H).

[0254] Example 25 [ka] 4-[8-Fluoro-2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-4-(1,4-oxazepan-4-yl)quinazolin-7-yl]naphthalen-2-ol [ka] Step A, 4-(7-bromo-2-chloro-8-fluoro-quinazolin-4-yl)-1,4-oxazepane A mixture of 7-bromo-2,4-dichloro-8-fluoroquinazoline (500 mg, 1.69 mmol) and DIEA (1485.23 mg, 11.492 mmol) in DCM (10 ml) was heated at −40 °C under N 2 After stirring at 40° C. for 2 h, 1,4-oxazepane (279 mg, 2 mmol) was added and the mixture was heated at −40° C. with N 2 The mixture was stirred under reduced pressure for 0.5 h. The mixture was poured into water (100 mL) and extracted with DCM (25 mL×3). The combined organic layer was washed with brine (50 mL) and diluted with Na 2 SO4 After drying and concentrating in vacuum, the crude product was purified by silica gel column chromatography (petroleum ether / EtOAc=5 / 1 to petroleum ether / EtOAc=2 / 1 v / v) to give 4-(7-bromo-2-chloro-8-fluoro-quinazolin-4-yl)-1,4-oxazepane (500 mg, 82.04%) as a yellow solid. UPLC-MS (ES + , Method 4):1.7 min, m / z 361.9 [M+H] + 1 H NMR (400 MHz, DMSO-d 6 ) δ / ppm 7.89 - 7.86 (m, 1H), 7.70 - 7.66 (m, 1H), 4.09-4.01 (m, 4H), 3.90-3.86 (m, 2H), 3.77 - 3.68 (m, 2H), 2.11 - 2.01 (m, 2H).

[0255] Step B, 4-[2-chloro-8-fluoro-7-[3-(methoxymethoxy)-1-naphthyl]quinazolin-4-yl]-1,4-oxazepane 1,4-Dioxane (4 mL) and H 2 7-Bromo-2-chloro-8-fluoro-4-[1,4]oxazepan-4-yl-quinazoline (300 mg, 0.83 mmol), 2-(3-methoxymethoxy-naphthalen-1-yl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (261 mg, 0.83 mmol), Pd(dppf)Cl in O (1 mL). 2 (60.9 mg, 0.08 mmol) and K 2 CO 3 A mixture of (344 mg, 2.496 mmol) was heated at 60 °C with N 2The mixture was stirred at rt for 1.5 h. The mixture was concentrated in vacuo. The crude product was purified by silica gel column (petroleum ether / EtOAc=5 / 1 to petroleum ether / EtOAc=2 / 1 v / v) to give 4-[2-chloro-8-fluoro-7-[3-(methoxymethoxy)-1-naphthyl]quinazolin-4-yl]-1,4-oxazepane (300 mg, 77%) as a yellow solid. UPLC-MS (ES + , Method 4):1.9min, m / z 468.1 [M+H] + 1 H NMR (400 MHz, DMSO-d 6 ) δ / ppm 8.13 - 8.07 (m, 1H), 7.97 - 7.92 (m, 1H) 7.62 - 7.31 (m, 6H), 5.38 (s, 2H), 4.18 - 4.10 (m, 4H), 3.96 - 3.91 (m, 2H), 3.78 - 3.71 (m, 2H), 3.46 (s, 3H), 2.16 - 2.06 (m, 2H).

[0256] Step C, 4-[8-fluoro-2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-7-[3-(methoxymethoxy)-1-naphthyl]quinazolin-4-yl]-1,4-oxazepane A mixture of (tetrahydro-pyrrolidin-7a-yl)-methanol (171 mg, 1.2 mmol) in DMF (8 ml) was heated at 0° C. with N 2 After stirring under reduced pressure, NaH (77 mg, 3.248 mmol) was added and stirred at 0° C. for 0.5 h. 2-Chloro-8-fluoro-7-(3-methoxymethoxy-naphthalen-1-yl)-4-[1.4]oxazepan-4-yl-quinazoline (190 mg, 0.4 mmol) in DMF (2 mL) was added to the reaction mixture. The mixture was warmed to 65° C. and stirred overnight. The mixture was poured into water (20 mL) and extracted with EtOAc (20 mL×3). The combined organic layer was washed with brine (40 mL) and diluted with Na 2 SO 4Drying over and concentration in vacuo afforded 4-[8-fluoro-2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-7-[3-(methoxymethoxy)-1-naphthyl]quinazolin-4-yl]-1,4-oxazepane (70 mg, 30%) as a yellow solid. UPLC-MS (ES + , Method 4):1.9min, m / z 573.2 [M+H] + 1 H NMR (400 MHz, DMSO-d 6 ) δ / ppm 8.04-7.88 (m, 2H), 7.61 - 7.28 (m, 6H), 5.38 (s, 2H), 4.55 (s, 2H), 4.17 - 4.09 (m, 4H), 3.95 - 3.89 (m, 2H), 3.77 - 3.66 (m, 2H), 3.57 - 3.50 (m, 4H), 3.26 - 3.19 (m, 2H), 2.18 - 1.91 (m, 10H).

[0257] Step D, 4-[8-fluoro-2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-4-(1,4-oxazepan-4-yl)quinazolin-7-yl]naphthalen-2-ol A mixture of 4-[8-fluoro-2-(1,2,3,5,6,6,7-hexahydropyrrolidin-8-ylmethoxy)-7-[3-(methoxymethoxy)-1-naphthyl]quinazolin-4-yl]-1,4-oxazepane (60 mg, 0.10 mmol) in HCl-1,4-dioxane (4 M, 4 mL) was diluted with N 2 After stirring at 25° C. for 0.5 h under reduced pressure, the mixture was concentrated to give 4-[8-fluoro-2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-4-(1,4-oxazepan-4-yl)quinazolin-7-yl]naphthalen-2-ol (23.6 mg, 42%) as a white solid which was analyzed as the HCl salt. UPLC-MS (ES + , Method 4):1.0min, m / z 529.2 [M+H] + 1 H NMR (400 MHz, DMSO-d 6 ) δ / ppm 10.71 (s, 1H), 10.07 (s, 1H), 8.02 (d, J = 8.8 Hz, 1H), 7.80 (d, J = 8.3 Hz, 1H), 7.47 - 7.37 (m, 2H), 7.33 - 7.22 (m, 3H), 7.13 (d, J = 2.4 Hz, 1H), 4.56 (s, 2H), 4.13 (m, 4H), 3.93 (m, 2H), 3.75 (m, 2H), 3.51 (m, 2H), 3.23 - 3.16 (m, 2H), 2.12 (m, 6H), 2.03 - 1.95 (m, 4H).

[0258] Example 26 [ka] 5-Ethynyl-6-fluoro-4-[8-fluoro-4-(1,4-oxazepan-4-yl)-2-[[rac-(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]quinazolin-7-yl]naphthalen-2-ol [ka] Step A, 4-[7-bromo-8-fluoro-2-[[rac-(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]quinazolin-4-yl]-1,4-oxazepane 7-Bromo-2-chloro-8-fluoro-4-[1,4]oxazepan-4-yl-quinazoline (500 mg, 1.38 mmol) and (2-fluoro-tetrahydro-pyrrolidin-7a-yl)-methanol (220 mg, 1.38 mmol) in DMF (15 ml) were added to N 2 After stirring at 0° C. under reduced pressure, NaH (266 mg, 11.1 mmol) was added and stirred at 0° C. for 0.5 h. The reaction mixture was allowed to stand at room temperature overnight. The mixture was diluted with saturated NH 4The mixture was poured into aqueous Cl (150 mL) and extracted with EtOAc (40 mL×3). The combined organic layers were washed with brine (60 mL) and 2 SO 4 The mixture was dried over 100 ml of ethyl acetate and concentrated. The crude product was purified by silica gel column chromatography (DCM / MeOH=50 / 1 to DCM / MeOH=10 / 1, v / v) to give 4-[7-bromo-8-fluoro-2-[[rac-(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]quinazolin-4-yl]-1,4-oxazepane (550 mg, 82%) as a yellow solid. UPLC-MS (ES + , Method 4):0.9min, m / z 485.1 [M+H] + 1 H NMR (400 MHz, DMSO-d 6 ) δ / ppm 7.80 - 7.74 (m, 1H), 7.47 - 7.41 (m, 1H), 4.09 - 3.98 (m, 4H), 3.82 - 3.79 (m, 2H), 3.74 - 3.71 (m, 2H), 3.60 - 3.51 (m, 4H), 3.11 - 3.07 (m, 2H), 2.86 - 2.81 (m, 1H), 2.06 - 1.77 (m, 6H), 1.48 - 1.44 (m, 2H).

[0259] Step B, 2-[2-fluoro-8-[8-fluoro-4-(1,4-oxazepan-4-yl)-2-[[rac-(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]quinazolin-7-yl]-6-(methoxymethoxy)-1-naphthyl]ethynyl-triisopropyl-silane 3:1 1,4-dioxane / H 2O = 4-[7-bromo-8-fluoro-2-[[rac-(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]quinazolin-4-yl]-1,4-oxazepane (200 mg, 0.414 mmol), 2-{7-fluoro-3-methoxymethoxy-8-[(triisopropylsilanyl)-ethynyl]-naphthalen-1-yl}-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (318 mg, 0.62 mmol), Pd(dtpbf)Cl in (20 mL). 2 (26.7mg, 0.04mmol) and Cs 2 CO 3 (269.6mg, 0.82mmol) was added to N 2 The mixture was stirred at 50° C. for 2 hours under reduced pressure. The mixture was concentrated in vacuum and purified by silica gel column chromatography (DCM / MeOH=50 / 1 to DCM / MeOH=30 / 1, v / v) to give 2-[2-fluoro-8-[8-fluoro-4-(1,4-oxazepan-4-yl)-2-[[rac-(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]quinazolin-7-yl]-6-(methoxymethoxy)-1-naphthyl]ethynyl-triisopropyl-silane (120 mg, 37%) as a yellow solid. UPLC-MS (ES + , Method 4):1.9min, m / z 789.3 [M+H] +

[0260] Step C, 4-[7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[rac-(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]quinazolin-4-yl]-1,4-oxazepane A mixture of 2-[2-fluoro-8-[8-fluoro-4-(1,4-oxazepan-4-yl)-2-[[rac-(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]quinazolin-7-yl]-6-(methoxymethoxy)-1-naphthyl]ethynyl-triisopropyl-silane (110 mg, 0.139 mmol) and CsF (105.5 mg, 0.69 mmol) in DMF (10 mL) was stirred at 25° C. for 1 h. The mixture was poured into water (100 mL) and extracted with EtOAc (25 mL x 3). The combined organic layer was washed with brine (50 mL) and concentrated to 100 mL with NaCl. 2 SO 4 After drying and concentration, the crude product 4-[7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[rac-(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]quinazolin-4-yl]-1,4-oxazepane (100 mg, 90.69%) was obtained as a dark black solid, which was used directly in the next step. UPLC-MS (ES + , Method 4):1.3min, m / z 633.1 [M+H] +

[0261] Step D, 5-ethynyl-6-fluoro-4-[8-fluoro-4-(1,4-oxazepan-4-yl)-2-[[rac-(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]quinazolin-7-yl]naphthalen-2-ol A mixture of 4-[7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-2-[[rac-(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]quinazolin-4-yl]-1,4-oxazepane (90 mg, 0.14 mmol) in HCl-dioxane (4M, 5 mL) was stirred at room temperature for 0.5 hours. The mixture was concentrated in vacuo and subjected to preparative HPLC purification to give 5-ethynyl-6-fluoro-4-[8-fluoro-4-(1,4-oxazepan-4-yl)-2-[[rac-(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]quinazolin-7-yl]naphthalen-2-ol (23 mg, 28%) as a yellow solid. UPLC-MS (ES + , Method 4):1.8min, m / z 589.1 [M+H] + 1 H NMR (400 MHz, DMSO-d 6 ) δ / ppm 7.97 - 7.93 (m, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.47 - 7.43 (m, 1H), 7.35 (s, 1H), 7.19 - 7.16 (m, 1H), 7.06 (s, 1H), 5.28 (d, J = 54.1 Hz, 1H), 4.11 - 3.99 (m, 6H), 3.90 (d, J = 9.0 Hz, 2H), 3.76 (s, 2H), 3.15 - 2.99 (m, 4H), 2.86 - 2.82 (m, 1H), 2.18 - 1.69 (m, 8H).

[0262] Example 27 [ka] 8-Fluoro-2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-7-(3-hydroxy-1-naphthyl)-4-(1,4-oxazepan-4-yl)quinazoline-6-carbonitrile [ka] Step A, 2-amino-4-bromo-3-fluoro-5-iodo-benzoic acid To a solution of 2-amino-4-bromo-3-fluorobenzoic acid (4.84 g, 20.68 mmol) in DMF (20 mL) was added N-iodosuccinimide (6.98 g, 31.02 mmol) at rt. The mixture was stirred at 80° C. for 3 h, cooled to rt, and poured into water (200 mL). The fine precipitate was collected by filtration. The precipitate in the filter was washed with DCM / MeOH. The solution was reduced in vacuum. The dark solid was triturated with 20 mL, collected by vacuum filtration, and dried in vacuum at 50° C. to give 2-amino-4-bromo-3-fluoro-5-iodobenzoic acid (5.8 g, 78%) as an orange solid. UPLC-MS (ES + , Method 2):1.8min, m / z 359.9 / 361.8 [M+H] + 1 H NMR (400 MHz, DMSO-d 6 ) δ / ppm 13.36 (bs, 1H), 7.99 (s, 1H), 6.90 (bs, 2H).

[0263] Step B, Methyl 2-amino-4-bromo-3-fluoro-5-iodo-benzoate To a solution of 2-amino-4-bromo-3-fluoro-5-iodobenzoic acid (50 mg, 0.14 mmol) in DMF (0.5 mL) was added cesium carbonate (67.89 mg, 0.21 mmol). The suspension was stirred at rt for 2 h before adding iodomethane (8.65 uL, 0.14 mmol) diluted in DMF (0.5 mL). The mixture was stirred at rt over the weekend before being poured into brine. The aqueous layer was extracted with EtOAc (x4). The combined organics were washed with brine and diluted with Na 2 SO 4Drying at rt and concentration in vacuo afforded methyl-2-amino-4-bromo-3-fluoro-5-iodo-benzoate (41 mg, 80%) as a red solid. UPLC-MS (ES + , Method 2):2.1min, m / z 373.9 / 375.9 [M+H] + 1 H NMR (400 MHz, DMSO-d 6 ) δ / ppm 7.98 (d, J=1.8 Hz, 1H), 6.86 (bs, 2H), 3.83 (s, 3H).

[0264] Step C, Methyl 4-bromo-3-fluoro-5-iodo-2-(trichloromethylcarbamoylamino)benzoate To a stirred solution of methyl-2-amino-4-bromo-3-fluoro-5-iodo-benzoate (2000 mg, 5.35 mmol) in THF (50 mL) was added trichloroacetyl isocyanate (0.7 mL, 5.88 mmol) dropwise at rt. After 4 h, the volatiles were removed in vacuo. The residue was dissolved in Et 2 Trituration with O afforded methyl-4-bromo-3-fluoro-5-iodo-2-(trichloromethylcarbamoylamino)benzoate (2.8 g, 100%) as an off-white solid. UPLC-MS (ES + , Method 2):1.6min, m / z 416.9 / 418.9 [M+H] + 1 H NMR (400 MHz, DMSO-d 6 ) δ / ppm 1.83 (bs, 1H), 10.03 (s, 1H), 8.17 (d, J=1.7 Hz, 1H), 3.82 (s, 3H).

[0265] Step D, 7-bromo-8-fluoro-6-iodo-quinazoline-2,4-diol 7M ammonia / MeOH (3.63mL, 25.43mmol) was added to a suspension of methyl 4-bromo-3-fluoro-5-iodo-2-[(2,2,2-trichloroacetyl)carbamoylamino]benzoate (2860mg, 5.09mmol) in methanol (50mL) at room temperature and stirred at room temperature for 30 minutes. All volatiles were then removed under reduced pressure. The residue was triturated with diethyl ether and 7-bromo-8-fluoro-6-iodo-quinazoline-2,4-diol was collected as a white solid by filtration and dried under reduced pressure (1.9g, 100%). UPLC-MS (ES + , Method 2):1.6min, m / z 382.8 / 384.8 [MH] + 1 H NMR (400 MHz, DMSO-d 6 ) δ / ppm 8.27 (bs, 2H) ,8.07 (d, J=1.6 Hz, 1H) ppm.

[0266] Step E, 7-bromo-2-chloro-8-fluoro-6-iodo-quinazolin-4-ol A suspension of 7-bromo-8-fluoro-6-iodo-quinazoline-2,4-diol (954 mg, 2.48 mmol) in phosphorus oxychloride (6.93 mL, 74.35 mmol) was heated to 100° C., after which N,N-diisopropylethylamine (1.08 mL, 6.2 mmol) was added. The mixture was stirred at 100° C. for 2 h and cooled. The mixture was diluted with NaHCO 3 Poured into a stirred solution of (aq, sat, 500 mL) and extracted with DCM (x4). The combined organics were washed with brine and 2 SO 4 Drying at 40° C. and concentration in vacuo afforded 7-bromo-2-chloro-8-fluoro-6-iodo-quinazolin-4-ol (868 mg) as an orange solid which was used without purification. UPLC-MS (ES + , Method 2):2.39min, m / z 400.7 / 402.8 / 404.7 [MH]+

[0267] Step F, 4-(7-bromo-2-chloro-8-fluoro-6-iodo-quinazolin-4-yl)-1,4-oxazepane In an ice bath, 2 To a mixture of HATU (2 g, 5.34 mmol) and 7-bromo-2-chloro-8-fluoro-6-iodoquinazolin-4-ol (1077 mg, 2.67 mmol) in DMA (13 mL) was added N,N-diisopropylethylamine (2.79 mL, 16.02 mmol) under ambient conditions. After 30 min, [1,4]-oxazepane (0.59 mL, 5.34 mmol) was added at 0° C. The ice bath was removed and stirring was continued at room temperature. After 2 h, the mixture was diluted with DCM and washed with brine. The aqueous layer was extracted with DCM (×3), passed through a phase separator and concentrated under reduced pressure in vacuo. The residue was purified by flash chromatography (SiO 2 , 12 g, dry loaded in EtOAc / petroleum ether 0-100%) and residual solvent removed by co-distillation with toluene (x4). The product containing fractions were evaporated and further dried under vacuum to give 4-(7-bromo-2-chloro-8-fluoro-6-iodo-quinazolin-4-yl)-1,4-oxazepane (955 mg, 74%) as an orange solid. UPLC-MS (ES + , Method 2):2.2min, m / z 485.8 / 487.8 / 489.8 [M+H] + 1 H NMR (400 MHz, CDCl 3 ) δ / ppm 8.26 (d, J=2.0 Hz, 1H), 4.13 - 4.05 (m, 4H), 3.98 (dd, J=5.8, 3.3 Hz, 2H), 3.89 - 3.79 (m, 2H), 2.20 (m, 2H).

[0268] Step G, 7-bromo-2-chloro-8-fluoro-4-(1,4-oxazepan-4-yl)quinazoline-6-carbonitrile A mixture of 4-(7-bromo-2-chloro-8-fluoro-6-iodo-quinazolin-4-yl)-1,4-oxazepane (887 mg, 1.82 mmol) and copper cyanide (326.58 mg, 3.65 mmol) in DMF (9 mL) was dissolved in N 2 The mixture was purged with N for 15 min at 100 °C. 2 After 4.5 h, the mixture was cooled, diluted with EtOAc and washed with brine. The aqueous layer was extracted with EtOAc (x2) and the combined organics were washed with a minimal amount of brine. The organics were washed with Na 2 SO 4 The mixture was dried over 500 ml, concentrated in vacuo under reduced pressure, and the residual DMF was co-distilled with toluene (x2). The crude product was purified by flash chromatography (SiO 2 , 12 g, dry loaded into EtOAc / petroleum ether 0-70%) and the desired fractions concentrated to give 7-bromo-2-chloro-8-fluoro-4-(1,4-oxazepan-4-yl)quinazoline-6-carbonitrile (360 mg, 51%) as a yellow solid. UPLC-MS (ES + , Method 2):1.9min, m / z 385.0 / 387.0 [M+H] + 1 H NMR (400 MHz, CDCl 3 ) δ / ppm 8.52 (d, J=1.7 Hz, 1H), 4.15-4.07 (m, 4H), 3.91-3.86 (m, 2H), 3.70 (m, 2H), 2.04 (m, 2H).

[0269] Step H, 2-chloro-8-fluoro-7-[3-(methoxymethoxy)-1-naphthyl]-4-(1,4-oxazepan-4-yl)quinazoline-6-carbonitrile 2-(3-(2-methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (325.16 mg, 1.03 mmol), 7-bromo-2-chloro-8-fluoro-4-(1,4-oxazepan-4-yl)quinazoline-6-carbonitrile (307 mg, 0.8 mmol), cesium carbonate (518.78 mg, 1.59 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane complex (130.03 mg, 0.16 mmol) were suspended in 1,4-dioxane (7 mL) and 1,4-dioxane (7 mL). The vial was sealed and purged with N 2 The mixture was irradiated in a microwave to an internal temperature of 100° C. After 2 h, the resulting mixture was collected, filtered, and concentrated. The residue was purified by flash chromatography (SiO 2 , 4 g, dry loaded in EtOAc / petroleum ether 0-100%) and concentrated fractions containing product to give 2-chloro-8-fluoro-7-[3-(methoxymethoxy)-1-naphthyl]-4-(1,4-oxazepan-4-yl)-6-carbonitrile (136 mg, 22%) as a yellow solid. UPLC-MS (ES + , Method 2):2.1min, m / z 493.1 / 495.0 [M+H] + 1 H NMR (400 MHz, DMSO-d 6 ) δ / ppm 8.62 (d, J= .1 Hz, 1H), 7.99 (d, J=8.2 Hz, 1H), 7.70 (d, =2.5 Hz, 1H),7.60 -7.54 (m, 1H), 7.43 (d, J=2.5 Hz, 1H), 7.41 -7.37 (m, 2H), 5.42 (s, 2H), 4.25-4.15 (m, 4H), 3.96-3.92 (m, 2H), 3.77-3.70 (m, 2H), 3.47 (s, 3H), 2.14 -2.02 (m, 2H).

[0270] Step I, 8-fluoro-2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-7-[3-(methoxymethoxy)-1-naphthyl]-4-(1,4-oxazepan-4-yl)quinazoline-6-carbonitrile A solution of 2-chloro-8-fluoro-7-[3-(methoxymethoxy)-1-naphthyl]-4-(1,4-oxazepan-4-yl)quinazoline-6-carbonitrile (110 mg, 0.22 mmol), (tetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (126.05 mg, 0.89 mmol) and N,N-diisopropylethylamine (0.23 mL, 1.34 mmol) in dry 1,4-dioxane (1 mL) in a sealed vial was heated to 100° C. After 8 h, the temperature was reduced to 70° C. and stirring was continued overnight. The mixture was cooled to rt, the volatiles were removed in vacuo, and the mixture was dry loaded onto Celite and subjected to reverse phase chromatography (SiO 2 -C18, 4g, MeCN / H 2 O, 0~100%, 0.1% (NH 4 ) 2 CO 3 The desired fraction was concentrated to give 8-fluoro-2-(1,2,3,5,6,7-hexahydropyrrolidine-8-(methoxymethoxy)-7-[3-(methoxymethoxy)-1-naphthyl]-4-(1,4-oxazepan-4-yl)quinazoline-6-carbonitrile (56 mg, 42%) as a yellow solid. UPLC-MS (ES + , Method 2):1.7min, m / z 598.3 [M+H] + 1 H NMR (400 MHz, DMSO-d 6) δ / ppm 8.50 (s, 1H), 7.98 (d, J=8.4 Hz, 1H), 7.68 (d, J=2.4 Hz, 1H), 7.57 (ddd, J=3.6, 4.6, 8.3 Hz, 1H), 7.40 (d, J=2.5 Hz, 1H), 7.38 (d, J=4.0 Hz, 1H), 5.40 (s, 2H), 4.21-4.12 (m, 4H), 3.94 (m, 2H), 3.74 (m, 2H), 3.47 (s, 3H), 2.68 (m, 2H).

[0271] Step J, 8-fluoro-2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-7-(3-hydroxy-1-naphthyl)-4-(1,4-oxazepan-4-yl)quinazoline-6-carbonitrile To a solution of 8-fluoro-2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-7-[3-(methoxymethoxy)-1-naphthyl]-4-(1,4-oxazepan-4-yl)quinazoline-6-carbonitrile (54 mg, 0.09 mmol) and triethylsilane (0.04 mL, 0.27 mmol) in DCM (1.8 mL) was added trifluoroacetic acid (0.21 mL, 2.71 mmol). The mixture was stirred at rt. After 90 min, all volatiles were removed and the residue was dry loaded onto Celite and subjected to reverse phase chromatography (C18-SiO 2 , 4g, MeCN / H 2 O, 0~100%, 0.1%(NH 4 ) 2 CO 3 ) to give 8-fluoro-2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-7-(3-hydroxy-1-naphthyl)-4-(1,4-oxazepan-4-yl)quinazoline-6-carbonitrile (25 mg, 50%) as a yellow solid. UPLC-MS (ES + , Method 1):3.0min, m / z 554.4 [M+H] + 1H NMR (400 MHz, DMSO-d 6 ) δ / ppm 10.10 (s, 1H), 8.49 (s, 1H), 7.85 (d, J=8.4 Hz, 1H), 7.48 (ddd, J=1.8, 6.3, 8.1 Hz, 1H), 7.34 (d, J=2.3 Hz, 1H), 7.30 (d, J=7.8 Hz, 1H), 7.26 (dt, J=1.1, 7.3 Hz, 1H), 7.17 (d, J=2.4 Hz, 1H), 4.20-4.10 (m, 6H), 3.93 (m, 2H), 3.74 (m, 2H), 3.01 (m, 1H), 2.56-2.51 (m, 2H), 2.09 (m, 2H), 1.98-1.88 (m, 2H), 1.88-1.72 (m, 4H), 1.70-1.56 (m, 2H).

[0272] biological results HTRF nucleotide exchange assay The binding ability of compounds to KRAS G12D, other KRAS mutants and wild-type RAS isoforms was quantified using a HTRF nucleotide exchange assay. Recombinant human RAS protein (2 nM; aa1-188 KRAS WT, HRAS WT, NRAS WT, or KRAS with amino acid substitutions of G12D, G13D or Q61H or 4 nM KRAS; aa1-188 with amino acid substitutions of G12V, G12C, G12A or G12S, N-terminal 6xHis tag and leader sequence) and 2 nM europium-labeled anti-6xHis antibody were incubated in assay buffer (10 mM HEPES pH 7.3, 150 mM NaCl, 5 mM MgCl 2, 0.05% BSA, 0.0025% NP-40, 100 mM KF) in a 384-well plate with various concentrations of compounds. After 60 min incubation at room temperature, 5 ul of 200 nM EDA-GTP-DY647P1 (diluted in assay buffer) was added to the plate. After 30 min incubation at room temperature, time-resolved fluorescence was measured on a PerkinElmer Envision plate reader. DMSO (0.3%) and unlabeled GDP (1 μM) or equivalent tool compound were used to obtain Max and Min assay signals, respectively. Data are presented as IC 50 At least two independent replicates were performed for each compound, and the results are shown in Table 5. 50 In the table, "A" stands for IC 50 ≦10nM, "B" is IC50>10nM-100nM, "C" is >100nM-10μM, "D" is >10%-49% inhibition at 10μM, ND=undetermined:

[0273] [Table 5]

[0274] As can be seen from Table 5, the compounds of the present invention exhibit KRAS inhibition covering a broad range of KRAS proteins, including wild type KRAS and mutant KRAS.

Claims

1. Formula (I): 【Chemical 1】 [wherein, R 1 is selected independently from C 0 -C 3 -alkylene-R 1a and C 2 -C 6 -alkylene-R 1b ; where R 1a is a 4- to 7-membered heterocycloalkyl ring, a fused or spiro-fused bicyclic 6- to 11-membered heterocycloalkyl group optionally substituted with 1 to 4 R 9 groups and is selected independently from C 3 -C 7 -cycloalkyl ring; said heterocycloalkyl ring or said cycloalkyl ring may optionally be substituted with 1 to 4 R 9 groups; R 1b is independently selected from OR 8 , SR 8 , SOR 8 , SO 2 R 8 , SO(NH)R 8 , OC(O)R 8 and SO 2 NR 7 R 8 ; or R 1 and R 5 together with the nitrogen to which they are attached form a monocyclic 4- to 7-membered heterocycloalkyl group optionally substituted with 1 to 4 R 9 groups; and a fused, spiro-fused or bridged bicyclic 6- to 11-membered heterocycloalkyl group optionally substituted with 1 to 4 R 9 groups; wherein R 1 and R 5 are selected such that NR 1 R 5 contains one or fewer amines, said one amine may be a primary, secondary or tertiary amine; R 2 is, independently, C 1 -C 6 -alkyl, C 1 -C 4 -haloalkyl, C 0 -C 4 -alkylene-R 2a 、C 1 -C 4 -alkylene-R 2b 、C 2 -C 4 -alkylene-R 2c and; R 2a is independently selected from a monocyclic 4- to 7-membered heterocycloalkyl group; a fused, spiro-fused or bridged bicyclic 6- to 11-membered heterocycloalkyl group; a 5-, 6-, 9- or 10-membered monocyclic or bicyclic heteroaryl group; phenyl; and C 3 -C 7 -cycloalkyl; wherein the R 2a group, when it is any heterocycloalkyl or cycloalkyl, may optionally be substituted with 1 to 6 R 10 groups, and the R 2a group, when it is any heteroaryl or phenyl, may optionally be substituted with 1 to 6 R 11 groups; R 2b is CONR 12 R 12 and CO 2 R 12 is independently selected from; R 2c is NR 12 R 13 and OR 12 is independently selected from; or R 2 and R 6 together with the nitrogen to which they are attached form a ring system selected from monocyclic 4- to 7-membered heterocycloalkyl groups; and fused, spiro-fused or bridged bicyclic 6- to 11-membered heterocycloalkyl groups, said heterocycloalkyl group being optionally substituted with 1 to 6 R 10 groups; R 3a 、R 3b and R 3c are each independently selected from H, halo, C 1 -C 4 -alkyl, O-C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, O-C 1 -C 4 -haloalkyl, cyclopropyl, nitro and cyano: R 4 is phenyl (the phenyl may be optionally condensed with a C 5 -C 7 - cycloalkyl ring); naphthyl; and independently selected from 5-membered, 6-membered, 9-membered or 10-membered monocyclic or bicyclic heteroaryl, where R 4 may optionally be substituted with 1 to 4 R 14 groups; R 5 、R 6 、R 8 and R 12 are each independently selected from H, C 1 -C 4 -haloalkyl and C 1 -C 4 -alkyl; R 7 and R 13 each independently is selected from H, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl and C(O)-C 1 -C 4 -alkyl; R 9 and R 10 are each independently oxo, halo, cyano, NR 12 R 13 , OR 12 , CO 2 R 12 , CONR 12 R 12 , C 1 -C 4 -alkyl, NR 12 R 13 -substituted C 1 -C 4 -alkyl, OR 12 -substituted C 1 -C 4 -alkyl, cyano-substituted C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, C 1 -C 4 -haloalkyl and cyclopropyl; R 11 and R 14 are each independently selected from halo, cyano, nitro, NR 12 R 13 , OR 12 CO 2 R 12 CONR 12 R 12 C 1 -C 4 -alkyl, NR 12 R 13 substituted C 1 -C 4 -alkyl, OR 12 substituted C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, C 1 -C 4 -haloalkyl and cyclopropyl; and any of the alkyl, alkylene or cyclopropyl groups may optionally be substituted with 1 to 5 substituents each independently selected from the group consisting of C 1 -C 4 -alkyl, halo, nitro, cyano, NR a R b , OR a SR a CO 2 R a C(O)R a CONR a R a ; where R a is independently selected from H, C 1 -C 4 -alkyl and C 1 -C 4 -haloalkyl; and R b is independently selected from H, C 1 -C 4 -alkyl, C(O)-C 1 -C 4 -alkyl and S(O) 2 -C 1 -C 4 -alkyl selected independently from each other] a compound of, or a pharmaceutically acceptable salt thereof.

2. R 1 and R 5 together with the nitrogen to which they are attached form a monocyclic 4- to 7-membered heterocycloalkyl group optionally substituted with 1 to 4 R 9 groups; a fused or spiro-fused bicyclic 6- to 11-membered heterocycloalkyl group optionally substituted with 1 to 4 R 9 groups; and a bridged bicyclic 6- to 11-membered heterocycloalkyl group optionally substituted with 1 to 4 R 9 groups, wherein the nitrogen to which R 1 and R 5 are attached is the only nitrogen within the ring, the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

3. R 1 and R 5 is NR 1 R 5 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein one of the nitrogens of NR is selected such that one of the nitrogens is an amine.

4. R 1 is C 0 -C 3 -alkylene-R 1a wherein R 1a is independently selected from a 4- to 7-membered heterocycloalkyl ring; and a C 7 R 8 -cycloalkyl ring substituted with an NR 3 -C 7 -group; and the heterocycloalkyl ring or the cycloalkyl ring may optionally be substituted with 1 to 4 R 9 -groups; a compound according to claim 1 or a pharmaceutically acceptable salt thereof.

5. R 1 and R 5 together with the nitrogen to which they are attached form a monocyclic 4- to 7-membered heterocycloalkyl group optionally substituted with 1 to 4 R 9 groups; and a fused or spiro-fused bicyclic 6- to 11-membered heterocycloalkyl group optionally substituted with 1 to 4 R 9 groups, the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

6. R 1 and R 5 together with the nitrogen to which they are attached form the following structure: [Chemical Formula 2] (wherein R 9a is selected from NR 12 R 13 and NR 12 R 13 substituted C 1 -C 4 -alkyl; p1 is selected from 0, 1, 2 and 3; q1 is selected from 0, 1 and 2; and r1 is selected from 0, 1, 2 and 3) The compound according to claim 5, or a pharmaceutically acceptable salt thereof, which forms a ring system having

7. R 1 and R 5 together with the nitrogen to which they are attached form the following structure: 【Chemical 3】 (wherein Z 6 is independently selected from C(O)NR 9b , O, S, S(O) 2 , S(O), S(O)(NR 9b ), and S(O)(NH); R 9b is selected from H and C 1 -C 4 -alkyl; p2 is selected from 2 and 3; q2 is 2; and r2 is selected from 0, 1, 2, and 3) The compound according to claim 5, or a pharmaceutically acceptable salt thereof, which forms a ring system having

8. R 1 and R 5 together with the nitrogen to which they are attached form a bridged bicyclic 6- to 11-membered heterocycloalkyl group optionally substituted with 1 to 4 R 9 groups, the compound according to claim 5 or a pharmaceutically acceptable salt thereof.

9. R 2 has the following structure: 【Chemical 4】 (wherein, R 15 is independently selected from H, C 1 -C 4 -alkyl; wherein, R 16 is independently selected from H, C 1 -C 4 -alkyl and cyclopropyl; or, R 15 and R 16 together with the atom to which they are attached form a 5- or 6-membered heterocycloalkyl ring, which may optionally be substituted with 1 or 2 R 10 groups; and y is independently selected from 0, 1, 2, 3 and 4) The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which has

10. R 2 has the following structure: 【Chemical Formula 5】 (wherein z is independently selected from 0, 1, 2, 3 and 4) The compound according to claim 9, or a pharmaceutically acceptable salt thereof, which has

11. R 3b The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R is F.

12. R 3a and R 3c both are H, the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

13. R 4 is phenyl, and the phenyl may optionally be C 5 -C 7 -condensed with a cycloalkyl ring, and R 4 may optionally be substituted with 1 to 4 R 14 groups, the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

14. R 4 has the following structure: [[Chemical Formula 6]] (wherein x is independently selected from 0, 1, 2, 3 and 4) The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which has

15. R 4 has the following structure: 【Chemical Formula 7】 (wherein, R 12a is independently H or C 1 -C 4 -alkyl; and x2 is independently selected from 0, 1, 2, and 3) The compound according to claim 14, or a pharmaceutically acceptable salt thereof, which has

16. R 4 is a 5-, 6-, 9- or 10-membered monocyclic or bicyclic heteroaryl which may optionally be substituted with 1 to 4 R 14 groups, and is the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

17. The compound of formula (I) is the following: [Chemical Formula 8] 【Chemical Formula 9】 【Chemical Formula 10】 【Chemical 11】 【Chemical 12】 【Chemical 13】 【Chemical 14】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is selected from

18. A medicament comprising the compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof.

19. The medicament according to claim 18, for use in the treatment of cancer.

20. The medicament for use according to claim 19, wherein the cancer is selected from pancreatic cancer, colorectal cancer, rectal cancer, endometrial cancer, non-small cell lung cancer, gastric cancer, ovarian cancer and small cell lung cancer.

21. The medicament for use according to claim 19, wherein the subject to be treated suffers from cancer having wild-type KRAS.

22. The medicament for use according to claim 19, wherein the subject to be treated suffers from cancer having a KRAS mutation selected from KRAS G12D, KRAS G12C, KRAS G12V, KRAS G12A, KRAS G13D and KRAS Q61H.

23. A pharmaceutical composition comprising the compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

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