compound

Abstract

The present invention relates to a compound that may be useful for inhibiting RAS protein. More specifically, the present invention relates to a compound for inhibiting broad-spectrum KRAS mutant protein. Therefore, the compound of the present invention can be used to treat conditions mediated by KRAS protein. For example, the compound can be used to treat cancer.

Description

[Technical Field]

[0001] The present invention relates to compounds and their use methods. In particular, the compounds of the present invention can be 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 conditions mediated by KRAS protein. For example, the compounds can be used to treat cancer. [Background technology]

[0002] RAS (HRAS, KRAS4A and 4B, and NRAS) proteins are a group of closely related monomeric globular proteins that function as molecular switches, cycling between inactive (GDP-bound) and active (GTP-bound) states to transmit upstream cellular signals to downstream effectors and regulate various processes, including cell proliferation. RAS is the most frequently mutated oncogene in cancer (approximately 30%), and KRAS is the most commonly mutated isoform, accounting for approximately 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 that causes an amino acid substitution in which glycine (G) at position 12 of the codon is replaced by aspartic acid. It is the most common KRAS mutation in cancer, accounting for approximately 26% of all KRAS mutations. 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 high unmet medical needs, with few effective targeted therapy options available. For many of these patients, the mainstay of treatment remains chemotherapy combinations, which are associated with significant side effects and lack efficacy.

[0004] Amino acid substitutions at codon 12, codon 13, and codon 61, as well as other KRAS missense gains in function mutations that cause amplification of wild-type KRAS protein, also lead to the development of cancer. Substitutions in KRAS are found in approximately one in seven cancers (Hoffman et al., Cancer Discovery (2022) 12, 924-937). Activating mutations in KRAS are very common in solid tumors, primarily found in 35% of lung cancers, 45% of colorectal cancers, and up to 90% of pancreatic cancers. G12D, G12V, and G12C are the most frequently occurring KRAS mutations, found in more than half of KRAS-induced cancers. Other KRAS mutations include KRAS G12V, KRAS G12A, KRAS G13D, and KRAS Q61H. KRAS amplification is found in approximately 7% of cancers with KRAS substitutions and commonly occurs in ovarian, breast, lung, gastric, uterine, and esophagogastric cancers (Hoffman review). Pan-KRAS inhibitors have the potential to treat a broader range of patients, including those with KRAS mutations, as well as cancers resulting from amplification of wild-type KRAS and loss of the tumor suppressor NF1. Furthermore, pan-KRAS inhibitors could potentially be used to treat cancers with acquired resistance to allele-specific inhibitors (e.g., KRAS G12C inhibitors).

[0005] Due to the high prevalence of KRAS mutations in multiple different tumor types and the established role of KRAS as a causative 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 affecting KRAS activity has proven challenging, and research efforts have focused on other targets in the signaling pathways upstream or downstream of KRAS. Other approaches to inhibit KRAS activity include acting at other points in the MAPK pathway (English et al., 2002; Adjei 2014; Chin et al., 2020), many of which have demonstrated MAPK pathway inhibition and clinical efficacy. Recently, a selective inhibitor of mutant KRAS G12C was reported (Kettle and Cassar 2020), which irreversibly binds to the allotropic pocket and has progressed to clinical trials, demonstrating responses in select 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), however, these compounds are thought to be of limited therapeutic benefit due to insufficient potency and little selectivity for KRAS over HRAS and NRAS isoforms.

[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 some embodiments of the present invention to provide novel compounds for use in treating conditions regulated by RAS proteins. For example, it is an object of some embodiments of the present invention to provide compounds for use in treating cancer. The compounds may be more selective for KRAS proteins having the G12D mutation than other KRAS proteins compared to prior art compounds. Alternatively, the compounds may have broad-spectrum activity against KRAS proteins.

[0009] It is an object of some embodiments of the present invention to provide novel cancer treatments. In particular, it is an object of some embodiments of the present invention to provide compounds that have activity comparable to existing treatments, and, optionally, should have activity superior to existing treatments.

[0010] It is an object of some embodiments of the present invention to provide compounds that exhibit reduced cytotoxicity compared to prior art compounds and existing treatments.

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

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

[0013] In accordance with the present invention, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof: [ka] [In the formula, Z 1 are independently -O- and -NR 5 -Selected from; Z 2 are independently absent, -O- and -NR 6 -Selected from; L 1 is a bond and -C(R 18 )2-Selected X 1 is -C(R 3a )2 and -NR 3b -Selected from; R 1 are independently C0-C3-alkylene-R 1a and C2-C6-alkylene-R 1b where R is selected from 1a are independently a 4- to 7-membered heterocycloalkyl ring; a phenyl ring; and NR 7 R 8 wherein the heterocycloalkyl ring, the phenyl ring or the cycloalkyl ring is selected from a C3-C7 cycloalkyl ring optionally substituted with 1 to 4 R 9 optionally substituted with R 1b is independent, NR 7 R 8 , OR 8 , S.R. 8 , SOR 8 , SO2R 8 and SO(NH)R 8 Select from; Alternatively, R 1 and R 5 together with the nitrogen to which they are attached, form 1 to 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, spirofused or bridged bicyclic 6- to 11-membered heterocyclyl groups, optionally substituted with a group; R 2 are independently C1-C6-alkyl, C1-C4-haloalkyl, C0-C4-alkylene-R 2a , C1-C4-alkylene-R 2b , C2-C4-alkylene-R 2c and; R2a are 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; C3-C7-cycloalkyl; wherein R is any heterocycloalkyl or cycloalkyl; 2a The group is 1 to 6 R 10 R is optionally substituted with a heteroaryl or phenyl group. 2a The group is 1 to 6 R 11 optionally substituted with groups; where R 2b independently, CONR 12 R 12 and CO2R 12 Selected from; where R 2c is independent, NR 12 R 13 and OR 12 Select from; Alternatively, 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 groups; R 3a is independently at each occurrence H, C1-C4-alkyl, C1-C4-haloalkyl, NR 12 R 13 C1-C4-alkyl substituted with OR 12 or wherein two R 3a groups, taken together with the carbons to which they are attached, form a spiro-fused cyclopropyl group; R 3b is independently selected from H, C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl; R 4 is independently selected from phenyl, said phenyl optionally fused to a C5-C7 cycloalkyl ring; naphthyl; monocyclic 4- to 7-membered cycloalkyl or heterocycloalkyl; and 5- to 10-membered monocyclic or bicyclic heterocyclyl; wherein R 4 is 1 to 4 R 14 optionally substituted with groups; R 5 , R 6 , R 8 and R 12 each occurrence independently selected from H, C1-C4-haloalkyl, cyclopropyl, and C1-C4-alkyl; R 7 and R 13 is independently selected at each occurrence from H, C1-C4-alkyl, C1-C4-haloalkyl and C(O)-C1-C4-alkyl; Alternatively, R 12 and R 13 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 groups; R 9 each occurrence independently represents oxo, halo, cyano, or NR 12 R 13 , OR 12 , C.O.R. 12 , CO2R 12 ,CONR 12 R 12 ,CONR 12 R 13 , C1-C4-alkyl, NR 12 R 13 C1-C4-alkyl substituted with OR 12C1-C4-alkyl substituted with, C1-C4-alkyl substituted with cyano, C1-C4-alkyl substituted with phenyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl; R 10 each occurrence independently represents oxo, halo, cyano, or NR 12 R 13 , OR 12 , C.O.R. 12 , CO2R 12 ,CONR 12 R 12 , C1-C4-alkyl, NR 12 R 13 C1-C4-alkyl substituted with OR 12 C1-C4-alkyl substituted with, C1-C4-alkyl substituted with cyano, C1-C4-alkyl substituted with phenyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl; R 11 are independently halo, cyano, nitro, and NR 12 R 13 , OR 12 , CO2R 12 ,CONR 12 R 12 , C1-C4-alkyl, NR 12 R 13 C1-C4-alkyl substituted with OR 12 C1-C4-alkyl substituted with, monocyclic 4- to 7-membered cycloalkyl or heterocycloalkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl; R 14 are each independently H, halo, cyano, nitro, or NR 12 R 13 , OR 12 , CO2R 12 ,CONR 12 R 12 , C1-C4-alkyl, NR 12 R 13 C1-C4-alkyl substituted with OR 12C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, phenyl and cyclopropyl substituted with; R 18 are each independently H, halo, cyano, nitro, or NR 12 R 13 , OR 12 , CO2R 12 ,CONR 12 R 12 , C1-C4-alkyl, NR 12 R 13 C1-C4-alkyl substituted with OR 12 or wherein two R are selected from C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl substituted with 18 groups, taken together with the carbons to which they are attached, form a spiro-fused cyclopropyl group; wherein any of the aforementioned alkyl, alkylene, phenyl or cyclopropyl groups may be optionally substituted, where chemically possible, with 1 to 5 substituents independently selected at each occurrence from the group consisting of: C1-C4-alkyl, OR a C1-C4-alkyl, halo, nitro, cyano, NR a R b , OR a , S.R. a , CO2R a , C(O)R a ,CONR a R a ;where R a is independently selected at each occurrence from H, C1-C4-alkyl and C1-C4-haloalkyl; R b is independently selected at each occurrence from H, C1-C4-alkyl, C(O)-C1-C4-alkyl and S(O)2-C1-C4-alkyl.

[0014] In accordance with the present invention, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof: [ka] [In the formula, Z 1 are independently -O- and -NR 5 -Selected from; Z 2 are independently absent or -O- and -NR 6 -Selected from; L 1 is a bond and -C(R 18 )2-Selected X 1 is -C(R 3a )2 and -NR 3b -Selected from; R 1 are independently C0-C3-alkylene-R 1a and C2-C6-alkylene-R 1b where R is selected from 1a are independently an oxygen-containing 4- to 7-membered heterocycloalkyl ring, a 4- to 7-membered heterocycloalkyl ring; and NR 7 R 8 wherein the heterocycloalkyl ring or the cycloalkyl ring is selected from a C3-C7 cycloalkyl ring substituted with 1 to 4 R 9 optionally substituted with R 1b is independent, NR 7 R 8 , OR 8 , S.R. 8 , SOR 8 , SO2R 8 and SO(NH)R 8 Select from; Alternatively, R 1 and R 5 together with the nitrogen to which they are attached, form 1 to 4 R 9 a monocyclic 4- to 7-membered heterocycloalkyl group optionally substituted with a group; 9 forming a ring system selected from fused, spirofused or bridged bicyclic 6- to 11-membered heterocyclyl groups, optionally substituted with a group; R 2are independently C1-C6-alkyl, C1-C4-haloalkyl, C0-C4-alkylene-R 2a , C1-C4-alkylene-R 2b , C2-C4-alkylene-R 2c and; R 2a are independently selected from: a monocyclic 4- to 7-membered heterocycloalkyl group; a fused, spirofused, or bridged bicyclic 6- to 11-membered heterocycloalkyl group; a 5-, 6-, 9-, or 10-membered monocyclic or bicyclic heteroaryl group; phenyl; C3-C7-cycloalkyl; wherein R is any heterocycloalkyl or cycloalkyl; 2a The group is 1 to 6 R 10 R may be optionally substituted with a group and is any heteroaryl or phenyl. 2a The group is 1 to 6 R 11 optionally substituted with groups; where R 2b independently, CONR 12 R 12 and CO2R 12 Selected from; where R 2c is independent, NR 12 R 13 and OR 12 Select from; Alternatively, 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, 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 groups; R 3a is independently at each occurrence H, C1-C4-alkyl, C1-C4-haloalkyl, NR 12 R 13 C1-C4-alkyl substituted with OR 12 or wherein two R3a groups, taken together with the carbons to which they are attached, form a spiro-fused cyclopropyl group; R 3b is independently selected from H, C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl; R 4 are independently selected from phenyl, optionally fused to a C5-C7 cycloalkyl ring; naphthyl; monocyclic 4- to 7-membered cycloalkyl or heterocycloalkyl; and 5- to 10-membered monocyclic or bicyclic heterocyclyl, wherein R 4 is 1 to 4 R 14 optionally substituted with groups; R 5 , R 6 , R 8 and R 12 is independently selected at each occurrence from H, C1-C4-haloalkyl, and C1-C4-alkyl; R 7 and R 13 is independently selected at each occurrence from H, C1-C4-alkyl, C1-C4-haloalkyl and C(O)-C1-C4-alkyl; Alternatively, R 12 and R 13 together with the nitrogen to which they are attached form a ring system selected from monocyclic 4- to 7-membered heterocycloalkyl groups, 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 groups; R 9 and R 10 each occurrence independently represents oxo, halo, cyano, or NR 12 R 13 , OR 12 , CO2R 12 ,CONR 12 R 12 , C1-C4-alkyl, NR 12 R 13 C1-C4-alkyl substituted with OR 12C1-C4-alkyl substituted with, C1-C4-alkyl substituted with cyano, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl; R 11 are independently halo, cyano, nitro, and NR 12 R 13 , OR 12 , CO2R 12 ,CONR 12 R 12 , C1-C4-alkyl, NR 12 R 13 C1-C4-alkyl substituted with OR 12 C1-C4-alkyl substituted with, monocyclic 4- to 7-membered cycloalkyl or heterocycloalkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl; R 14 are each independently H, halo, cyano, nitro, or NR 12 R 13 , OR 12 , CO2R 12 ,CONR 12 R 12 , C1-C4-alkyl, NR 12 R 13 C1-C4-alkyl substituted with OR 12 C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl substituted with; R 18 are each independently H, halo, cyano, nitro, or NR 12 R 13 , OR 12 , CO2R 12 ,CONR 12 R 12 , C1-C4-alkyl, NR 12 R 13 C1-C4-alkyl substituted with OR 12 or wherein two R are selected from C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl substituted with18 groups, taken together with the carbons to which they are attached, form a spiro-fused cyclopropyl group; wherein any of the aforementioned alkyl, alkylene or cyclopropyl groups may be optionally substituted, where chemically possible, with 1 to 5 substituents independently selected at each occurrence from the group consisting of C1-C4-alkyl, halo, nitro, cyano, NR a R b , OR a , S.R. a , CO2R a , C(O)R a ,CONR a R a ;where R a is independently selected at each occurrence from H, C1-C4-alkyl and C1-C4-haloalkyl; R b is independently selected at each occurrence from H, C1-C4-alkyl, C(O)-C1-C4-alkyl and S(O)2-C1-C4-alkyl.

[0015] In accordance with the present invention, there is provided a compound of formula (Ia), or a pharmaceutically acceptable salt thereof: [ka] [In the formula, L 1 is a bond and -C(R 18 )2-selected; X 1 is -C(R 3a )2 and -NR 3b -Selected from; R 1 are independently C0-C3-alkylene-R 1a and C2-C6-alkylene-R 1b where R is selected from 1a are independently a 4- to 7-membered heterocycloalkyl ring; a phenyl ring; and NR 7 R 8wherein the heterocycloalkyl ring, the phenyl ring or the cycloalkyl ring is selected from a C3-C7 cycloalkyl ring optionally substituted with 1 to 4 R 9 optionally substituted with R 1b is independent, NR 7 R 8 , OR 8 , S.R. 8 , SOR 8 , SO2R 8 and SO(NH)R 8 Select from; Alternatively, R 1 and R 5 together with the nitrogen to which they are attached, form 1 to 4 R 9 a monocyclic 4- to 7-membered heterocycloalkyl group optionally substituted with a group; 9 forming a ring system selected from fused, spirofused or bridged bicyclic 6- to 11-membered heterocyclyl groups, optionally substituted with a group; R 2 are independently C1-C6-alkyl, C1-C4-haloalkyl, C0-C4-alkylene-R 2a , C1-C4-alkylene-R 2b , C2-C4-alkylene-R 2c and; R 2a are 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; C3-C7-cycloalkyl; wherein R is any heterocycloalkyl or cycloalkyl; 2a The group is 1 to 6 R 10 R is optionally substituted with a heteroaryl or phenyl group. 2a The group is 1 to 6 R 11 optionally substituted with groups; where R 2b independently, CONR 12 R 12 and CO2R 12 Selected from; where R 2c is independent, NR 12 R 13 and OR 12 Select from; Alternatively, 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, 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 groups; R 3a is independently at each occurrence H, C1-C4-alkyl, C1-C4-haloalkyl, NR 12 R 13 C1-C4-alkyl substituted with OR 12 or wherein two R 3a groups, taken together with the carbons to which they are attached, form a spiro-fused cyclopropyl group; R 3b is independently selected from H, C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl; R 4 are independently selected from phenyl, optionally fused with a C5-C7 cycloalkyl ring; naphthyl; monocyclic 4- to 7-membered cycloalkyl or heterocycloalkyl; and 5- to 10-membered monocyclic or bicyclic heterocyclyl; 4 is 1 to 4 R 14 optionally substituted with groups; R 5 , R 6 , R 8 and R 12 are each independently selected at each occurrence from H, C1-C4-haloalkyl, cyclopropyl, and C1-C4-alkyl; R 7 and R 13is independently selected at each occurrence from H, C1-C4-alkyl, C1-C4-haloalkyl and C(O)-C1-C4-alkyl; Alternatively, R 12 and R 13 together with the nitrogen to which they are attached form a ring system selected from a monocyclic 4- to 7-membered heterocycloalkyl group, a fused, spiro-fused or bridged bicyclic 6- to 11-membered heterocycloalkyl group; said heterocycloalkyl group being selected from 1 to 6 R 10 optionally substituted with groups; R 9 and R 10 each occurrence independently represents oxo, halo, cyano, or NR 12 R 13 , OR 12 , C.O.R. 12 , CO2R 12 ,CONR 12 R 12 ,CONR 12 R 13 , C1-C4-alkyl, NR 12 R 13 C1-C4-alkyl substituted with OR 12 C1-C4-alkyl substituted with, C1-C4-alkyl substituted with cyano, C1-C4-alkyl substituted with phenyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl; R 11 are independently halo, cyano, nitro, and NR 12 R 13 , OR 12 , CO2R 12 ,CONR 12 R 12 , C1-C4-alkyl, NR 12 R 13 C1-C4-alkyl substituted with OR 12 C1-C4-alkyl substituted with, monocyclic 4- to 7-membered cycloalkyl or heterocycloalkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl; R 14independently for each occurrence: H, halo, cyano, nitro, NR 12 R 13 , OR 12 , CO2R 12 ,CONR 12 R 12 , C1-C4-alkyl, NR 12 R 13 C1-C4-alkyl substituted with OR 12 C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, phenyl and cyclopropyl substituted with; R 18 independently for each occurrence: H, halo, cyano, nitro, NR 12 R 13 , OR 12 , CO2R 12 ,CONR 12 R 12 , C1-C4-alkyl, NR 12 R 13 C1-C4-alkyl substituted with OR 12 or wherein two R are selected from C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl substituted with 18 groups, taken together with the carbons to which they are attached, form a spiro-fused cyclopropyl group; wherein any of the aforementioned alkyl, alkylene, phenyl or cyclopropyl groups may be optionally substituted, where chemically possible, with 1 to 5 substituents independently selected at each occurrence from the group consisting of: C1-C4-alkyl, OR a C1-C4-alkyl, halo, nitro, cyano, NR a R b , OR a , S.R. a , CO2R a , C(O)R a ,CONR a R a ;where R a is independently selected at each occurrence from H, C1-C4-alkyl and C1-C4-haloalkyl; R bis independently selected at each occurrence from H, C1-C4-alkyl, C(O)-C1-C4-alkyl and S(O)2-C1-C4-alkyl.

[0016] In accordance with the present invention, there is provided a compound of formula (Ia), or a pharmaceutically acceptable salt thereof: [ka] [In the formula, L 1 is a bond and -C(R 18 )2-Selected X 1 is -C(R 3a )2 and -NR 3b -Selected from; R 1 are independently C0-C3-alkylene-R 1a and C2-C6-alkylene-R 1b where R is selected from 1a are independently an oxygen-containing 4- to 7-membered heterocycloalkyl ring, a 4- to 7-membered heterocycloalkyl ring; and NR 7 R 8 wherein the heterocycloalkyl ring or the cycloalkyl ring is selected from a C3-C7 cycloalkyl ring substituted with 1 to 4 R 9 optionally substituted with R 1b is independent, NR 7 R 8 , OR 8 , S.R. 8 , SOR 8 , SO2R 8 and SO(NH)R 8 Select from; Alternatively, R 1 and R 5 together with the nitrogen to which they are attached, form 1 to 4 R 9 a monocyclic 4- to 7-membered heterocycloalkyl group optionally substituted with a group; 9 forming a ring system selected from fused, spirofused or bridged bicyclic 6- to 11-membered heterocyclyl groups, optionally substituted with a group; R2 are independently C1-C6-alkyl, C1-C4-haloalkyl, C0-C4-alkylene-R 2a , C1-C4-alkylene-R 2b , C2-C4-alkylene-R 2c and; R 2a are independently selected from: a monocyclic 4- to 7-membered heterocycloalkyl group; a fused, spirofused, or bridged bicyclic 6- to 11-membered heterocycloalkyl group; a 5-, 6-, 9-, or 10-membered monocyclic or bicyclic heteroaryl group; phenyl; C3-C7-cycloalkyl; wherein R is any heterocycloalkyl or cycloalkyl; 2a The group is 1 to 6 R 10 R is optionally substituted with a heteroaryl or phenyl group. 2a The group is 1 to 6 R 11 optionally substituted with groups; where R 2b independently, CONR 12 R 12 and CO2R 12 Selected from; where R 2c is independent, NR 12 R 13 and OR 12 Select from; Alternatively, 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, 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 groups; R 3a is independently at each occurrence H, C1-C4-alkyl, C1-C4-haloalkyl, NR 12 R 13 C1-C4-alkyl substituted with OR 12or wherein two R are selected from C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl substituted with 3a groups, taken together with the carbons to which they are attached, form a spiro-fused cyclopropyl group; R 3b is independently selected from H, C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl; R 4 is independently selected from phenyl, said phenyl optionally fused to a C5-C7 cycloalkyl ring; naphthyl; monocyclic 4- to 7-membered cycloalkyl or heterocycloalkyl; and 5- to 10-membered monocyclic or bicyclic heterocyclyl, wherein R 4 is 1 to 4 R 14 optionally substituted with groups; R 5 , R 6 , R 8 and R 12 are each independently selected at each occurrence from H, C1-C4-haloalkyl, and C1-C4-alkyl; R 7 and R 13 is independently selected at each occurrence from H, C1-C4-alkyl, C1-C4-haloalkyl and C(O)-C1-C4-alkyl; Alternatively, R 12 and R 13 together with the nitrogen to which they are attached form a ring system selected from monocyclic 4- to 7-membered heterocycloalkyl groups, 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 R 9 and R 10 each occurrence independently represents oxo, halo, cyano, or NR 12 R 13 , OR 12 , CO2R 12 ,CONR 12 R 12, C1-C4-alkyl, NR 12 R 13 C1-C4-alkyl substituted with OR 12 C1-C4-alkyl substituted with, C1-C4-alkyl substituted with cyano, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl; R 11 are independently halo, cyano, nitro, and NR 12 R 13 , OR 12 , CO2R 12 ,CONR 12 R 12 , C1-C4-alkyl, NR 12 R 13 C1-C4-alkyl substituted with OR 12 C1-C4-alkyl substituted with, monocyclic 4- to 7-membered cycloalkyl or heterocycloalkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl; R 14 independently for each occurrence: H, halo, cyano, nitro, NR 12 R 13 , OR 12 , CO2R 12 ,CONR 12 R 12 , C1-C4-alkyl, NR 12 R 13 C1-C4-alkyl substituted with OR 12 C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl substituted with; R 18 independently for each occurrence: H, halo, cyano, nitro, NR 12 R 13 , OR 12 , CO2R 12 ,CONR 12 R 12 , C1-C4-alkyl, NR 12 R 13 C1-C4-alkyl substituted with OR 12or wherein two R are selected from C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl substituted with 18 groups, taken together with the carbons to which they are attached, form a spiro-fused cyclopropyl group; wherein any of the aforementioned alkyl, alkylene or cyclopropyl groups may be optionally substituted, where chemically possible, with 1 to 5 substituents independently selected at each occurrence from the group consisting of C1-C4-alkyl, halo, nitro, cyano, NR a R b , OR a , S.R. a , CO2R a , C(O)R a ,CONR a R a ;where R a is independently selected at each occurrence from H, C1-C4-alkyl and C1-C4-haloalkyl; R b is independently selected at each occurrence from H, C1-C4-alkyl, C(O)-C1-C4-alkyl and S(O)2-C1-C4-alkyl.

[0017] In certain embodiments, the compound of Formula (I) is a compound of Formula (II): [ka] [In the formula, R 1 , R 2 , R 14 , L 1 , X 1 , Z 1 and Z 2 is as defined 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.

[0018] In certain embodiments, the compound of Formula (I) is a compound of Formula (IIa): [ka] [In the formula, R 1 , R 2 , R 5 , R 14 , L 1 and X 1 is as defined 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.

[0019] In certain embodiments, the compound of Formula (I) is a compound of Formula (III): [ka] [In the formula, R 1 , R 4 , R 10 , L 1 , X 1 , Z 1 and Z 2 is as described above for compounds of formula (I); 15 are independently selected from H, C1-C4 alkyl; 16 are independently selected from H, C1-C4-alkyl and cyclopropyl; or where R 15 and R 16 together with the atoms to which they are attached, form one or two R 10 y is independently selected from 0, 1, 2, 3, and 4.

[0020] In certain embodiments, the compound of Formula (I) is a compound of Formula (IIIa): [ka] [In the formula, R 1 , R 4 , R 10 , L 1 and X1 is as described above for compounds of formula (I); 15 are independently selected from H, C1-C4 alkyl; 16 are independently selected from H, C1-C4-alkyl and cyclopropyl; or where R 15 and R 16 together with the atoms to which they are attached, form one or two R 10 y is independently selected from 0, 1, 2, 3, and 4.

[0021] In certain embodiments, the compound of Formula (I) is a compound of Formula (IV): [ka] [In the formula, R 1 , R 10 , R 14 , L 1 , X 1 , Z 1 and Z 2 is as described above for compounds of formula (I); 15 are independently selected from H, C1-C4 alkyl; 16 are independently selected from H, C1-C4-alkyl and cyclopropyl; or where R 15 and R 16 together with the atoms to which they are attached, form 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.

[0022] In certain embodiments, the compound of Formula (I) is a compound of Formula (IVa): [ka] [In the formula, R 1 , R 5 , R10 , R 14 , L 1 and X 1 is as described above for compounds of formula (I); 15 are independently selected from H, C1-C4 alkyl; 16 are independently selected from H, C1-C4-alkyl and cyclopropyl; or where R 15 and R 16 together with the atoms to which they are attached, form 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.

[0023] In certain embodiments, the compound of Formula (I) is a compound of Formula (V): [ka] [In the formula, R 1 , R 4 , R 10 , L 1 , X 1 , Z 1 and Z 2 are as defined above for compounds of formula (I); where z is independently selected from 0, 1, 2, 3, and 4. For the avoidance of doubt, throughout this specification it is intended that z R 10 The group may be attached to either ring of the pyrrolididinyl group.

[0024] In certain embodiments, the compound of Formula (I) is a compound of Formula (Va): [ka] [In the formula, R 1 , R 4 , R 5 , R 10 , L 1 , and X 1are as defined above for compounds of formula (I); where z is independently selected from 0, 1, 2, 3, and 4. For the avoidance of doubt, throughout this specification it is intended that z R 10 The group may be attached to either ring of the pyrrolididinyl group.

[0025] In certain embodiments, the compound of Formula (I) is a compound of Formula (VI): [ka] [In the formula, R 1 , R 10 , R 14 , L 1 , X 1 , Z 1 and Z 2 is as described above for compounds of formula (I); where x is independently selected from 0, 1, 2, 3, and 4; and where z is independently selected from 0, 1, 2, 3, and 4.

[0026] In certain embodiments, the compound of Formula (I) is a compound of Formula (VIa): [ka] [In the formula, R 1 , R 5 , R 10 , R 14 , L 1 , and X 1 is as described above for compounds of formula (I); where x is independently selected from 0, 1, 2, 3, and 4; and where z is independently selected from 0, 1, 2, 3, and 4.

[0027] In certain embodiments, the compound of Formula (I) or (Ia) is a compound of Formula (VII): [ka] [In the formula, R 1 , R 2 , R 3a , R 4 and R5 is as described above for compounds of formula (I) or (Ia)].

[0028] In certain embodiments, the compound of Formula (I) or (Ia) is a compound of Formula (VIII): [ka] [In the formula, R 1 , R 2 , R 3a , R 5 and R 14 is as described above for compounds of formula (I) or (Ia); and x is independently selected from 0, 1, 2, 3, and 4.

[0029] In certain embodiments, the compound of Formula (I) is a compound of Formula (IX): [ka] [In the formula, R 1 , R 2 , R 3a , R 4 , Z 1 and Z 2 is as described above for compounds of formula (I)].

[0030] In certain embodiments, the compound of Formula (I) or (Ia) is a compound of Formula (IXa): [ka] [In the formula, R 1 , R 2 , R 3a , R 4 and Z 1 is as described above for compounds of formula (I) or (Ia)].

[0031] In certain embodiments, the compound of Formula (I) or (Ia) is a compound of Formula (IXb): [ka] [In the formula, R1 , R 2 , R 3a , R 4 , Z 1 and Z 2 is as described above for compounds of formula (I) or (Ia)].

[0032] In certain embodiments, the compound of Formula (I) is a compound of Formula (X): [ka] [In the formula, R 1 , R 2 , R 3a , R 14 , Z 1 and Z 2 is as defined 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.

[0033] In certain embodiments, the compound of Formula (I) or (Ia) is a compound of Formula (Xa): [ka] [In the formula, R 1 , R 2 , R 3a , 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.

[0034] In certain embodiments, the compound of formula (I) is a compound of formula (XI): [ka] [In the formula, R 1 , R 3a , R4 , R 10 , Z 1 and Z 2 is as described above for compounds of formula (I); 15 are independently selected from H, C1-C4 alkyl; 16 are independently selected from H, C1-C4-alkyl and cyclopropyl; or where R 15 and R 16 together with the atoms to which they are attached, form one or two R 10 y is independently selected from 0, 1, 2, 3, and 4.

[0035] In certain embodiments, the compound of Formula (I) or (Ia) is a compound of Formula (XIa): [ka] [In the formula, R 1 , R 3a , R 4 , R 5 , and R 10 is as described above for compounds of formula (I) or (Ia); 15 are independently selected from H, C1-C4 alkyl; 16 are independently selected from H, C1-C4-alkyl and cyclopropyl; or where R 15 and R 16 together with the atoms to which they are attached, form one or two R 10 y is independently selected from 0, 1, 2, 3, and 4.

[0036] In certain embodiments, the compound of Formula (I) is a compound of Formula (XII): [ka] [In the formula, R 1 , R 3a, R 10 , R 14 , Z 1 and Z 2 is as described above for compounds of formula (I); 15 are independently selected from H, C1-C4 alkyl; 16 are independently selected from H, C1-C4-alkyl and cyclopropyl; or where R 15 and R 16 together with the atoms to which they are attached, form 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.

[0037] In certain embodiments, the compound of Formula (I) or (Ia) is a compound of Formula (XIIa): [ka] [In the formula, R 1 , R 3a , R 5 , R 10 , and R 14 is as described above for compounds of formula (I) or (Ia); 15 are independently selected from H, C1-C4 alkyl; 16 are independently selected from H, C1-C4-alkyl and cyclopropyl; or where R 15 and R 16 together with the atoms to which they are attached, form 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.

[0038] In certain embodiments, the compound of Formula (I) is a compound of Formula (XIII): [ka] [where R 1 , R 3a , R 4 , R 10 , Z 1 and Z 2 are as defined above for compounds of formula (I); where z is independently selected from 0, 1, 2, 3, and 4. For the avoidance of doubt, throughout this specification it is intended that z R 10 The group may be attached to either ring of the pyrrolididinyl group.

[0039] In certain embodiments, the compound of Formula (I) or (Ia) is a compound of Formula (XIII): [ka] [In the formula, R 1 , R 3a , R 4 , R 5 and R 10 are as defined above for compounds of formula (I); where z is independently selected from 0, 1, 2, 3, and 4. For the avoidance of doubt, throughout this specification it is intended that z R 10 The group may be attached to either ring of the pyrrolididinyl group.

[0040] In certain embodiments, the compound of Formula (I) is a compound of Formula (XIV): [ka] [In the formula, R 1 , R 3a , R 10 , R 14 , Z 1 and Z 2 is as described above for compounds of formula (I); where x is independently selected from 0, 1, 2, 3, and 4; and where z is independently selected from 0, 1, 2, 3, and 4.

[0041] In certain embodiments, the compound of Formula (I) or (Ia) is a compound of Formula (XIVa): [ka] [In the formula, R 1 , R 3a , R 5 , R 10 , and R 14 is as described above for compounds of formula (I); where x is independently selected from 0, 1, 2, 3, and 4; and where z is independently selected from 0, 1, 2, 3, and 4.

[0042] In certain embodiments, the compound of Formula (I) or (Ia) is a compound of Formula (XV): [ka] [In the formula, R 1 , R 2 , R 3b , R 4 and R 5 is as described above for compounds of formula (I) or (Ia)].

[0043] In certain embodiments, the compound of Formula (I) or (Ia) is a compound of Formula (XVI): [ka] [In the formula, R 1 , R 2 , R 3b , R 5 and R 14 is as described above for compounds of formula (I) or (Ia); where x is independently selected from 0, 1, 2, 3, and 4].

[0044] In certain embodiments, the compound of Formula (I) or (Ia) is a compound of Formula (XVII): [ka] [In the formula, R 1 , R 2 , R 3a , R 4 , R5 and R 18 is as described above for compounds of formula (I) or (Ia)].

[0045] In certain embodiments, the compound of Formula (I) or (Ia) is a compound of Formula (XVIII): [ka] [In the formula, R 1 , R 2 , R 3a , R 5 , R 14 and R 18 is as described above for compounds of formula (I) or (Ia); and x is independently selected from 0, 1, 2, 3, and 4.

[0046] The following embodiments apply to compounds of any of Formulas (I) to (XVIII). These embodiments are independent and interchangeable. Any one embodiment may be combined with any other embodiment, if chemically permissible. In other words, any feature described in the following embodiments may be combined with one or more other embodiments (if chemically permissible). In particular, when a compound is exemplified or illustrated herein, any two or more of the embodiments listed below, expressed at any level of generality and encompassing that compound, may be combined to provide further embodiments, which form part of the present disclosure.

[0047] L 1 may be a bond. 1 -C(R 18 )2- may also be used.

[0048] R 18 represents independently at each occurrence H, C1-C4 alkyl, NR 12 R 13 C1-C4-alkyl substituted with OR 12or wherein two R 18 The R groups, together with the carbons to which they are attached, form a spiro-fused cyclopropyl group. 18 may be independently selected at each occurrence from H, C1-C4-alkyl, cyclopropyl. 18 The R groups, together with the carbons to which they are attached, may form a spiro-fused cyclopropyl group. 18 may be H for each occurrence, i.e., where L 1 is -(CH2)-.

[0049] X 1 is -C(R 3a )2. X 1 is -NR 3b - may be.

[0050] L 1 is a bond and X 1 -C(R 3a )2. Therefore, L 1 and X 1 The ring containing L is a five-membered ring. 1 is a bond and X 1 Ha-NR 3b - may be. L 1 -C(R 18 )2- and X 1 -C(R 3a )2. Therefore, L and X 1 The ring containing L is a six-membered ring. 1 -C(R 18 )2-, and X 1 Ha-NR 3b - may be.

[0051] Z 1 may be -O-. 1 Ha-NR 5 - may be.

[0052] Z 2 may be -O-. 2 Ha-NR 6 - may be.

[0053] R 1 is C0-C3-alkylene-R 1a where R 1a are independently a 4- to 7-membered heterocycloalkyl ring; a phenyl ring; and NR 7 R 8 wherein the heterocycloalkyl ring, the phenyl ring or the cycloalkyl ring is selected from a C3-C7 cycloalkyl ring optionally substituted with 1 to 4 R 9 It may be optionally substituted with a group.

[0054] R 1 are independently C0-C3-alkylene-R 1a where R 1a are independently a 4- to 7-membered heterocycloalkyl ring; and NR 7 R 8 wherein the heterocycloalkyl ring or the cycloalkyl ring is selected from a C3-C7 cycloalkyl ring substituted with 1 to 4 R 9 It may be optionally substituted with a group.

[0055] R 1 is C0-C3-alkylene-R 1a R 1 is C0-C3-alkylene-R 1a where R 1a are independently an oxygen-containing 4- to 7-membered heterocycloalkyl ring, a 4- to 7-membered heterocycloalkyl ring; and NR 7 R 8 wherein the heterocycloalkyl ring or the cycloalkyl ring is selected from a C3-C7 cycloalkyl ring substituted with 1 to 4 R 9 R 1 is CH2-R 1a where R 1aare independently a 4- to 7-membered heterocycloalkyl ring; and NR 7 R 8 wherein the heterocycloalkyl ring or the cycloalkyl ring is selected from a C3-C7 cycloalkyl ring substituted with 1 to 4 R 9 It may be optionally substituted with a group.

[0056] R 1 is C0-C3-alkylene-R 1a where R 1a are independently an oxygen-containing 4- to 7-membered heterocycloalkyl ring, a nitrogen-containing 4- to 7-membered heterocycloalkyl ring; and NR 7 R 8 wherein the heterocycloalkyl ring or the cycloalkyl ring is selected from a C3-C7 cycloalkyl ring substituted with 1 to 4 R 9 R1 may be optionally substituted with a CH2-R group. 1a where R 1a are independently a nitrogen-containing 4- to 7-membered heterocycloalkyl ring; and NR 7 R 8 wherein the heterocycloalkyl ring or the cycloalkyl ring is selected from a C3-C7 cycloalkyl ring substituted with 1 to 4 R 9 It may be optionally substituted with a group.

[0057] R 1 is R 1a where R 1a are independently a 4- to 7-membered heterocycloalkyl ring; and NR 7 R 8 wherein the heterocycloalkyl ring or the cycloalkyl ring is selected from a C3-C7 cycloalkyl ring substituted with 1 to 4 R 9 It may be optionally substituted with a group.

[0058] R 1 is R 1a where R 1a are independently a nitrogen-containing 4- to 7-membered heterocycloalkyl ring; and NR7 R 8 wherein the heterocycloalkyl ring or the cycloalkyl ring is selected from a C3-C7 cycloalkyl ring substituted with 1 to 4 R 9 R 1 is R 1a where R may be 1a is an oxygen-containing 4- to 7-membered heterocycloalkyl ring; wherein the heterocycloalkyl ring is 9 R1 may be optionally substituted with R 1a where R 1a is an oxygen-containing 4- to 7-membered heterocycloalkyl ring, such as a tetrahydropyranyl ring.

[0059] R 1 are independently C0-C3-alkylene-R 1a where R 1a are independently a 4- to 7-membered heterocycloalkyl ring; and NR 7 R 8 wherein said heterocycloalkyl ring or said cycloalkyl ring is selected from a C3-C7 cycloalkyl ring optionally substituted with 1 to 4 R 9 It may be optionally substituted with a group.

[0060] R 1 is C0-C3-alkylene-R 1a R 1 is C0-C3-alkylene-R 1a where R 1a are independently an oxygen-containing 4- to 7-membered heterocycloalkyl ring, a 4- to 7-membered heterocycloalkyl ring; and NR 7 R 8 wherein said heterocycloalkyl ring or said cycloalkyl ring is selected from a C3-C7 cycloalkyl ring optionally substituted with 1 to 4 R 9 R 1 is CH2-R 1a where R 1aare independently a 4- to 7-membered heterocycloalkyl ring; and NR 7 R 8 wherein the heterocycloalkyl ring or the cycloalkyl ring is selected from a C3-C7 cycloalkyl ring substituted with 1 to 4 R 9 It may be optionally substituted with a group.

[0061] R 1 is C0-C3-alkylene-R 1a where R 1a are independently an oxygen-containing 4- to 7-membered heterocycloalkyl ring, a nitrogen-containing 4- to 7-membered heterocycloalkyl ring; and NR 7 R 8 wherein said heterocycloalkyl ring or said cycloalkyl ring is selected from a C3-C7 cycloalkyl ring optionally substituted with 1 to 4 R 9 R 1 is CH2-R 1a where R 1a are independently a nitrogen-containing 4- to 7-membered heterocycloalkyl ring; and NR 7 R 8 wherein the heterocycloalkyl ring or the cycloalkyl ring is selected from a C3-C7 cycloalkyl ring substituted with 1 to 4 R 9 It may be optionally substituted with a group.

[0062] R 1 is R 1a where R 1a are independently a 4- to 7-membered heterocycloalkyl ring; and NR 7 R 8 wherein said heterocycloalkyl ring or said cycloalkyl ring is selected from a C3-C7 cycloalkyl ring optionally substituted with 1 to 4 R 9 It may be optionally substituted with a group.

[0063] R 1 is R 1a where R 1aare independently a nitrogen-containing 4- to 7-membered heterocycloalkyl ring; and NR 7 R 8 wherein said heterocycloalkyl ring or said cycloalkyl ring is selected from a C3-C7 cycloalkyl ring optionally substituted with 1 to 4 R 9 R 1 is R 1a where R 1a is an oxygen-containing 4- to 7-membered heterocycloalkyl ring; wherein the heterocycloalkyl ring is 9 R 1 is R 1a where R 1a is an oxygen-containing 4- to 7-membered heterocycloalkyl ring, such as a tetrahydropyranyl ring.

[0064] R 1 is C0-C3-alkylene-R 1a where R 1a is a 4- to 7-membered heterocycloalkyl ring; wherein said heterocycloalkyl ring is 9 R 1 is CH2-alkylene-R 1a where R 1a is a 4- to 7-membered heterocycloalkyl ring; wherein said heterocycloalkyl ring is 9 and optionally substituted with groups.

[0065] R 1 is C0-C3-alkylene-R 1a where R 1a is a nitrogen-containing 4- to 7-membered heterocycloalkyl ring; wherein said heterocycloalkyl ring is 9 R 1 is CH2-alkylene-R 1a where R 1a is a nitrogen-containing 4- to 7-membered heterocycloalkyl ring; wherein said heterocycloalkyl ring is9 It may be optionally substituted with a group.

[0066] R 1 is C0-C3-alkylene-R 1a where R 1a is a 4- to 7-membered heterocycloalkyl ring, wherein said ring does not contain any nitrogen atoms; and wherein said heterocycloalkyl ring is 9 R 1 is CH2-alkylene-R 1a where R 1a is a 4- to 7-membered heterocycloalkyl ring, wherein said ring does not contain any nitrogen atoms; and wherein said heterocycloalkyl ring is 9 It may be optionally substituted with a group.

[0067] R 1 is R 1a where R 1a is a 4- to 7-membered heterocycloalkyl ring; wherein said heterocycloalkyl ring is 9 R 1 is R 1a where R 1a is a nitrogen-containing 4- to 7-membered heterocycloalkyl ring; wherein said heterocycloalkyl ring is 9 R 1 is R 1a where R 1a is a 4- to 7-membered heterocycloalkyl ring; wherein said heterocycloalkyl ring is 9 groups, wherein the ring does not contain any nitrogen atoms.

[0068] R 1 is C0-C3-alkylene-R 1a where R 1a is NR 7 R 8a C3-C7-cycloalkyl ring substituted with 1 to 4 R groups; 9 R 1 is CH2-alkylene-R 1a where R 1a is NR 7 R 8 a C3-C7-cycloalkyl ring substituted with 1 to 4 R groups; 9 It may be optionally substituted with a group.

[0069] R 1 is R 1a where R 1a is NR 7 R 8 a C3-C7-cycloalkyl ring optionally substituted with 1 to 4 R 9 It may be optionally substituted with a group.

[0070] R 1 is R 1a where R 1a is NR 7 R 8 a C3-C7-cycloalkyl ring substituted with 1 to 4 R groups; 9 It may be optionally substituted with a group.

[0071] R 1 is R 1a where R 1a is 1 to 4 R 9 R is phenyl optionally substituted with a group. 1 is R 1a where R 1a is a substituted phenyl.

[0072] R 1 is C2~C6-alkylene-R 1b R 1 is C2~C3-alkylene-R 1b R1 is C 3 -Alkylene-R 1b R 1b may be independently selected from: NR 7 R 8 , OR 8 and S.R. 8 .R 1b is OR 8 R 1b is SR 8 R 1b is NR 7 R 8 R 8 is C1-C4-alkyl, for example Me.

[0073] R 1 and R 5 is NR 1 R 5 may be selected to contain only one amine, where said one amine may be a primary, secondary, or tertiary amine. 1 and R 5 is NR 1 R 5 may be selected to contain only one secondary or tertiary amine, where the one amine may be a secondary or tertiary amine.Compounds with only one amine at this position surprisingly show broad-spectrum inhibition at similar concentrations across the range of KRAS mutants and wild-type KRAS, rather than specific KRAS G12C and G12D proteins.The compounds of the present invention show broad-spectrum inhibition at similar concentrations of KRAS mutants, including KRAS G12D, KRAS G12C, KRAS G12V, KRAS G12A, KRAS G13D and KRAS Q61H, and wild-type KRAS.Therefore, these compounds may be therapeutically beneficial for treating cancers with KRAS mutations other than G12D and G12C, as well as cancers dependent on wild-type KRAS.

[0074] R 1 and R 5 But NR 1 R5 may be selected to include two or more amines, where the amines may be primary, secondary or tertiary amines. 1 and R 5 But NR 1 R 5 may be selected to include two or more amines, where the amines may be secondary or tertiary amines. 1 and R 5 But NR 1 R 5a may be selected to include two amines, where the amines may be primary, secondary, or tertiary amines. 1 and R 5 But NR 1 R 5 may be selected to include two amines, where the amines may be secondary or tertiary amines. 1 and R 5 But NR 1 R 5 Compounds in which is selected to contain two or more amines, for example two amines, generally selectively inhibit KRAS G12D.

[0075] R 1 and R 5 may be taken together with the nitrogen to which they are attached to form a ring system selected from: 1 to 4 R 9 a monocyclic 4- to 7-membered heterocycloalkyl group optionally substituted with a group; 9 a fused or spirofused bicyclic 6- to 11-membered heterocyclyl group, optionally substituted with a group; and one to four R 9 a bridged bicyclic 6- to 11-membered heterocycloalkyl group optionally substituted with a group; 1 and R 5 is the only heteroatom in the ring system.

[0076] R 1 and R 5may be taken together with the nitrogen to which they are attached to form a ring system selected from: 1 to 4 R 9 a monocyclic 4- to 7-membered heterocycloalkyl group optionally substituted with a group; 9 a fused or spirofused bicyclic 6- to 11-membered heterocyclyl group, optionally substituted with a group; and one to four R 9 a bridged bicyclic 6- to 11-membered heterocycloalkyl group optionally substituted with a group; 1 and R 5 is attached to the only nitrogen in said ring system.

[0077] R 1 and R 5 is NR 1 R 5 The nitrogen of R may be selected to be the nitrogen of only one amine. 1 and R 5 is NR 1 R 5 may be selected to be the only amine. For the avoidance of doubt, the term "amine" as used herein includes primary amines, such as methylamine; secondary amines, such as dimethylamine; tertiary amines, such as trimethylamine; and cyclic amines, such as piperidine. For the avoidance of doubt, the term "amine" as used herein excludes amides and lactams, such as piperazinonyl.

[0078] 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 is selected from H and C1-C4 alkyl, and p5 and q5 are each selected from 0, 1, 2, and 3; provided that the sum of p5 and q5 is 1 or greater.

[0079] R 1 and R5 may be taken together with the nitrogen to which they are attached to form a ring system having a structure selected from: [ka] wherein r6 is selected from 0, 1 and 2.

[0080] 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: [ka] wherein r7 is selected from 0, 1 and 2.

[0081] R 1 and R 5 may be taken together with the nitrogen to which they are attached to form a ring system selected from: 1 to 4 R 9 a monocyclic 4- to 7-membered heterocycloalkyl group optionally substituted with a group; 9 a fused, spirofused or bridged bicyclic 6- to 11-membered heterocyclyl group, optionally substituted with a group;

[0082] R 1 and R 5 may be taken together with the nitrogen to which they are attached to form a ring system selected from: 1 to 4 R 9 a monocyclic 4- to 7-membered heterocycloalkyl group optionally substituted with a group; 9 a fused, spirofused or bridged bicyclic 6- to 11-membered heterocyclyl group, optionally substituted with a group; wherein the ring system is 1 and R 5 does not contain any nitrogen other than the nitrogen to which it is bonded.

[0083] R 1 and R 5 may be taken together with the nitrogen to which they are attached to form a ring system selected from: 1 to 4 R9 a monocyclic 4- to 7-membered heterocycloalkyl group optionally substituted with a group; 9 a fused or spirofused bicyclic 6- to 11-membered heterocyclyl group, optionally substituted with a group; and one to four R 9 and a bridged bicyclic 6- to 11-membered heterocycloalkyl group, optionally substituted with a group.

[0084] R 1 and R 5 may be taken together with the nitrogen to which they are attached to form a ring system selected from: 1 to 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 heterocyclyl group, optionally substituted with a group;

[0085] R 1 and R 5 together with the nitrogen to which they are attached, form 1 to 4 R 9 R may form a 6- or 7-membered heterocycloalkyl group, optionally substituted with a group. 1 and R 5 together with the nitrogen to which they are attached, form 1 to 4 R 9 R may form a 6- or 7-membered heterocycloalkyl group, optionally substituted with a group, wherein the total number of heteroatoms in said 6- or 7-membered heterocycloalkyl group is 1 or 2. The total number of heteroatoms may also be 2. 1 and R 5 together with the nitrogen to which they are attached form one R 9 It may also form a 6 or 7 membered heterocycloalkyl group, optionally substituted with a group.

[0086] R 1 and R 5 together with the nitrogen to which they are attached, form 1 to 4 R 9 R may form a monocyclic 4- to 7-membered heterocycloalkyl group, which may be optionally substituted with a group. 1and R 5 may be taken together with the nitrogen to which they are attached to form an unsubstituted monocyclic 4- to 7-membered heterocycloalkyl group. At least one R 9 group may be present, and said R 9 At least one of the groups is NR 12 R 13 and N.R. 12 R 13 R may be selected from C1-C4 alkyl substituted with 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 9a is NR 12 R 13 and N.R. 12 R 13 p1 is selected from 0, 1, 2 and 3, q1 is selected from 0, 1 and 2; r1 is selected from 0, 1, 2 and 3. r1 may be 0. R 9 R may, independently at each occurrence, be methyl. 9a is NHR 12 and NHR 12 may be selected from C1-C4 alkyl substituted with

[0087] R 1 and R 5 together with the nitrogen to which they are attached contain two nitrogen atoms in a ring and 1 to 4 R 9 It may also form a monocyclic 4- to 7-membered heterocycloalkyl group which may be appropriately substituted with a group.

[0088] 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, Z6 are independently C(O)NR 9b , N.R. 9b , O, S, S(O)2, S(O), S(O)(NR 9b ) and S(O)(NH); R 9b is selected from H and C1-C4 alkyl; p2 is selected from 2 and 3, q2 is 2; and r2 is selected from 0, 1, 2 and 3. Z 6 is NR 9b , O, S, S(O), 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 may be selected from O, S, S(O), S(O) and S(O)(NH). Z 6 is NR 9b , O and S. Z 6 may be selected from O and S. Z 6 may be O.

[0089] 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 is selected from H and C1-C4-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 R may, independently at each occurrence, be methyl. 9b may be H. 9b may be C1-C4 alkyl.

[0090] R 1 and R 5 together with the nitrogen to which they are attached, form 1 to 4 R9 R may form a fused or spiro-fused bicyclic 6- to 11-membered heterocyclyl group, optionally substituted with a R group. 1 and R 5 together with the nitrogen to which they are attached contain two nitrogen atoms in a ring system and 1 to 4 R 9 and optionally substituted with a substituted or spiro-fused bicyclic 6- to 11-membered heterocyclyl group.

[0091] R 1 and R 5 together with the nitrogen to which they are attached, form 1 to 4 R 9 R may form a 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 contain two nitrogen atoms in a ring system and 1 to 4 R 9 R may form a spiro-fused bicyclic 6- to 11-membered heterocycloalkyl group, 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 is selected from H and C1-C4-alkyl; p3, p4, q3 and q4 are each independently selected from 0, 1, 2 and 3; with the proviso that the sum of p3, p4, q3 and q4 is 3 to 8, the sum of p3 and q3 is 2 or more, and the sum of p4 and q4 is 2 or more; and r3 is selected from 0, 1, 2 and 3. For the avoidance of doubt, throughout this specification it is understood that r3 R 9 The group may be attached to either ring of the spiro-fused bicyclic ring system. r3 may be 0. R 9 R may, independently at each occurrence, be methyl. 9b may be H.

[0092] R1 and R 5 together with the nitrogen to which they are attached, form 1 to 4 R 9 R may form a fused bicyclic 6- to 11-membered heterocyclyl group, optionally substituted with a R group. 1 and R 5 together with the nitrogen to which they are attached, form a ring system containing 1 to 4 nitrogen atoms 9 R may form a fused bicyclic 6- to 11-membered heterocyclyl group, 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 is selected from H and C1-C4-alkyl; p5, p6, q5 are each selected from 0, 1, 2, and 3; with the proviso that the sum of p3, p4, q3, and q4 is 2 to 7, the sum of p5 and q5 is 1 or more, and the sum 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, it is understood that r5 R 9 The group may be attached to either ring of the fused bicyclic ring system. r5 may be 0. R 9 R may, independently at each occurrence, be methyl. 9b may be H.

[0093] R 1 and R 5 together with the nitrogen to which they are attached, form 1 to 4 R 9 It may also form a bridged bicyclic 6- to 11-membered heterocycloalkyl group, which may be optionally substituted with a group.

[0094] R 1 and R 5 together with the nitrogen to which they are attached, form 1 to 4 R 9The fused bicyclic 6- to 11-membered heterocycloalkyl group may be optionally substituted with a group.

[0095] R 1 and R 5 may be taken together with the nitrogen to which they are attached to form a ring system selected from: 1 to 4 R 9 a monocyclic 4- to 7-membered heterocycloalkyl group optionally substituted with a group; 1 to 4 R 9 a fused or spirofused bicyclic 6- to 11-membered heterocycloalkyl group, optionally substituted with a group; and one to four R 9 a bridged bicyclic 6- to 11-membered heterocycloalkyl group optionally substituted with a group, wherein the bridged bicyclic 6- to 11-membered heterocycloalkyl group has the following structure: [ka] isn't it.

[0096] R 1 and R 5 together with the nitrogen to which they are attached, form 1 to 4 R 9 and optionally substituted with a 6- to 11-membered bicyclic heterocycloalkyl group, wherein the bridged bicyclic 6- to 11-membered heterocycloalkyl group has the following structure: [ka] isn't it.

[0097] 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, Y 1 are independently C(O)NR 9d , O and NR 17 Selected from Z 3are independently CH2, CH2CH2, CH2-O-CH2CH2, CH2-O-CH2, CH2-NR 17 -CH2CH2 and CH2-NR 17 -CH2; R 17 is independently selected at each occurrence from H, C-C-haloalkyl, and C-C-alkyl; R 9d are independently selected from H and C1-C4-alkyl; 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 a bridged bicyclic ring system. Z 3 may be independently selected from CH2, CH2CH2, CH2-O-CH2CH2, CH2-O-CH2; and Y 1 are independently O and NR 17 Y 1 is NR 17 Y 1 may be NH. n1 may be 0. R 9 may, independently at each occurrence, be methyl.

[0098] 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, Y 1 are independently C(O)NR 9d , O and NR 17 Selected from Z 4 are independently CH2, CH2CH2, CH2-O-CH2CH2, CH2-O-CH2, CH2-NR 17 -CH2CH2 and CH2-NR 17 -CH2; R 17 is independently selected at each occurrence from H, C-C-haloalkyl, and C-C-alkyl; R 9dare independently selected from H and C1-C4-alkyl; and n2 is an integer selected from 0, 1, 2, 3 and 4. For the avoidance of doubt, throughout this specification, n2 R 9 The group may be attached to either ring of a bridged bicyclic ring system. 4 may be independently selected from CH2, CH2CH2, CH2-O-CH2CH2, CH2-O-CH2; and Y 1 are independently O and NR 17 Y 1 is NR 17 Y 1 may be NH. n2 may be 0. R 9 may, independently at each occurrence, be methyl.

[0099] 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, Y 1 are independently C(O)NR 9d , O and NR 17 Selected from;R 17 is independently selected at each occurrence from H, C-C-haloalkyl, and C-C-alkyl; R 9d are independently selected from H and C1-C4-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 a bridged bicyclic ring system. 1 are independently O and NR 17 Y 1 is NR 17 Y 1 may be NH. n3 may be 0. R 9 may, independently at each occurrence, be methyl.

[0100] 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, Y 1 are independently C(O)NR 9d , O and NR 17 Selected from Z 5 are independently CH2, CH2CH2, CH2-O-CH2CH2, CH2-O-CH2, CH2-NR 17 -CH2CH2 and CH2-NR 17 -CH2; R 17 is independently selected at each occurrence from H, C-C-haloalkyl, and C-C-alkyl; R 9d are independently selected from H and C1-C4-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 a bridged bicyclic ring system. Z 5 is independently selected from CH2, CH2CH2, CH2-O-CH2CH2, CH2-O-CH2. Y 1 are independently O and NR 17 Y 1 is NR 17 Y 1 may be NH. n5 may be 0. R 9 may, independently at each occurrence, be methyl.

[0101] 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 are independently C(O)NR 9b, O, S, S(O)2, S(O), S(O)(NR 9b ), S(O)(NH) and NR 9b Selected from;R 9b is independently selected at each occurrence from H and C1-C4 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), S(O) and S(O)(NH). Z 6 may be selected from O, S, S(O), S(O) and S(O)(NH). Z 6 is NR 9b , O and S. Z 6 may be selected from O and S. Z 6 may be O.

[0102] R 1 and R 5 may, together with the nitrogen to which they are attached, form a ring system having the structure: [ka] wherein n7 is an integer selected from 0, 1, 2 and 3.

[0103] R 1 and R 5 may, together with the nitrogen to which they are attached, form a ring system having the structure: [ka] wherein n7 is an integer selected from 0, 1, 2 and 3.

[0104] R 1 and R 5 may, together with the nitrogen to which they are attached, form a ring system having the structure: [ka] wherein n8 is an integer selected from 0, 1, 2 and 3.

[0105] n7 may be 0.

[0106] 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 12 is independently selected at each occurrence from H, C1-C4-haloalkyl, and C1-C4-alkyl; and n9 is an integer selected from 0, 1, 2, and 3.

[0107] 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 group consisting of: [ka]

[0108] R 1 and R 5 may, together with the nitrogen to which they are attached, form a ring system having the structure: [ka]

[0109] R 2 is C0-C4-alkylene-R 2a R 2 is CH2-R 2a R 2amay be selected from monocyclic 4- to 7-membered heterocycloalkyl groups, 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 the ring system. 2a R may contain only one nitrogen in the ring system. 2a may be selected from monocyclic 4- to 7-membered heterocycloalkyl groups, fused, spiro-fused or bridged bicyclic 6- to 11-membered heterocycloalkyl groups; 2a The group is 1 to 6 R 10 optionally substituted with groups, where R 2a R contains at least one nitrogen in the ring system. 2a may be a monocyclic 4- to 7-membered heterocycloalkyl group; 2a The group is 1 to 6 R 10 optionally substituted with groups, where R 2a R contains at least one nitrogen in the ring system. 2a may be a fused, spirofused, or bridged bicyclic 6- to 11-membered heterocycloalkyl group; 2a The group is 1 to 6 R 10 optionally substituted with groups, where R 2a contains at least one nitrogen in the ring system.

[0110] R 2 may have the following structure: [ka] [In the formula, R 15 are independently selected from H, C1-C4 alkyl; 16 are independently selected from H, C1-C4-alkyl and cyclopropyl; or where R 15 and R 16 together with the atoms to which they are attached, form one or two R 10y 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 may be C1-C4 alkyl.

[0111] R 2 may have 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.

[0112] R 2 may have the following structure: [ka]

[0113] R 2 may have the following structure: [ka]

[0114] R 3a may be independently selected at each occurrence from H, C-C-alkyl, C-C-haloalkyl, and cyclopropyl; or wherein two R 3a The R groups, together with the carbons to which they are attached, form a spiro-fused cyclopropyl group. 3a may be H. 3a may be C1-C4-alkyl, for example methyl.

[0115] R 3b may be selected from H and C1-C4-alkyl. 3bmay be H. 3b may be C1-C4-alkyl, for example methyl.

[0116] R 4 may be phenyl, said phenyl optionally fused to a C5-C7-cycloalkyl ring, wherein R 4 is 1 to 4 R 14 R 4 is 1 to 4 R 14 R may be phenyl optionally substituted with a group. 4 R may be a monocyclic 4- to 7-membered cycloalkyl. 4 R may be a monocyclic 4- to 7-membered heterocycloalkyl, which may be optionally fused to a C5-C6-heteroaryl ring. 4 R may be a 5-membered heterocycloalkyl (e.g., thiophenyl) optionally fused to a monocyclic 5- to 6-membered cycloalkyl (e.g., cyclohexyl). 4 is 1 to 4 R 14 For the avoidance of doubt, R 4 When R contains a fused ring structure, e.g., a 5-membered heterocycloalkyl fused to a monocyclic 5- to 6-membered cycloalkyl, 1 to 4 R 14 Groups may be attached to either ring, for example, a 5-membered heterocycloalkyl may be substituted, for example, with cyano and -NH2, and the monocyclic 5- to 6-membered cycloalkyl to which it is fused may be further substituted, for example, with C1-C4-alkyl.

[0117] R 4 may have the following structure: [ka] [In the formula, R 12a is independently H or C1-C4-alkyl; x1 is independently selected from 0, 1, 2 and 3. 12a may be H.

[0118] R 4 is 1 to 4 R 14 It may also be naphthyl optionally substituted with a group. R 4 may have the following structure: [ka] wherein 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.

[0119] R 4 may have the following structure: [ka] [In the formula, R 12a are independently H or C1-C4-alkyl; x2 are 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.

[0120] R 4 may have the following structure: [ka] [In the formula, R 14 are independently H, cyano, and NR 12 R 13 and C1-C4-alkyl. x3 is independently selected from 0, 1, 2 and 3. For the avoidance of doubt, throughout this specification, x3 R 14 Groups may be attached to either ring of the heterocyclyl group.

[0121] R 4 may have the following structure: [ka]

[0122] 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 It may also be a 9- or 10-membered bicyclic heteroaryl optionally substituted with a group.

[0123] R 5 may be H. 5 may be C1-C4-alkyl, for example methyl.

[0124] R 6 may be H. 6 may be C1-C4-alkyl, for example methyl.

[0125] R 7 may be selected from H and C1-C4-alkyl. 7 may be H. 7 may be C1-C4-alkyl, for example methyl.

[0126] R 8 may be selected from H and C1-C4-alkyl. 8 may be H. 8 may be C1-C4-alkyl, for example methyl.

[0127] R 9 is independently, at each occurrence, oxo, fluoro, cyano, NR 12 R 13 , OR 12 , C.O.R. 12 , C1-C4-alkyl, CONR 12 R 13 ;NR 12 R 13 C1-C4-alkyl substituted with OR 12C1-C4-alkyl substituted with , C1-C4-alkyl substituted with cyano, C1-C4-alkyl substituted with phenyl. R 9 is independently, at each occurrence, oxo, fluoro, NR 12 R 13 , OR 12 , C.O.R. 12 ,CONR 12 R 13 C1-C4 alkyl, NR 12 R 13 C1-C4-alkyl substituted with phenyl, C1-C4-alkyl substituted with OR 12 may be selected from C1-C4 alkyl substituted with

[0128] R 9 is independently, at each occurrence, oxo, fluoro, cyano, NR 12 R 13 , OR 12 , C1-C4-alkyl, NR 12 R 13 C1-C4-alkyl substituted with OR 12 R may be selected from C1-C4-alkyl substituted with , C1-C4-alkyl substituted with cyano. 9 is independently, at each occurrence, oxo, fluoro, NR 12 R 13 , OR 12 , C1-C4-alkyl, NR 12 R 13 C1-C4-alkyl and OR substituted 12 may be selected from C1-C4 alkyl substituted with

[0129] R 9 independently for each occurrence: oxo, halo, cyano, NR 12 R 13 (However, R 12 is R, not H 13 is not H), OR 12 , C.O.R. 12 , CO2R 12 ,CONR 12 R 12 , C1-C4-alkyl, NR12 R 13 C1-C4-alkyl substituted with (wherein R 12 is R, not H 13 is not H), OR 12 C1-C4-alkyl substituted with , C1-C4-alkyl substituted with cyano, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl.

[0130] R 9 independently for each occurrence: oxo, halo, cyano, NR 12 R 13 (However, R 12 is R, not H 13 is not H), OR 12 , CO2R 12 ,CONR 12 R 12 , C1-C4-alkyl, NR 12 R 13 C1-C4-alkyl substituted with (wherein R 12 is R, not H 13 is not H), OR 12 C1-C4-alkyl substituted with , C1-C4-alkyl substituted with cyano, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl.

[0131] R 10 independently for each occurrence: oxo, halo, cyano, NR 12 R 13 , OR 12 , CO2R 12 ,CONR 12 R 12 , C1-C4-alkyl, NR 12 R 13 C1-C4-alkyl substituted with OR 12 C1-C4-alkyl substituted with phenyl, C1-C4-alkyl substituted with cyano, C1-C4-alkyl substituted with phenyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl.

[0132] R 10 independently for each occurrence: oxo, halo, cyano, NR 12 R 13 , OR 12 , CO2R 12 ,CONR 12 R 12 , C1-C4-alkyl, NR 12 R 13 C1-C4-alkyl substituted with OR 12 C1-C4-alkyl substituted with , C1-C4-alkyl substituted with cyano, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl.

[0133] R 10 is independently, at each occurrence, oxo, fluoro, NR 12 R 13 , OR 12 , C1-C4-alkyl, C1-C4-alkyl substituted with phenyl, NR 12 R 13 C1-C4-alkyl and OR substituted 12 may be selected from C1-C4 alkyl substituted with

[0134] R 10 is independently, at each occurrence, oxo, fluoro, NR 12 R 13 , OR 12 , C1-C4-alkyl, NR 12 R 13 C1-C4-alkyl and OR substituted 12 may be selected from C1-C4 alkyl substituted with

[0135] R 11 are each independently halo, cyano, nitro, NR 12 R 13 , OR 12 , C1-C4-alkyl, NR 12 R 13 C1-C4-alkyl substituted with OR 12R may be selected from C1-C4-alkyl substituted with R, monocyclic 4- to 7-membered cycloalkyl or heterocycloalkyl, C1-C4-haloalkyl and cyclopropyl. 11 are, independently for each occurrence, OR 12 , monocyclic 4-7 membered cycloalkyl or heterocycloalkyl, C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl.

[0136] R 11 are each independently halo, cyano, nitro, NR 12 R 13 , OR 12 , C1-C4-alkyl, NR 12 R 13 C1-C4-alkyl substituted with OR 12 R may be selected from C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl substituted with R 11 are, independently for each occurrence, OR 12 , C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl.

[0137] R 12 may be independently selected at each occurrence from H, C-C-haloalkyl, C-C-alkyl and cyclopropyl; R 13 may be independently selected at each occurrence from H, C1-C4-alkyl, C1-C4-haloalkyl and C(O)-C1-C4-alkyl.

[0138] R 12 may be independently selected at each occurrence from H, C1-C4-haloalkyl, and C1-C4-alkyl; R 13 may be independently selected at each occurrence from H, C1-C4-alkyl, C1-C4-haloalkyl and C(O)-C1-C4-alkyl.

[0139] R 12may be independently selected at each occurrence from H, cyclopropyl and C1-C4-alkyl.

[0140] R 12 may be independently selected at each occurrence from H and C1-C4-alkyl.

[0141] R 12 may, independently at each occurrence, be cyclopropyl.

[0142] R 13 may be independently selected at each occurrence from H and C1-C4-alkyl.

[0143] R 12 and R 13 may, together with the nitrogen to which they are attached, form a ring system selected from: a monocyclic 4- to 7-membered heterocycloalkyl group; a fused, spiro-fused, or bridged bicyclic 6- to 11-membered heterocycloalkyl group, said heterocycloalkyl group being substituted with 1 to 6 R 10 R 12 and R 13 may be taken together with the nitrogen to which they are attached to form a monocyclic 4- to 7-membered heterocycloalkyl group, such as piperidinyl.

[0144] R 14 are each independently halo, cyano, nitro, NR 12 R 13 , OR 12 , C1-C4-alkyl, NR 12 R 13 C1-C4-alkyl substituted with OR 12 R may be selected from C1-C4-alkyl substituted with C1-C4-haloalkyl, phenyl and cyclopropyl. 14 are, independently for each occurrence, OR 12 , C1-C4-alkyl, C1-C4-haloalkyl, phenyl and cyclopropyl.

[0145] R14 are each independently halo, cyano, nitro, NR 12 R 13 , OR 12 , C1-C4-alkyl, NR 12 R 13 C1-C4-alkyl substituted with OR 12 R may be selected from C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl substituted with R 14 are, independently for each occurrence, OR 12 , C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl.

[0146] The compound of formula (I) may be selected from: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0147] Compounds of formula (I) may be selected from the following structures: [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] This application also includes the following numbered sections: 1. A compound of formula (I), or a pharmaceutically acceptable salt thereof: [ka] [In the formula, Z 1 are independently -O- and -NR 5 -Selected from; Z 2are independently absent or -O- and -NR 6 -Selected from; L 1 is a bond and -C(R 18 )2-Selected X 1 is -C(R 3a )2 and -NR 3b -Selected from; R 1 are independently C0-C3-alkylene-R 1a and C2-C6-alkylene-R 1b where R is selected from 1a are independently an oxygen-containing 4- to 7-membered heterocycloalkyl ring, a 4- to 7-membered heterocycloalkyl ring; and NR 7 R 8 wherein the heterocycloalkyl ring or the cycloalkyl ring is selected from a C3-C7 cycloalkyl ring substituted with 1 to 4 R 9 optionally substituted with R 1b is independent, NR 7 R 8 , OR 8 , S.R. 8 , SOR 8 , SO2R 8 and SO(NH)R 8 Select from; Or R 1 and R 5 together with the nitrogen to which they are attached, form 1 to 4 R 9 a monocyclic 4- to 7-membered heterocycloalkyl group optionally substituted with a group; 9 forming a ring system selected from fused, spirofused or bridged bicyclic 6- to 11-membered heterocyclyl groups, optionally substituted with a group; R 2 are independently C1-C6-alkyl, C1-C4-haloalkyl, C0-C4-alkylene-R 2a , C1-C4-alkylene-R 2b , C2-C4-alkylene-R 2c and; R 2aare independently selected from: a monocyclic 4- to 7-membered heterocycloalkyl group; a fused, spirofused, or bridged bicyclic 6- to 11-membered heterocycloalkyl group; a 5-, 6-, 9-, or 10-membered monocyclic or bicyclic heteroaryl group; phenyl; C3-C7-cycloalkyl; wherein R is either heterocycloalkyl or cycloalkyl. 2a The group is 1 to 6 R 10 R is optionally substituted with a heteroaryl or phenyl group. 2a The group is 1 to 6 R 11 optionally substituted with groups; where R 2b independently, CONR 12 R 12 and CO2R 12 Selected from; where R 2c is independent, NR 12 R 13 and OR 12 Select 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, 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 groups; R 3a is independently at each occurrence H, C1-C4-alkyl, C1-C4-haloalkyl, NR 12 R 13 C1-C4-alkyl substituted with OR 12 or wherein two R 3a groups, taken together with the carbons to which they are attached, form a spiro-fused cyclopropyl group; R 3b is independently selected from H, C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl; R4 is independently phenyl, said phenyl being selected from phenyl optionally fused to a C5-C7-cycloalkyl ring; naphthyl; monocyclic 4- to 7-membered cycloalkyl or heterocycloalkyl; and 5- to 10-membered monocyclic or bicyclic heterocyclyl, wherein R 4 is 1 to 4 R 14 optionally substituted with groups; R 5 , R 6 , R 8 and R 12 is independently selected at each occurrence from H, C1-C4-haloalkyl, and C1-C4-alkyl; R 7 and R 13 is independently selected at each occurrence from H, C1-C4-alkyl, C1-C4-haloalkyl and C(O)-C1-C4-alkyl; R 9 and R 10 is independently oxo, halo, cyano, NR 12 R 13 , OR 12 , CO2R 12 ,CONR 12 R 12 , C1-C4-alkyl, NR 12 R 13 C1-C4-alkyl substituted with OR 12 C1-C4-alkyl substituted with, C1-C4-alkyl substituted with cyano, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl; R 11 are independently halo, cyano, nitro, and NR 12 R 13 , OR 12 , CO2R 12 ,CONR 12 R 12 , C1-C4-alkyl, NR 12 R 13 C1-C4-alkyl substituted with OR 12C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl substituted with; R 14 independently for each occurrence: H, halo, cyano, nitro, NR 12 R 13 , OR 12 , CO2R 12 ,CONR 12 R 12 , C1-C4-alkyl, NR 12 R 13 C1-C4-alkyl substituted with OR 12 C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl substituted with; R 18 independently for each occurrence: H, halo, cyano, nitro, NR 12 R 13 , OR 12 , CO2R 12 ,CONR 12 R 12 , C1-C4-alkyl, NR 12 R 13 C1-C4-alkyl substituted with OR 12 or wherein two R 18 groups, taken together with the carbons to which they are attached, form a spiro-fused cyclopropyl group; wherein any of the aforementioned alkyl, alkylene or cyclopropyl groups may be optionally substituted, where chemically possible, with 1 to 5 substituents independently selected at each occurrence from the group consisting of C1-C4-alkyl, halo, nitro, cyano, NR a R b , OR a , S.R. a , CO2R a , C(O)R a ,CONR a R a ;where R ais independently selected at each occurrence from H, C1-C4-alkyl and C1-C4-haloalkyl; R b is independently selected at each occurrence from H, C1-C4-alkyl, C(O)-C1-C4-alkyl and S(O)2-C1-C4-alkyl. 2. The compound of claim 1, wherein R 1 and R 5 But, NR1R 5 is selected to contain only one amine, wherein the only amine may be a primary, secondary, or tertiary amine. 3. A compound according to claim 1 or 2, wherein R 1 and R 5 However, together with the nitrogen to which they are attached, there are 1 to 4 R 9 a monocyclic 4- to 7-membered heterocycloalkyl group optionally substituted with a group; 9 a fused or spirofused bicyclic 6- to 11-membered heterocyclyl group, optionally substituted with a group; and one to four R 9 and forming a ring system selected from the group consisting of bridged bicyclic 6- to 11-membered heterocyclyl groups, optionally substituted with R 1 and R 5 3. The compound of claim 1 or claim 2, wherein the nitrogen to which is attached is the only nitrogen in the ring system. 4. A compound according to any one of claims 1 to 3, wherein R 1 and R 5 However, together with the nitrogen to which they are attached, there are 1 to 4 R 9 a monocyclic 4- to 7-membered heterocycloalkyl group optionally substituted with a group; 1 to 4 R 9 The heterocycloalkyl groups form a ring system selected from fused or spirofused bicyclic 6- to 11-membered heterocycloalkyl groups, optionally substituted with a group. 5. The compound of claim 4, wherein R 1 and R 5may, together with the nitrogen to which they are attached, form a ring system having the structure: [ka] [In the formula, Z 6 are independently C(O)NR 9b , N.R. 9b , O, S, S(O)2, S(O), S(O)(NR 9b ) and S(O)(NH); R 9b is selected from H and C1-C4-alkyl; p2 is selected from 2 and 3, q2 is 2; and r2 is selected from 0, 1, 2 and 3. 6. 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 are independently C(O)NR 9b , O, S, S(O)2, S(O), S(O)(NR 9b ), S(O)(NH) and NR 9b Selected from;R 9b is independently selected at each occurrence from H and C1-C4-alkyl; and n6 is an integer selected from 0, 1, 2, 3 and 4. 7. 7.Z 6 7. The compound of claim 6, wherein R is optionally O. 2 The compound of any one of claims 1 to 7, wherein the compound has the following structure: [ka] [In the formula, R 15 are independently selected from H, C1-C4 alkyl; R 16 are independently selected from H, C1-C4-alkyl and cyclopropyl; or where R 15 and R 16together with the atoms to which they are attached, form one or two R 10 y is independently selected from 0, 1, 2, 3, and 4. 8. R 2 8. The compound of claim 7, wherein: [ka] wherein z is independently selected from 0, 1, 2, 3, and 4. 9. L 1 The compound according to any one of claims 1 to 8, wherein is a bond. 10. L 1 -C(R 18 9. The compound according to claim 1, wherein R is 2-. 11. R 18 11. The compound of claim 10, wherein each occurrence is H. 12. X 1 -C(R 3a 12. The compound according to claim 1, wherein R is 2-. 13. R 3a is independently selected at each occurrence from H, C1-C4-alkyl, C1-C4-haloalkyl, and cyclopropyl; or two R 3a 13. The compound of claim 12, wherein the groups, together with the carbon to which they are attached, form a spiro-fused cyclopropyl group. 14. R 3 13. The compound of claim 11 or 12, wherein each occurrence is H. 15. X 1 Ga-NR 3b The compound according to any one of claims 1 to 11, wherein - 16. R 3b16. The compound of claim 15, wherein is selected from H and C1-C4-alkyl. 17. R 4 is phenyl, said phenyl optionally fused to a C5-C7-cycloalkyl ring, wherein R 4 1 to 4 R 14 17. The compound according to claim 1, which may be appropriately substituted with a group. 18. R 4 17. The compound of any one of claims 1 to 16, wherein the compound has the following structure: [ka] wherein x is independently selected from 0, 1, 2, 3, and 4. 19. R 4 19. The compound of claim 18, wherein said compound has the following structure: [ka] [In the formula, R 12a are independently H or C1-C4-alkyl; x2 are independently selected from 0, 1, 2 and 3. 20. R 4 However, 1 to 4 R 14 17. The compound according to any one of claims 1 to 16, which is a 5-, 6-, 9- or 10-membered, monocyclic or bicyclic heteroaryl optionally substituted with a group. 21. The compound of claim 1, wherein the compound of formula (I) is selected from the following: [ka] [ka] [ka] [ka] 22. A compound according to any one of claims 1 to 21 for pharmaceutical use. 23. A compound according to any one of claims 1 to 21 for use in treating cancer. 24. The compound for use according to claim 23, 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. 25. The compound for use according to claim 23 or 24, wherein the subject to be treated has a cancer with wild-type KRAS. 26. The compound for use according to claim 23 or 24, wherein the subject to be treated has a cancer with a KRAS mutation selected from the following: KRAS G12D, KRAS G12C, KRAS G12V, KRAS G12A, KRAS G12D, KRAS G13D and KRAS Q61H. 27. A pharmaceutical composition comprising a compound according to any one of claims 1 to 21 and a pharmaceutically acceptable excipient. This application also includes the following numbered sections: 1. A compound of formula (I), or a pharmaceutically acceptable salt thereof: [ka] [In the formula, Z 1 are independently -O- and -NR 5 -Selected from; Z 2 are independently absent, -O- and -NR 6 -Selected from; L 1 is a bond and -C(R 18 )2-Selected X 1 is -C(R 3a )2 and -NR 3b -Selected from; R 1are independently C0-C3-alkylene-R 1a and C2-C6-alkylene-R 1b where R is selected from 1a are independently an oxygen-containing 4- to 7-membered heterocycloalkyl ring, a 4- to 7-membered heterocycloalkyl ring; and NR 7 R 8 wherein the heterocycloalkyl ring or the cycloalkyl ring is selected from a C3-C7 cycloalkyl ring substituted with 1 to 4 R 9 optionally substituted with R 1b is independent, NR 7 R 8 , OR 8 , S.R. 8 , SOR 8 , SO2R 8 and SO(NH)R 8 Select from; Or R 1 and R 5 together with the nitrogen to which they are attached, form 1 to 4 R 9 a monocyclic 4- to 7-membered heterocycloalkyl group optionally substituted with a group; 9 forming a ring system selected from fused, spirofused or bridged bicyclic 6- to 11-membered heterocyclyl groups, optionally substituted with a group; R 2 are independently C1-C6-alkyl, C1-C4-haloalkyl, C0-C4-alkylene-R 2a , C1-C4-alkylene-R 2b , C2-C4-alkylene-R 2c and; R 2a are independently selected from: a monocyclic 4- to 7-membered heterocycloalkyl group; a fused, spirofused, or bridged bicyclic 6- to 11-membered heterocycloalkyl group; a 5-, 6-, 9-, or 10-membered monocyclic or bicyclic heteroaryl group; phenyl; C3-C7-cycloalkyl; wherein R is either heterocycloalkyl or cycloalkyl. 2a The group is 1 to 6 R 10 R is optionally substituted with a heteroaryl or phenyl group.2a The group is 1 to 6 R 11 optionally substituted with groups; where R 2b independently, CONR 12 R 12 and CO2R 12 Selected from; where R 2c is independent, NR 12 R 13 and OR 12 Select from; Alternatively, R 2 and R 6 together with the nitrogen to which they are attached form a monocyclic 4- to 7-membered heterocycloalkyl group, 1 to 6 R 10 forming a ring system selected from fused, spirofused or bridged bicyclic 6- to 11-membered heterocycloalkyl groups, optionally substituted with a group; R 3a is independently at each occurrence H, C1-C4-alkyl, C1-C4-haloalkyl, NR 12 R 13 C1-C4-alkyl substituted with OR 12 or wherein two R 3a groups, taken together with the carbons to which they are attached, form a spiro-fused cyclopropyl group; R 3b is independently selected from H, C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl; R 4 is independently selected from phenyl, said phenyl optionally fused to a C5-C7 cycloalkyl ring; naphthyl; monocyclic 4- to 7-membered cycloalkyl or heterocycloalkyl; and 5- to 10-membered monocyclic or bicyclic heterocyclyl, wherein R 4 is 1 to 4 R 14 optionally substituted with groups; R 5 , R 6 , R 8and R 12 is independently selected at each occurrence from H, C1-C4-haloalkyl, and C1-C4-alkyl; R 7 and R 13 is independently selected at each occurrence from H, C1-C4-alkyl, C1-C4-haloalkyl and C(O)-C1-C4-alkyl; Or R 12 and R 13 together with the nitrogen to which they are attached form a monocyclic 4- to 7-membered heterocycloalkyl group, 1 to 6 R 10 forming a ring system selected from optionally substituted fused, spirofused or bridged bicyclic 6- to 11-membered heterocycloalkyl groups; R 9 and R 10 is independently oxo, halo, cyano, NR 12 R 13 , OR 12 , CO2R 12 ,CONR 12 R 12 , C1-C4-alkyl, NR 12 R 13 C1-C4-alkyl substituted with OR 12 C1-C4-alkyl substituted with, C1-C4-alkyl substituted with cyano, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl; R 11 are independently halo, cyano, nitro, and NR 12 R 13 , OR 12 , CO2R 12 ,CONR 12 R 12 , C1-C4-alkyl, NR 12 R 13 C1-C4-alkyl substituted with OR 12 C1-C4-alkyl substituted with, monocyclic 4- to 7-membered cycloalkyl or heterocycloalkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl; R 14 is independently H, halo, cyano, nitro, NR 12 R 13 , OR 12 , CO2R 12 ,CONR 12 R 12 , C1-C4-alkyl, NR 12 R 13 C1-C4-alkyl substituted with OR 12 C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl substituted with; R 18 is independently H, halo, cyano, nitro, NR 12 R 13 , OR 12 , CO2R 12 ,CONR 12 R 12 , C1-C4-alkyl, NR 12 R 13 C1-C4-alkyl substituted with OR 12 or wherein two R are selected from C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl substituted with 18 groups together with the carbons to which they are attached form a spiro-fused cyclopropyl group; wherein any of the foregoing alkyl, alkylene or cyclopropyl groups may be optionally substituted, where chemically possible, with 1 to 5 substituents, each independently selected at each occurrence from the group consisting of C1-C4-alkyl, halo, nitro, cyano, NR a R b , OR a , S.R. a , CO2R a , C(O)R a ,CONR a R a ;where R a is independently selected at each occurrence from H, C1-C4-alkyl and C1-C4-haloalkyl; R bis independently selected at each occurrence from H, C1-C4-alkyl, C(O)-C1-C4-alkyl and S(O)2-C1-C4-alkyl. 2. R 1 and R 5 But NR 1 R 5 is selected to contain only one amine, wherein the only amine may be a primary, secondary, or tertiary amine. 3. R 1 and R 5 However, together with the nitrogen to which they are attached, there are 1 to 4 R 9 a monocyclic 4- to 7-membered heterocycloalkyl group optionally substituted with a group; 1 to 4 R 9 a fused or spirofused bicyclic 6- to 11-membered heterocyclyl group, optionally substituted with a group; and one to four R 9 and forming a ring system selected from the group consisting of bridged bicyclic 6- to 11-membered heterocyclyl groups, optionally substituted with R 1 and R 5 is the only nitrogen in the ring system. 4. R 1 and R 5 However, together with the nitrogen to which they are attached, there are 1 to 4 R 9 a monocyclic 4- to 7-membered heterocycloalkyl group optionally substituted with a group; 1 to 4 R 9 Item 4. The compound according to any one of Items 1 to 3, wherein the compound forms a ring system selected from fused or spiro-fused bicyclic 6- to 11-membered heterocycloalkyl groups, optionally substituted with a group. 5. 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, Z6 are independently C(O)NR 9b , N.R. 9b , O, S, S(O)2, S(O), S(O)(NR 9b ) and S(O)(NH); R 9b is selected from H and C1-C4-alkyl; p2 is selected from 2 and 3, q2 is 2; and r2 is selected from 0, 1, 2 and 3. 6. 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 are independently C(O)NR 9b , O, S, S(O)2, S(O), S(O)(NR 9b ), S(O)(NH) and NR 9b Selected from;R 9b is independently selected at each occurrence from H and C1-C4-alkyl; and n6 is an integer selected from 0, 1, 2, 3 and 4. 7. Z 6 Item 7. The compound according to item 6, wherein: 8. R 2 The compound according to any one of items 1 to 7, wherein the compound has the following structure: [ka] [In the formula, R 15 are independently selected from H, C1-C4 alkyl; 16 are independently selected from H, C1-C4-alkyl and cyclopropyl; or where R 15 and R 16 together with the atoms to which they are attached, form one or two R 10y is independently selected from 0, 1, 2, 3, and 4. 9. R 2 Item 9. The compound according to item 8, wherein the compound has the following structure: [ka] wherein z is independently selected from 0, 1, 2, 3, and 4. 10. L 1 Item 10. The compound according to any one of items 1 to 9, wherein is a bond. 11. L 1 -C(R 18 Item 10. The compound according to any one of items 1 to 9, wherein R is 1-. 12. R 18 Item 12. The compound according to item 11, wherein each occurrence of is H. 13. X 1 -C(R 3a 13. The compound according to any one of items 1 to 12, wherein R 1 is 1-. 14. R 3a is independently selected at each occurrence from H, C1-C4-alkyl, C1-C4-haloalkyl, and cyclopropyl; or wherein two R 3a 14. The compound of clause 13, wherein the groups, together with the carbon to which they are attached, form a spiro-fused cyclopropyl group. 15. R 3a is H at each occurrence. 16. X 1 Ga-NR 3b Item 13. The compound according to any one of Items 1 to 12, wherein - 17. R 3b Item 17. The compound according to item 16, wherein is selected from H and C1-C4 alkyl. 18. R 4is phenyl, said phenyl optionally fused to a C5-C7-cycloalkyl ring, wherein R 4 However, 1 to 4 R 14 Item 18. The compound according to any one of items 1 to 17, which may be appropriately substituted with a group. 19. R 4 The compound according to any one of items 1 to 17, wherein the compound has the following structure: [ka] wherein x is independently selected from 0, 1, 2, 3, and 4. 20. R 4 20. The compound according to clause 19, wherein the compound has the following structure: [ka] [In the formula, R 12a are independently H or C1-C4-alkyl; x2 are independently selected from 0, 1, 2 and 3. 21. R 4 However, 1 to 4 R 14 Item 18. The compound according to any one of items 1 to 17, wherein the heteroaryl is a 5-, 6-, 9-, or 10-membered monocyclic or bicyclic heteroaryl optionally substituted with a group. 22. The compound according to clause 1, wherein the compound of formula (I) is selected from the following: [ka] [ka] [ka] [ka] [ka] [ka] 23. A compound according to any one of items 1 to 22 for pharmaceutical use. 24. A compound according to any one of clauses 1 to 22 for use in treating cancer. 25. The compound for use according to clause 24, 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. 26. The compound according to paragraph 24 or 25, wherein the subject to be treated has a cancer with wild-type KRAS. 27. The compound for use according to paragraph 24 or 25, wherein the subject to be treated has a cancer with a KRAS mutation selected from the following: KRAS G12D, KRAS G12C, KRAS G12V, KRAS G12A, KRAS G12D, KRAS G12S, KRAS G13D and KRAS Q61H. 28. A pharmaceutical composition comprising the compound according to any one of items 1 to 22 and a pharmaceutically acceptable excipient. DETAILED DESCRIPTION OF THE INVENTION

[0148] Detailed Description In one aspect of the invention, there is provided a compound of the invention for use as a pharmaceutical.

[0149] In another aspect, the present invention provides a method for treating a condition that can be regulated by inhibiting a KRAS protein having a G12D mutation, said method comprising administering a therapeutically effective amount of a compound of the present invention to a subject in need thereof.

[0150] In another aspect, the present invention provides a pharmaceutical formulation comprising a compound of the present invention and a pharmaceutically acceptable excipient.

[0151] In some embodiments, the pharmaceutical composition may be a combination product that includes an additional pharmacologically 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 therapy, or a tyrosine kinase inhibitor.

[0152] In one aspect of the present invention, there is provided a compound of the present invention for use in treating cancer.

[0153] In one aspect of the invention, there is provided a method of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the invention.

[0154] In one aspect of the invention, there is provided the use of a compound of the invention for the manufacture of a medicament for treating cancer.

[0155] The cancer may be a solid or liquid tumor. The cancer may be an epithelial cancer.

[0156] The cancer may be selected from cervical cancer, endometrial cancer, multiple myeloma, gastric cancer, bladder cancer, uterine cancer, esophageal squamous cell carcinoma, gastric cancer, glioblastoma, astrocytoma; retinoblastoma, osteosarcoma, chondo sarcoma, Ewing's sarcoma, rhabdomy sarcoma, Wilms' 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, carcinoma of unknown primary site, ampulla of Vater carcinoma, ovarian cancer, acute myeloid leukemia, small cell lung cancer, germ cell tumor, small intestine cancer, melanoma, soft tissue sarcoma, gastrointestinal stromal tumor, thyroid cancer, gastrointestinal neuroendocrine tumor, renal cell carcinoma, and histiocytosis.

[0157] The cancer may be selected from pancreatic cancer, colorectal cancer, rectal cancer, endometrial cancer, non-small cell lung cancer, gastric cancer, ovarian cancer and small cell lung cancer.

[0158] The cancer may have wild-type KRAS. The cancer may have a KRAS mutation. The cancer may have a KRAS mutation selected from the following: KRAS G12D, KRAS G12C, KRAS G12V, KRAS G12A, KRAS G12S, KRAS G13D, and KRAS Q61H. The cancer may have a KRAS G12D mutation. The cancer may have a KRAS G12D mutation, and the cancer may be selected from pancreatic cancer, colorectal cancer, rectal cancer, endometrial cancer, non-small cell lung cancer, gastric cancer, ovarian cancer, and small cell lung cancer.

[0159] The cancer may have a confirmed KRAS G12D mutation. The cancer may have a confirmed KRAS G12D mutation, 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.

[0160] The subject may be a human.

[0161] The subject may have a cancer with a KRAS G12D mutation, 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.

[0162] The subject may have a cancer with a confirmed KRAS G12D mutation, 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.

[0163] The subject may have a confirmed G12D mutation in the tumor. To be confirmed, a test for the presence of G12D in the tumor must have an assay selectivity of greater than 95% for detecting mutations in the KRAS gene. Such validated tests include commercially available tests, namely, Foundation One CDx and CARIS DNA sequencing.

[0164] As noted above, the present invention includes a method of treating cancer, which may include: a) confirming that the subject has cancer with the G12D mutation; and b) administering to a subject in need of treatment a therapeutically effective amount of a compound of the present invention.

[0165] The term "halo" refers to one of the halogens, group 17 of the periodic table. In particular, the term refers to fluorine, chlorine, bromine, and iodine. Preferably, the term refers to fluorine or chlorine.

[0166] 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, e.g., methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl. 0~4 When designated as alkyl, it should be understood that this represents the possibility that said alkyl unit may be absent or may be 1, 2, 3, or 4 carbon atoms in length. Alkylene groups may similarly be straight or branched chain and may have two points of attachment to the remainder of the molecule. Furthermore, alkylene groups may correspond, for example, to one of the alkyl groups listed in this paragraph. Alkyl and alkylene groups may be unsubstituted or substituted with one or more substituents. Possible substituents are described below. Substituents for alkyl groups may be halogens, such as fluorine, chlorine, bromine, and iodine, and may include OH, C, and the like. 1~6 It may also be alkoxy.

[0167] The term "alkoxy" refers to an alkyl group 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 oxygen. It includes moieties in which the alkyl portion may be straight or branched and contain 1, 2, 3, 4, 5, or 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl. Thus, alkoxy groups may be methoxy, ethoxy, n-propoxy, isopropoxy, 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 on alkyl groups may be halogens, such as fluorine, chlorine, bromine, and iodine, and may include OH, C ... 1~6 It may also be alkoxy.

[0168] The term "haloalkyl" refers to a hydrocarbon chain substituted with at least one halogen atom, such as fluorine, chlorine, bromine, and iodine, independently selected at each occurrence. 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 may refer to chloromethyl, fluoromethyl, trifluoromethyl, chloroethyl, such as 1-chloromethyl and 2-chloroethyl, trichloroethyl, such as 1,2,2-trichloroethyl, 2,2,2-trichloroethyl, fluoroethyl, such as 1-fluoromethyl and 2-fluoroethyl, trifluoroethyl, such as 1,2,2-trifluoroethyl and 2,2,2-trifluoroethyl, chloropropyl, trichloropropyl, fluoropropyl, trifluoropropyl.

[0169] The term "alkenyl" refers to a branched or straight hydrocarbon chain containing at least one double bond. For example, the term "C 2~6"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(s) may be present as E or Z isomers. The double bond may be in any available position on the hydrocarbon chain. For example, C 2~6 "Alkenyl" may be ethenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl and hexadienyl.

[0170] The term "alkynyl" refers to a branched or straight-chain hydrocarbon chain containing at least one triple bond. For example, the term "C 2~6 "Alkynyl" refers to a branched or straight hydrocarbon chain containing at least one triple bond and containing 2, 3, 4, 5, or 6 carbon atoms. The triple bond may be in any available position on the hydrocarbon chain. For example, C 2~6 "Alkynyl" may be ethynyl, propynyl, butynyl, pentynyl and hexynyl.

[0171] The term "heteroalkyl" refers to a branched or straight-chain hydrocarbon chain containing at least one heteroatom selected from N, O, and S, positioned between any carbon atoms within the chain or at the end of the chain. For example, the term "C 1~6 "Heteroalkyl" refers to a branched or straight-chain hydrocarbon chain containing 1, 2, 3, 4, 5, or 6 carbon atoms and at least one heteroatom selected from N, O, and S, positioned between any carbon atoms within the chain or at the end of the chain. For example, the hydrocarbon chain may contain one or two heteroatoms. 1~6 A heteroalkyl may 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 may be O-alkyl.

[0172] The term "cycloalkyl" refers to a saturated hydrocarbon ring system. For example, "C 3~8"Cycloalkyl" may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

[0173] The term "cycloalkenyl" refers to an unsaturated hydrocarbon ring system, including rings that are not aromatic. The ring may contain two or more double bonds, provided that the ring system is not aromatic. For example, "C 3~8 "Cycloalkyl" may be cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadiene, cyclooctenyl and cycloatadienyl.

[0174] The term "heterocycloalkyl" refers to a saturated hydrocarbon ring system containing carbon atoms and at least one heteroatom selected from N, O, and S within the ring. For example, there may be 1, 2, or 3 heteroatoms, optionally 1 or 2. A "heterocycloalkyl" may be attached to the remainder of the molecule through any carbon atom or heteroatom. For example, a "heterocycloalkyl" is defined as "C 3~8 The term "C" may also be used interchangeably with "heterocycloalkyl." 3~8 "Heterocycloalkyl" refers to a saturated hydrocarbon ring system containing 3, 4, 5, 6, 7, or 8 carbon atoms and containing at least one heteroatom selected from N, O, and S in the ring. For example, there may be 1, 2, or 3 heteroatoms, or optionally 1 or 2. "C 3~8 A "heterocycloalkyl" may be attached to the remainder of the molecule through any carbon atom or heteroatom. A "heterocycloalkyl" group may be monocyclic. A "heterocycloalkyl" group may be bicyclic, e.g., a fused, spiro-fused, or bridged heterocycloalkyl ring system. For example, "C 3~8The "heterocycloalkyl" may be oxirane, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine, and tetrahydropyran.

[0175] The term "heterocyclyl" refers to a saturated or unsaturated hydrocarbon ring system containing carbon atoms and at least one heteroatom selected from N, O, and S within the ring. For example, there may be 1, 2, or 3 heteroatoms, and optionally 1 or 2. A "heterocyclyl" may be attached to the remainder of the molecule via any carbon atom or heteroatom. A "heterocyclyl" may be a heterocycloalkyl. A "heterocyclyl" may be a heteroaryl. A "heterocyclyl" may be a bicyclic heterocyclyl, such as a bicyclic heteroaryl or a bicyclic heterocycloalkyl. A "heterocyclyl" may be a heterocycloalkyl ring fused to an aryl or heteroaryl ring. A "heterocyclyl" may be a heteroaryl ring fused to a cycloalkyl or heterocycloalkyl ring. A "heterocyclyl" may be a monocyclic heterocyclyl, such as a monocyclic heteroaryl or a monocyclic heterocycloalkyl.

[0176] 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 within the ring. For example, there may be 1, 2, or 3 heteroatoms, and optionally 1 or 2. A "heterocycloalkenyl" may be attached to the remainder of the molecule through any carbon atom or heteroatom. For example, a "heterocycloalkenyl" is defined as "C 3~8 The term "C" may also be "heterocycloalkenyl". 3~8"Heterocycloalkenyl" refers to a saturated hydrocarbon ring system containing 3, 4, 5, 6, 7, or 8 atoms, at least one of which is a heteroatom in the ring selected from N, O, and S. "Heterocycloalkenyl" can also be tetrahydropyridine, dihydropyran, dihydrofuran, pyrroline.

[0177] The term "fused" refers to a bicyclic ring system in which two rings are joined through two adjacent atoms on each ring.

[0178] The term "spirofused" refers to a bicyclic ring system in which the two rings are joined through one atom.

[0179] The term "bridged" refers to a bicyclic ring system in which two rings are joined through two atoms on either ring that are not adjacent to each other.

[0180] The term "aromatic," when applied to a substituent as a whole, means a monocyclic or polycyclic ring system having 4n+2 electrons in a conjugated π system within the ring or ring system, where all atoms contributing to said conjugated π system are coplanar.

[0181] The term "aryl" refers to a hydrocarbon ring system that is aromatic. The ring system has 4n+2 electrons in the ring that are in a conjugated π system, where all atoms contributing to the conjugated π system are on the same plane. For example, "aryl" can be phenyl and naphthyl. The aryl system itself can be substituted with other groups.

[0182] 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 fused ring system. The ring or ring system has 4n+2 electrons in a conjugated π system, where all atoms contributing to the conjugated π system are on the same plane. For example, a "heteroaryl" can be imidazole, thiene, furan, thianthrene, pyrrole, benzimidazole, pyrazole, pyrazine, pyridine, pyrimidine, and indole.

[0183] As used herein, the term "halogen" includes reference to F, Cl, Br, and I. A halogen may be Br. A halogen may be I.

[0184] structure: [ka] A bond that is terminal indicates that the bond is attached to another atom not shown in the structure. A bond that is terminal within a ring structure and is not terminal to an atom of the ring structure indicates that the bond may be attached to any atom in the ring structure, valence permitting.

[0185] If a moiety is substituted, it may be substituted at any position on the moiety, provided that this is chemically feasible and satisfies valence requirements. The moiety may be substituted with one or more substituents, e.g., 1, 2, 3, or 4 substituents; where appropriate, one or two substituents may be present on a group. When there are two or more substituents, the substituents may be the same or different.

[0186] Substituents are present only at chemically possible positions where one skilled in the art can determine (experimentally or theoretically) without undue trial and error which substitutions are chemically possible and which are not.

[0187] 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, be they simple groups, such as the fluoro groups in the examples below, or the structure: [ka] It is part of another molecule indicated by a bond ending in . [ka]

[0188] "Meta" substitution is a substitution pattern in which two substituents are on carbons one carbon away from each other, i.e., there is one carbon atom between the substituted carbons. In other words, the substituent is on the second atom from the atom bearing the other substituent. For example, the following group is meta-substituted: [ka]

[0189] "Para" substitution is a substitution pattern in which two substituents are on carbons two carbons apart from each other, i.e., there are two carbon atoms between the substituted carbons. In other words, the substituent is on the third atom from the atom bearing the other substituent. For example, the following group is para-substituted: [ka]

[0190] Throughout the description, the disclosure of a compound also encompasses its pharmaceutically acceptable salts, solvates, and stereoisomers. When a compound has a stereocenter, both the (R) and (S) stereoisomers are contemplated by the present invention, as are mixtures of stereoisomers or racemic mixtures. When a compound of the present invention has more than one stereocenter, any combination of the (R) and (S) stereoisomers is contemplated. A combination of the (R) and (S) stereoisomers may result in a diastereomeric mixture or a single diastereoisomer. The compound 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 further contain other diastereoisomers or enantiomers as impurities. Thus, a single stereoisomer does not necessarily have 100% enantiomeric excess (ee) or diastereomeric excess (de), but may have an ee or de of at least about 85%, at least about 60%, or less. For example, the ee or de may be 90% or greater, 90% or greater, 80% or greater, 70% or greater, 60% or greater, 50% or greater, 40% or greater, 30% or greater, 20% or greater, or 10% or greater.

[0191] The present invention contemplates pharmaceutically acceptable salts of the compounds of the present invention. These may include acid addition and base salts of the compounds. These may be acid addition and base salts of the compounds. Additionally, the present invention contemplates solvates of the compounds. These may be hydrates or other solvate forms of the compounds.

[0192] 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, glucuronate, hexafluorophosphate, hybenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, butyrate, 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 salts.

[0193] Suitable base salts are formed from bases which form non-toxic salts. Examples include aluminum salts, arginine salts, benzathine salts, calcium salts, choline salts, diethylamine salts, diolamine salts, glycine salts, lysine salts, magnesium salts, meglumine salts, olamine salts, potassium salts, sodium salts, tromethamine salts, and zinc salts. Hemi-salts 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).

[0194] Pharmaceutically acceptable salts of compounds of formula (I) may be prepared by one or more of three methods: (i) reacting a compound of the present invention with a desired acid or base: (ii) removing an acid- or base-labile protecting group from a suitable precursor of a compound of the invention, or opening a suitable ring precursor, e.g., a lactone or lactam, with a desired acid or base; or (iii) Converting a salt of a compound of the present invention into another salt by reaction with an appropriate acid or base or by means of a suitable ion exchange column.

[0195] All three reactions are generally carried out in solution. The resulting salt may be collected by filtration or recovered by evaporation of the solvent. The degree of ionization of the resulting salt may vary from completely ionized to mostly non-ionized.

[0196] The compound of the present invention may exist in both non-solvated and solvated form.The term "solvate" is used herein to describe a molecular complex comprising the compound of the present invention and one or more stoichiometric amounts of pharmaceutically acceptable solvent molecules (e.g., ethanol).The term "hydrate" is used when the solvent is water.

[0197] Complexes such as clathrates and drug-host inclusion complexes are included within the scope of the present invention, where, in contrast to the aforementioned solvates, the drug and host are present in stoichiometric or non-stoichiometric amounts. Also included are drug complexes containing 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).

[0198] Hereinafter, references to compounds of any formula include references to salts, solvates and complexes thereof and to solvates and complexes of salts thereof.

[0199] The compounds of the present invention include compounds of the various formulas defined herein, as defined below, including all polymorphs and crystal habits thereof, prodrugs thereof, and isomers (including optical, geometric and tautomeric isomers), including isotopically labeled compounds of the present invention.

[0200] The present invention also includes all pharmaceutically 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 a different atomic mass or mass number from the atomic mass or mass number most commonly found in nature.

[0201] Examples of isotopes suitable for inclusion in compounds of the present invention include hydrogen isotopes, e.g. 2 H and 3 H, carbon isotopes, e.g. 11 C. 13 C and 14 C, chlorine isotopes, e.g. 36 Cl, fluorine isotopes, e.g. 18 F, iodine isotopes, e.g. 123 I and 125 I, nitrogen isotopes, e.g. 13 N and 15 N, oxygen isotopes, e.g. 15 O. 17 O and 18 O, phosphorus isotopes, e.g. 32 P, and sulfur isotopes, e.g. 35 Examples include S.

[0202] Some isotopically labeled compounds, for example, incorporate a radioactive isotope and are useful in drug research 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.

[0203] Heavier isotopes, such as deuterium, i.e. 2 Substitution with H may offer several therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and may therefore be preferred in some conditions.

[0204] Before purification, the compounds of the present invention may exist as a mixture of enantiomers depending on the synthetic procedures used. Enantiomers can be separated by conventional techniques known in the art. Thus, the present invention encompasses individual enantiomers as well as mixtures thereof.

[0205] For some steps in the preparation process of the compounds of the present invention, it may be necessary to protect potentially reactive functional groups that are not desired to react, and ultimately to cleave the protecting groups. In such cases, any suitable protecting group may be used. In particular, protection and deprotection methods, such as those described by T. W. Greene (Protective Groups in Organic Synthesis, A. Wiley-Interscience Publication, 1981) or P. J. Kocienski (Protecting groups, Georg Thieme Verlag, 1994), may be used. The above reactions and preparation of new starting materials used in the aforementioned methods are all conventional and suitable reagents and reaction conditions for carrying them out or preparing them, as well as procedures for isolating the desired products, which will be well known to those skilled in the art by referring to the prior art and the examples and preparations herein.

[0206] Additionally, the compounds of the present invention, as well as the intermediates for their preparation, may be purified according to various well-known methods, such as crystallization or chromatography.

[0207] One or more compounds of the present invention may be combined with one or more pharmaceutical agents, such as anti-inflammatory agents, anti-fibrotic agents, chemotherapeutic agents, anti-cancer agents, immunosuppressants, anti-tumor vaccines, cytokine therapy, or tyrosine kinase inhibitors, to treat conditions modulated by inhibition of RAS proteins, such as carcinomas, sarcomas, melanomas, skin cancers, hematological tumors, lymphomas, cancers, and leukemias.

[0208] The therapeutic methods or compounds for use in treating carcinoma, sarcoma, melanoma, skin cancer, hematological tumors, lymphoma, cancer, and leukemia as defined herein above may be applied as sole therapy or in combination therapy with additional active agents.

[0209] The compound for use in the treatment of cancer, sarcoma, melanoma, skin cancer, hematological tumors, lymphoma, cancer, and leukemia may contain 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, such as corticosteroids, glucocorticoids and mineralocorticoids, such as aclomethasone, aclomethasone dipropionate, aldosterone, amcinonide, beclomethasone, beclomethasone dipropionate, betamethasone, betamethasone dipropionate, betamethasone sodium phosphate, betamethasone valerate, budesonide, clobetasone, clobetasone butyrate, clobetazone flupropionate, cloprednol, cortisone, cortisone acetate, cortivazol, deoxycortone, desonide, desoximetasone, dexamethasone, dexamethasone sodium phosphate, dexamethasone isonicotinate, difluorocortolone, fluchlorolone, flumethasone, flunisolide, fluocinolone, fluocinolone acetonide, fluocinonide, fluocortin butyl, Examples include 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, icometasone, icometasone embutate, meprednisone, methylprednisolone, mometasone paramethasone, mometasone furoate monohydrate, prednicarbate, prednisolone, prednisone, tixocortol, tixocortol pivalate, triamcinolone, triamcinolone acetonide, triamcinolone alcohol, and pharmaceutically acceptable derivatives of each. Combinations of steroids may be used, for example, a combination of two or more of the steroids mentioned in this paragraph may be used; (ii) TNF inhibitors, such as etanercept; monoclonal antibodies (e.g., infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia), golimumab (Simponi)); fusion proteins (e.g., etanercept (Enbrel)); and 5-HT2A agonists (e.g., 2,5-dimethoxy-4-iodoamphetamine, TCB-2, lysergic acid diethylamide (LSD), lysergic acid dimethylazetizide); (iii) anti-inflammatory drugs, such as nonsteroidal anti-inflammatory drugs; (iv) dihydrofolate reductase inhibitors / antifolates, such as methotrexate, trimethoprim, brodimoprim, tetroxoprim, iclaprim, pemetrexed, ralitrexed, and pralatrexate; and (v) Immunosuppressants, such as cyclosporines, tacrolimus, sirolimus-spimecrolimus, 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, lactokinins, and 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), PGDH 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 therapies, such as: 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 (Aricept), Galantamine (Razadyne), rivastigmine (Exelon), memantine (Ebixa, Axura), aducanumab, ocrelizumab, interferon beta-1a (Avonex, Rebif), peginterferon beta-1a (Plegridy), teriflunomide (Aubagio), fingolimod (Gilenya), mitoxantrone (Novantrone), dimethyl fumarate (Tecfidera), natalizumab (Tysabri).

[0210] Therapeutic methods or compounds for use in the treatment of carcinomas, sarcomas, melanomas, skin cancers, hematological tumors, lymphomas, cancers, leukemias, and central nervous system disorders may include, in addition to the compounds of the present invention, conventional surgery, 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, such as alkylating agents (e.g., cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, uracil mustard, bendamustine, melphalan, chlorambucil, chlormethine, busulfan, temozolomide, nitrosoureas, ifosamide, melphalan, pipobroman, triethylene-melamine, triethylenethiophosphoramine, triethylenedi ... thylenethiophoporamine, carmustine, lomustine, stroptozocin, and dacarbazine); antimetabolites (e.g., gemcitabine and antifolates, e.g., fluoropyrimidines such as 5-fluorouracil and tegafur, raltitrexed, methotrexate, pemetrexed, cytosine arabinoside, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate anti-mitotic drugs (e.g., vinca alkaloids such as vincristine, vinblastine, vindesine, and vinorelbine, taxanes such as taxol and taxotere); antibiotics (e.g., anthracyclines such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin, and mithramycin); anti-mitotic drugs (e.g., vinca alkaloids such as vincristine, vinblastine, vindesine, and vinorelbine, taxanes such as taxol and taxotere); proteasome inhibitors, such as carfilzomib and bortezomib; interferon therapy; and topoisomerase inhibitors (e.g., epipodophyllotoxins such as etoposide and teniposide, amsacrine, topotecan, mitoxantrone, and camptothecin); bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, ara-C, paclitaxel (Taxol), TM ), nab-paclitaxel, docetaxel, mithramycin, deoxyco-formycin, mitomycin-C, L-asparaginase, interferons (especially IFN-a), etoposide, and teniposide; (ii) Cytostatics, such as antiestrogens (e.g., tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene, and idoxifene), antiandrogens (e.g., bicalutamide, flutamide, nilutamide, and cyproterone acetate), LHRH antagonists or agonists (e.g., goserelin, leuprorelin, and buserelin), progestogens (e.g., megestrol acetate), aromatase inhibitors (e.g., anastrozole, letrozole, vorazole, and exemestane), and 5 * - reductase inhibitors, such as finasteride; and navelbene, CPT-11, anastrozole, letrozole, capecitabine, reloxafme, cyclophosphamide, ifosamide, and droloxafine; (iii) anti-invasive agents, such as dasatinib and bosutinib (SKI-606), and metalloproteinase inhibitors, plasminogen activator receptor function inhibitors, urokinase or heparanase antibodies; (iv) Inhibitors of growth factor function: For example, such inhibitors include: Growth factor and growth factor receptor antibodies (e.g., trastuzumab, an anti-erbB2 antibody [Herceptin TM], the anti-EGFR antibody panitumumab, the anti-erbB1 antibody cetuximab), tyrosine kinase inhibitors (e.g., inhibitors of the epidermal growth factor family (e.g., EGFR family tyrosine kinase inhibitors, e.g., gefitinib, erlotinib, 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine (CI1033), erbB2 tyrosine kinase inhibitors, e.g., lapatinib) and antibodies against costimulatory molecules (e.g., CTLA-4, 4-lBB, and PD-1), or antibodies against cytokines (IL-10, TGF-beta); inhibitors of the hepatocyte growth factor family; inhibitors of the insulin growth factor family; modulators of cell apoptosis control proteins ( for example, Bcl-2 inhibitors); inhibitors of the platelet-derived growth factor family (e.g., imatinib and / or nilotinib (AMN107)); serine / threonine kinase inhibitors (e.g., Ras / Raf signaling inhibitors, for example, farnesyltransferase inhibitors, such as sorafenib, tipifarnib, and lonafarnib), inhibitors of cell signaling via MEK and / or AKT kinase, c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1R kinase inhibitors, IGF receptor kinase inhibitors; Aurora kinase inhibitors and cyclin-dependent kinase inhibitors (e.g., CDK2 and / or CDK4 inhibitors); and CCR2, CCR4, or CCR6 modulators; (v) Antiangiogenic agents, such as those that inhibit the action of vascular endothelial growth factor, for example, bevacizumab (Avastin), an anti-vascular endothelial growth factor antibody. TM ); thalidomide; lenalidomide; and for example, VEGF receptor tyrosine kinase inhibitors, such as vandetanib, vatalanib, sunitinib, axitinib and pazopanib; (vi) gene therapy approaches, for example, approaches to replace abnormal genes such as p53 gene abnormalities or BRCA1 or BRCA2 abnormalities; (vii) immunotherapies, such as antibody therapies, e.g., alemtuzumab, rituximab, ibritumomab tiuxetan (Zevalin®), and ofatumumab; interferons such as interferon alpha; interleukins such as IL-2 (aldesleukin); interleukin inhibitors (e.g., IRAK4 inhibitors); cancer vaccines, including prophylactic and therapeutic vaccines, e.g., HPV vaccines, e.g., Gardasil, Cervarix, Oncophage, and sipuleucel-T (Provenge); gp100; dendritic cell-based vaccines (e.g., Ad.p53 DC); and toll-like receptor modulators, e.g., TLR-7 or TLR-9 agonists; and (viii) Cytotoxic drugs, such as fludarabine (Fludara), cladribine, pentostatin (Nipent TM ); (ix) steroids such as corticosteroids, including Glucocorticoids and mineralocorticoids, such as aclomethasone, aclomethasone dipropionate, aldosterone, amcinonide, beclomethasone, beclomethasone dipropionate, betamethasone, betamethasone dipropionate, betamethasone sodium phosphate, betamethasone valerate, budesonide, clobetasone, clobetasone butyrate, clobetasol propionate, cloprednol, cortisone, cortisone acetate, cortivazol, deoxycortone, desonide, desoximetasone, dexamethasone, dexamethasone sodium phosphate, dexamethasone isonicotinate, difluorocortolone, fluchlorone, flumethasone, flunisolide, fluocinolone, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluorocortolone, Examples of suitable antiperspirants include thixocortol, fluorocortolone, fluocortol 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 pharmaceutically acceptable derivatives of each of these. Combinations of steroids may be used, for example, a combination of two or more of the steroids mentioned in this paragraph; (x) targeted therapies, such as PI3Kd inhibitors, e.g., idelalisib and perifosine; PD-1, PD-L1, PD-L2 and CTL4-A modulators, antibodies and vaccines; other IDO inhibitors (e.g., indoximod); anti-PD-1 monoclonal antibodies (e.g., MK-3475 and nivolumab); anti-PD-L1 monoclonal antibodies (e.g., MEDI-4736 and RG-7446); anti-PD-L2 monoclonal antibodies; and anti-CTLA-4 antibodies (e.g., ipilimumab); (xii) Chimeric antigen receptors, anticancer vaccines and arginase inhibitors.

[0211] Such combination therapy may be achieved by the simultaneous, sequential or separate dosing of the individual therapeutic components. Such combination products will contain the compounds of this invention within the therapeutically effective dosage ranges previously described herein and the other pharmaceutically active agent(s) within their approved dosage ranges.

[0212] The compounds of the present invention may exist in a single crystalline form, as a mixture of crystalline forms, or may be amorphous. Thus, 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. Microwave or radio frequency drying may be used for this purpose.

[0213] For the compounds of the present invention described above, the administered dose will, of course, vary depending on the compound used, the mode of administration, the desired treatment and indication. For example, when the compounds of the present invention are administered orally, the daily dose of the compounds of the present invention may range from 0.01 μg per kg of body weight (μg / kg) to 100 mg per kg of body weight (mg / kg).

[0214] Although the compounds of the present invention, or pharmaceutically acceptable salts thereof, may be used per se, they will generally be administered in the form of a pharmaceutical composition in which they are combined with a pharmaceutically acceptable adjuvant, diluent, or carrier. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described, for example, in "Pharmaceuticals - The Science of Dosage Form Designs", M.E. Aulton, Churchill Livingstone, 1988.

[0215] Depending on the mode of administration of the compounds of the present invention, the pharmaceutical compositions used to administer the compounds of the present invention preferably contain 0.05 to 99% by weight (wt %) of the compounds of the present invention, more preferably 0.05 to 80% by weight of the compounds of the present invention, even more preferably 0.10 to 70% by weight of the compounds of the present invention, and even more preferably 0.10 to 50% by weight of the compounds of the present invention, all wt % being based on the total weight of the composition.

[0216] Pharmaceutical compositions may 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 in the form of tablets, capsules, syrups, powders, or granules; or by parenteral administration in the form of sterile solutions, suspensions, or emulsions for injection (including intravenous, subcutaneous, intramuscular, intravascular, or infusion); by rectal administration in the form of suppositories; or by inhalation in the form of an aerosol.

[0217] For oral administration, the compounds of the present invention may be mixed with adjuvants 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, beeswax, paraffin, etc., and then compressed into tablets. If coated tablets are required, the cores prepared as described above may be coated with a concentrated sugar solution (which may contain, for example, gum arabic, gelatin, talc, and titanium dioxide). Alternatively, tablets may be coated with a suitable polymer dissolved in a highly volatile organic solvent.

[0218] For the preparation of soft gelatin capsules, the compounds of the present invention may be mixed with, for example, vegetable oil or polyethylene glycol. Hard gelatin capsules may contain granules of the compounds using any of the excipients for tablets mentioned above. Liquid or semisolid preparations of the compounds 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 compounds of the present invention, the balance being a mixture of sugar and ethanol, water, glycerol, and propylene glycol. Such liquid preparations may optionally contain colorants, flavors, sweeteners (e.g., saccharin), carboxymethylcellulose as a preservative and / or thickener, or other excipients known to those skilled in the art.

[0219] For intravenous (parenteral) administration, the compounds of the present invention may be administered as a sterile aqueous or oily solution.

[0220] The dosage of the compounds of the invention for therapeutic purposes will naturally vary according to well-known principles of medicine, depending on the nature and severity of the condition, the age and sex of the animal or patient, and the route of administration.

[0221] Dose levels, frequency of administration, and duration of treatment of the compounds of the invention are expected to vary depending on the formulation, as well as the clinical indication, age, and coexisting medical conditions of the patient.

[0222] Throughout the description and claims herein, the terms "comprise" and "contain" and variations thereof mean "including, but not limited to," and they are not intended to (and do not) exclude other moieties, additives, ingredients, integers, or steps. Throughout the description and claims herein, the singular includes the plural unless the context requires otherwise. In particular, where the indefinite article is used, it should be understood that the description contemplates the plural as well as the singular, unless the context requires otherwise.

[0223] It should be understood that any feature, integer, characteristic, compound, chemical moiety, or group described in connection with a particular aspect, embodiment, or example of the present invention is applicable to any other aspect, embodiment, or example described herein, unless inappropriate. All features described herein (including any accompanying claims, abstract, and drawings) and / or all steps of any method or all processes disclosed may be combined in any combination (except combinations in which at least some of such features and / or steps are mutually exclusive). The present invention is not limited to the details of any of the foregoing embodiments. The present invention extends to any novel feature or any novel combination of features disclosed herein (including any accompanying claims, abstract, and drawings), or any novel step or process or any novel combination of steps or processes of any method similarly disclosed.

[0224] The reader's attention is directed to all articles and documents in connection with this application, whether submitted herewith or submitted earlier hereto, that are published herewith, and the entire contents of such articles and documents are incorporated herein by reference.

[0225] experiment Solvents, reagents, and starting materials were purchased from commercial suppliers and used as received unless otherwise noted. All reactions were performed at room temperature unless otherwise noted. Compound identity and purity were confirmed by LCMS UV using a Waters Acquity SQ Detector 2 (ACQ-SQD2#LCA081). The diode array detector wavelength was set to 254 nM, and MS was performed in positive and negative electrospray mode (m / z: 150–800). A 2 μL aliquot was injected onto a guard column (0.2 μm × 2 mm filter) and a UPLC column (C18, 50 × 2.1 mm, <2 μm) in that order, 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 / water) and B (0.1% (v / v) formic acid / acetonitrile) according to the gradient shown in Table 1 below. Retention times (RT) are reported in minutes. The following methods were also used where appropriate throughout the experimental section, with the concentration gradients detailed in Table 1. Method 3 was performed using a Shimadzu 2020 Series spectrometer equipped with a binary pump and a diode array detector (acquisition wavelengths of 214 and 254 nm). MS was performed in positive and negative electrospray mode (m / z: 100-900). 2 μL aliquots 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 a mobile phase consisting of: A: 0.05% formic acid / water (v / v), B: 0.05% formic acid / MeCN (v / v). Method 4 used an Agilent Technologies 1290 series spectrometer equipped with a binary pump and a diode array detector (acquisition wavelengths 214 and 254 nm), and MS was in positive electrospray mode (m / z: 70-1000).A 2 μL aliquot was injected onto an Agilent Eclipse Plus RRHD C18 (1.8 μm, 3.0 × 50 mm) column maintained at 40°C and eluted at 0.8 ml / min with a mobile phase consisting of: A: 0.05% formic acid / water (v / v), B: 0.05% formic acid / MeCN (v / v). [Table 1] [Table 2]

[0226] NMR was also used to characterize the final compounds. NMR spectra were acquired on a Bruker AVIII 400 Nanobay equipped with a 5 mm BBFO probe. Rf values ​​of compounds were measured on silica thin-layer chromatography (TLC) plates, as appropriate.

[0227] Compound purification was performed by flash column silica chromatography or preparative LCMS. LCMS purification was performed using a Waters 3100 mass detector equipped with a Waters 2489 UV / Vis detector in positive and negative electrospray mode (m / z: 150-800). Samples were eluted at a flow rate of 20 mL / min (XBridge TM Preparative C18 5 μM OBD 19 × 100 mm column. The mobile phase system included A (0.1% (v / v) formic acid / water) and B (0.1% (v / v) formic acid / acetonitrile) according to the gradient summarized in Table 2 below. [Table 3]

[0228] General reaction scheme Some compounds of the invention can be made using the following general reaction scheme: Some compounds of the invention may be made according to or in analogy with the synthetic examples described below.

[0229] [ka] Compounds of formula (I) may be made by the synthetic route described in General Scheme 1. In Step A, compounds of formula GI-1 may be cyclized with urea or a urea equivalent in the presence of a base such as sodium hydroxide or an acid such as hydrochloric acid to give pyrimidines of formula GI-2. In Step B, dihydroxypyrimidines may be chlorinated with phosphoryl chloride to form dichloropyrimidines. In Step C, the dichlorides GI-3 may be chlorinated with a nucleophile (HZ) in the presence of a base such as DCM in an anhydrous solvent at room temperature. 1 R 1 In step D, the remaining chlorine in GI-4 can be converted to HZ under the same conditions as in step C. 2 R 2 or alternatively, via a suitable palladium-catalyzed Buchwald coupling to afford Z 2 R 2 In Step E, Boc-deprotection of GI-5 with an acid such as TFA provides the secondary amide GI-8. In Step F, the amide GI-8 can be converted to the halo-R via a suitable palladium-catalyzed Buchwald coupling. 4 or to the corresponding triflate reagent (X = Cl, Br, I or trifluoromethylsulfonate). Step G may or may not be required, and R 4 , Z 1 R 1 and Z 2 R 2 represents a global deprotection step to remove acid-labile protecting groups (if present) from reactive atoms of a group, e.g., R 4 may contain a methoxymethyl (MOM) protecting group on the OH of the naphthol, and / or Z 1 R 1 and / or Z 2 R 2may contain tert-butoxycarbamate (Boc) protecting groups on primary or secondary amines, all of which can be removed by treatment with an acid such as TFA. Alternatively, Steps C through F can be performed in a different order to obtain compounds of Formula (I). Dichloropyrimidine GI-3 can be boc-deprotected (Step E) to form GI-6, followed by a Buchwald reaction (Step F) to form GI-9, followed by a series of nucleophilic substitutions to replace the chlorine at the 4-position of the pyrimidine (Step C) to form GI-10, followed by replacement of the chlorine at the 2-position of the pyrimidine (Step D), and finally, if necessary, global deprotection (Step G). Alternatively, chloropyrimidine GI-4 can be boc-deprotected (Step E) to form GI-7, followed by a Buchwald reaction (Step F) to form chloropyrimidine GI-10, followed by replacement of the chlorine at the 2-position of the pyrimidine (Step D) and finally, if necessary, global deprotection (Step G).

[0230] [ka] Intermediates of formula GI-8 may be formed by the route described in General Scheme 2 and then subsequently transformed into compounds of formula (I) as previously shown in General Scheme 1. In Step A, 2-thiomethyl-4,6-dichloropyrimidines of formula GI-11 are reacted with an appropriate amine or alcohol nucleophile (HZ) in an anhydrous solvent such as THF or 1,4-dioxane. 1 R 1 The chlorine at the 4-position can be substituted regioselectively with a base-catalyzed nucleophilic substitution using CI-12 to give thiomethylpyrimidines of formula GI-12. In step B, GI-12 can be substituted at the chlorine at the 6-position of the pyrimidine with a nitrile source such as Zn(CN)2 in the presence of a Pd catalyst such as Pd(PPh3)4 to give 2-thiomethyl-6-cyanopyrimidines of formula GI-13. In step C, the thiomethyl group of GI-13 can be oxidized to the corresponding methyl sulfone using an oxidizing agent such as m-CPBA in a solvent such as DCM. The resulting sulfone can then be oxidized with a nucleophile (HZ) in the presence of a base such as NaH in a solvent such as DMF or THF.2 R 2 GI-13 is converted to an intermediate of formula GI-14 by nucleophilic substitution with GI-14. GI-14 can be treated with hydrogen gas and a heterogeneous catalyst such as palladium on carbon in the presence of an acid (e.g., 1N HCl) at elevated temperatures (e.g., 50°C). Under these conditions, the amine product of the hydrogenation of the nitrile can spontaneously cyclize at the proximal ester group to form an intermediate of formula GI-8. Alternatively, steps C, D, and E can be rearranged such that GI-13 is reduced / cyclized (step E) to form GI-15, followed by oxidation and displacement of the thiomethyl (steps C and D) to give an intermediate of formula GI-8.

[0231] [ka] The compounds of the present invention of formula (VII) can be prepared according to General Scheme 3. In Step A, compound GI-16 is oxidized with an oxidation catalyst reagent such as ruthenium trichloride in the presence of stoichiometric sodium periodate using EtOAc and water as co-solvents. In Step B, the dichloride GI-17 is oxidized with a nucleophile (HZ) in the presence of a base in an anhydrous solvent such as DCM at room temperature. 1 R 1 In step C, the remaining chlorine in GI-18 can be converted to HZ under the same conditions as in step B. 2 R 2 or alternatively, via a suitable palladium-catalyzed Buchwald coupling to afford Z 2 R 2 In Step D, Boc-deprotection of GI-19 with an acid such as TFA provides the secondary amide GI-20. In Step E, the amide GI-20 can be converted to the halo-R via a suitable palladium-catalyzed Buchwald coupling. 4 or can be coupled to the corresponding triflate reagent (X=Cl, Br, I or trifluoromethylsulfonate). Step F may or may not be required, and R 4 , Z 1 R1 and Z 2 R 2 represents a global deprotection step to remove acid-labile protecting groups (if present) from reactive atoms of a group, e.g., R 4 may contain a methoxymethyl (MOM) protecting group on the OH of the naphthol, and / or Z 1 R 1 and / or Z 2 R 2 may contain tert-butoxycarbamate (Boc) protecting groups on primary or secondary amines, all of which can be removed by treatment with an acid such as TFA. Alternatively, steps B through E can be performed in a different order to obtain compounds of formula (VII). Dichloropyrimidine GI-17 can be boc-deprotected (step D) to form GI-23, followed by a Buchwald reaction (step E) to form GI-24, followed by a series of nucleophilic substitutions to replace the chlorine at the 4-position of the pyrimidine (step B) to form GI-22, followed by replacement of the chlorine at the 2-position of the pyrimidine (step C), and finally, if necessary, global deprotection (step F). Alternatively, chloropyrimidine GI-18 can be boc-deprotected (step D) to form GI-21, followed by a Buchwald reaction (step E) to form chloropyrimidine GI-22, followed by replacement of the chlorine at the 2-position of the pyrimidine (step C) and finally, if necessary, global deprotection (step F).

[0232] Intermediates Intermediates I-1, 8-ethyl-7-fluoro-3-(methoxymethyloxy)naphthalen-1-ol and I-1a, [8-ethyl-7-fluoro-3-(methoxymethyloxy)-1-naphthyl]trifluoromethanesulfonate [ka]

[0233] Intermediates I-1 and I-1a were prepared by the following route described in Scheme 1. [ka] Step A, 2-bromoethynyl(triisopropyl)silane Under nitrogen, silver nitrate (302 mg, 1.78 mmol) was added to a solution of N-bromosuccinimide (3.49 g, 19.6 mmol) and triisopropylsilylethyne (4.0 mL, 17.8 mmol) in acetone (89 mL). The reaction mixture was stirred at room temperature for 1 hour. All volatiles were removed under reduced pressure. The residue was partitioned between petroleum (30 mL) and water (30 mL). The organic layer was separated. The aqueous layer was extracted with petroleum (30 mL). The combined organic extracts were washed with saturated brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 2-bromoethynyl(triisopropyl)silane (4.96 g, 19.0 mmol, 100% yield) as a colorless oil. 1 H NMR (400 MHz,CDCl3) δ / ppm: 1.11-1.02 (m,21H).

[0234] Step B: 7-fluoro-8-(2-triisopropylsilylethynyl)naphthalene-1,3-diol Dichloro(p-cymene)ruthenium(II) dimer (1.03 g, 1.68 mmol) was added to a suspension of 7-fluoronaphthalene-1,3-diol (3.00 g, 16.8 mmol), 2-bromoethynyl(triisopropyl)silane (4.62 g, 17.7 mmol), and potassium acetate (3.31 g, 33.7 mmol) in 1,4-dioxane (19.8 mL) (degassed with nitrogen). The mixture was then stirred at 110 °C for 1 h, cooled to room temperature, and all volatiles were removed under reduced pressure. Purification by flash column silica gel chromatography (eluting with 0–25% ethyl acetate / petrol) afforded 7-fluoro-8-(2-triisopropylsilylethynyl)naphthalene-1,3-diol (4.59 g, 12.8 mmol, 76% yield) as a black oil. UPLC-MS (ES-, Method 2): 2.47 min, m / z 357.4 [MH] - .

[0235] Step C, 7-fluoro-3-(methoxymethyloxy)-8-(2-triisopropylsilylethynyl)naphthalen-1-ol To a solution of 7-fluoro-8-(2-triisopropylsilylethynyl)naphthalene-1,3-diol (4.59 g, 12.8 mmol) and N,N-diisopropylethylamine (4.46 mL, 25.6 mmol) in DCM (64 mL) was added bromomethyl methyl ether (0.99 mL, 12.2 mmol) at 0 °C. The mixture was stirred at that temperature for 30 minutes, then concentrated under reduced pressure and partitioned between ethyl acetate (40 mL) and water (40 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (40 mL). The combined organic layers were washed with saturated brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by flash column chromatography on silica gel (eluting with 0-25% ethyl acetate / petroleum) gave 7-fluoro-3-(methoxymethyloxy)-8-(2-triisopropylsilylethynyl)naphthalen-1-ol (3.04 g, 7.55 mmol, 59% yield) as a brown oil. 1 H NMR (400 MHz,CDCl3) δ / ppm: 10.30 (s,1H),7.88 (dd,J = 9.1,5.7 Hz,1H),7.42-7.34 (m,1H),7.03 - 6.97 (m,1H),6.77-6.71 (m,1H),5.27 (s,2H),3.48-3.42 (m,3H),1.20-1.15 (m,21H).

[0236] Step D, [7-fluoro-3-(methoxymethyl)-8-(2-triisopropylsilylethynyl)-1-naphthyl]2,2-dimethylpropanoate To a solution of 7-fluoro-3-(methoxymethyloxy)-8-{2-[tris(propan-2-yl)silyl]ethynyl}naphthalen-1-ol (3.04 g, 7.55 mmol) and N,N-diisopropylethylamine (1.6 mL, 9.07 mmol) in DCM (15.1 mL) was added trimethylacetyl chloride (1.1 mL, 9.07 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 30 minutes, and additional trimethylacetyl chloride (2.2 mL, 18.1 mmol) and N,N-diisopropylethylamine (1.6 mL, 9.07 mmol) were added. The reaction mixture was stirred at 0° C. for 16 hours. The reaction mixture was concentrated under reduced pressure and partitioned with ethyl acetate (40 mL) and water (40 mL). The layers were separated, and the aqueous layer was extracted with ethyl acetate (40 mL). The combined organic layers were washed with saturated brine (20 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give [7-fluoro-3-(methoxymethyloxy)-8-(2-triisopropylsilylethynyl)-1-naphthyl] 2,2-dimethylpropanoate (4.88 g, 10.0 mmol, 100% yield) as a brown oil. 1 H NMR (400 MHz,CDCl3) δ / ppm: 7.68 (dd,J = 9.1,5.5 Hz,1H),7.28 (d,J = 2.4 Hz,1H),7.27-7.20 (m,1H),6.83 (d,J = 2.1 Hz,1H),5.25 (s,2H),3.50 (s,3H),1.47 (s,9H),1.22-1.09 (m,21H).

[0237] Step E, [8-ethynyl-7-fluoro-3-(methoxymethyloxy)-1-naphthyl]2,2-dimethylpropanoate Cesium fluoride (5.73 g, 37.8 mmol) was added to a suspension of [7-fluoro-3-(methoxymethyloxy)-8-(2-triisopropylsilylethynyl)-1-naphthyl] 2,2-dimethylpropanoate (3.68 g, 7.55 mmol) in DMF (15.1 mL). The mixture was then stirred at room temperature for 1 hour and partitioned between ethyl acetate (100 mL) and water (100 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (2 × 50 mL). The combined organic layers were washed with water (2 × 50 mL), saturated brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by flash column chromatography on silica gel (eluting with 0-30% ethyl acetate / petroleum) gave [8-ethynyl-7-fluoro-3-(methoxymethyloxy)-1-naphthyl] 2,2-dimethylpropanoate (2.48 g, 7.51 mmol, 99% yield) as a brown oil. UPLC-MS (ES + ,Method 2): 2.01 min,m / z 331.5 [M+H] + .

[0238] Step F, [8-ethyl-7-fluoro-3-(methoxymethyloxy)-1-naphthyl]2,2-dimethylpropanoate A solution of [8-ethynyl-7-fluoro-3-(methoxymethyloxy)-1-naphthyl]2,2-dimethylpropanoate (2.48 g, 7.51 mmol) in methanol (15.0 mL) was evacuated and refilled with nitrogen (×3). Palladium on carbon powder, 10 wt%, dry (240 mg, 2.25 mmol) was then added, and the mixture was evacuated and refilled with nitrogen (×3). The mixture was then evacuated and refilled with hydrogen (×2). The reaction was stirred at room temperature overnight. The mixture was then passed through a Celite pad, and the Celite pad was washed with MeOH. The filtrate was concentrated under reduced pressure to give [8-ethyl-7-fluoro-3-(methoxymethyloxy)-1-naphthyl]2,2-dimethylpropanoate (928 mg, 2.78 mmol, 37% yield) as a yellow oil. UPLC-MS (ES +,Method 2): 2.29 min,m / z 335.2 [M+H] + .

[0239] Step G, 8-ethyl-7-fluoro-3-(methoxymethyloxy)naphthalen-1-ol (I-1) Potassium hydroxide (467 mg, 8.33 mmol) was added to a solution of [8-ethyl-7-fluoro-3-(methoxymethyloxy)-1-naphthyl] 2,2-dimethylpropanoate (928 mg, 2.78 mmol) in methanol (13.9 mL). The mixture was stirred at room temperature for 30 minutes. All volatile components were removed under reduced pressure, and the pH was adjusted to 7 with saturated aqueous ammonium chloride. The reaction mixture was partitioned between ethyl acetate (40 mL) and water (40 mL). The organic layer was separated. The aqueous layer was extracted with ethyl acetate (40 mL). The combined organic layers were washed with saturated brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by flash column chromatography on silica gel (eluting with 0–30% ethyl acetate / petrol) afforded 8-ethyl-7-fluoro-3-(methoxymethyloxy)naphthalen-1-ol (411 mg, 1.64 mmol, 59% yield) as a brown oil. UPLC-MS (ES + ,Method 2): 1.90 min,m / z 251.1 [M+H] + .

[0240] Step H, [8-ethyl-7-fluoro-3-(methoxymethyloxy)-1-naphthyl]trifluoromethanesulfonate (I-1a) Trifluoromethanesulfonic anhydride (0.41 mL, 2.46 mmol) was added to a solution of N,N-diisopropylethylamine (0.86 mL, 4.92 mmol) and 8-ethyl-7-fluoro-3-(methoxymethyloxy)naphthalen-1-ol (411 mg, 1.64 mmol) in DCM (8.2 mL) at −40° C. The mixture was then stirred at that temperature for 30 minutes. The reaction mixture was diluted with ice water (20 mL), warmed to room temperature, and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with saturated brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by flash column chromatography on silica gel (eluting with 0–25% ethyl acetate / petroleum) afforded intermediate I-1a, [8-ethyl-7-fluoro-3-(methoxymethyloxy)-1-naphthyl]trifluoromethanesulfonate (515 mg, 1.35 mmol, 82% yield) as a yellow oil. UPLC-MS (ES + ,Method 2): 2.25 min,m / z 383.3 [M+H] + . 1 H NMR (400 MHz,CDCl3) δ / ppm: 7.62 (dd,J = 9.0,5.6 Hz,1H),7.42 (d,J = 2.4 Hz,1H),7.36 (d,J = 2.4 Hz,1H),7.32-7.25 (m,1H),5.28 (s,2H),3.52 (s,3H),3.24 (dq,J = 7.5,2.9 Hz,2H),1.24 (t,J = 7.6 Hz,3H).

[0241] Intermediate I-2, 1-bromo-3-(methoxymethyloxy)naphthalene [ka]

[0242] Intermediate I-2 was prepared according to the route described in Scheme 2. [ka] 1-Bromo-3-(methoxymethyloxy)naphthalene (I-2) To a solution of 4-bromonaphthalen-2-ol (2.00 g, 8.97 mmol) and N,N-diisopropylethylamine (4.7 mL, 26.9 mmol) in DCM (20 mL) was added chloromethyl methyl ether (1.0 mL, 13.5 mmol) at 0 °C. The reaction mixture was stirred for 90 min, then diluted with distilled water and extracted twice with DCM. The organic layers were combined, washed twice with brine, dried over Na2SO4, and filtered. The filtrate was evaporated under reduced pressure and purified by flash silica column chromatography (eluting with 0–60% EtOAc / petroleum ether) (40 g, dry load). The desired fractions were combined and evaporated under reduced pressure to give 1-bromo-3-(methoxymethyloxy)naphthalene (1.98 g, 7.41 mmol, 83% yield) as a colorless oil. UPLC-MS (ES + ,Method 2): 2.09 min,m / z 268.9 [M+H] + . 1 H NMR (400 MHz,CDCl3) δ / ppm: 8.09-8.05 (m,1H),7.68-7.64 (m,1H),7.50 (d,J = 2.0 Hz,1H),7.43-7.36 (m,2H),7.31 (d,J = 2.0 Hz,1H),5.21 (s,2H),3.45 (s,3H).

[0243] Intermediate I-3, N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide [ka]

[0244] Intermediate I-3 was prepared according to the procedure described in WO2022 / 133038 as shown in Scheme 3. [ka] Step A, 2-nitro-N-prop-2-ynyl-benzenesulfonamide A solution of propargylamine (29.1 mL, 454 mmol) and diisopropylethylamine (158 mL, 908 mmol) in DCM (1250 mL) was cooled to 0 °C. 2-Nitrobenzoylsulfonyl chloride (101 g, 454 mmol) was added portionwise, and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure, and the resulting residue was directly purified on silica gel (eluting with 20–50% EtOAc / petroleum ether) to give 2-nitro-N-prop-2-ynyl-benzenesulfonamide (100 g, 375 mmol, 83% yield) as a yellow solid. LC-MS (ES + ,Method 3): 1.30 min,m / z 258.00 [M+NH4] + 1 H NMR (400 MHz,DMSO-d6) δ / ppm: 8.54 (s,1H),8.08-8.02 (m,1H),8.01-7.94 (m,1H),7.90-7.83 (m,2H),3.85 (d,J = 2.3 Hz,2H),3.05 (t,J = 2.3 Hz,1H).

[0245] Step B, N-(3-chloropropyl)-2-nitro-N-prop-2-ynyl-benzenesulfonamide To a mixture of 2-nitro-N-prop-2-ynyl-benzenesulfonamide (50.0 g, 208 mmol) and CsCO (170 g, 520 mmol) in acetone (2000 mL) was added 1-bromo-3-chloropropane (154 mL, 1560 mmol). The reaction mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned between EtOAc (3000 mL) and water (2000 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (1500 mL × 2). The combined organic layers were dried over anhydrous NaSO and concentrated under reduced pressure. The crude product was purified by silica chromatography (petroleum ether / EtOAc = 2 / 1) to give N-(3-chloropropyl)-2-nitro-N-prop-2-ynyl-benzenesulfonamide (54.0 g, 162 mmol, 78% yield) as a yellow solid. LC-MS (ES + , Method 3): 1.93 min, m / z 317.0 [M+H] + 1 H NMR (400 MHz,DMSO-d6) δ / ppm: 8.10-8.04 (m,1H),8.02-7.97 (m,1H),7.95-7.82 (m,2H),4.23 (d,J = 2.2 Hz,2H),3.63 (t,J = 6.4 Hz,2H),3.46 (t,J = 7.0 Hz,2H),3.25 (t,J = 2.5 Hz,1H).

[0246] Step C, Ethyl 5-(2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylate To a solution of N-(3-chloropropyl)-2-nitro-N-prop-2-ynyl-benzenesulfonamide (2.00 g, 6.31 mmol) and ethyl diazoacetate (1.0 mL, 9.54 mmol) in benzene (6 mL) was added diisopropylethylamine (1.12 mL, 6.40 mmol). The resulting solution was heated at 140 °C for 1 h in a microwave reactor. After cooling to room temperature, CsCO (2.49 g, 7.64 mmol) and THF (4 mL) were added, and the reaction mixture was heated at 140 °C for 30 min. The reaction mixture was concentrated under reduced pressure, and the resulting residue was partitioned between water (300 mL) and EtOAc (200 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (200 mL × 3). The combined organic layer was washed with brine (200 mL × 2), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude product was purified by silica chromatography (petroleum ether / EtOAc = 1 / 1) to give ethyl 5-(2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylate (3.70 g, 7.51 mmol, estimated quantitative yield) as a brown solid. LC-MS (ES + ,Method 3): 1.63 min,m / z 395.1 [M+H] + 1 H NMR (400 MHz,DMSO-d6) δ / ppm: 8.06-7.97 (m,2H),7.94-7.87 (m,1H),7.86-7.78 (m,1H),6.72 (s,1H),4.67 (s,2H),4.54-4.44 (m,2H),4.24 (q,J = 7.1 Hz,2H),3.71-3.62 (m,2H),1.96-1.87 (m,2H),1.27 (t,J = 7.1 Hz,3H).

[0247] Step D, 5-(2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid To a solution of ethyl 5-(2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylate (4.70 g, 11.9 mmol) in methanol (25 mL) and THF (100 mL) was added 1 M LiOH (47.0 mL, 47.7 mmol). The resulting solution was stirred at room temperature for 2 hours. The reaction mixture was adjusted to pH 2 with 1 M HCl (47.0 mL). The precipitate was filtered, and the filtrate was concentrated in vacuo to give 5-(2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (4.00 g, 9.83 mmol, 82% yield) as a white solid. LC-MS (ES + ,Method 4): 1.20 min,m / z 367.1 [M+H] + 1 H NMR (400 MHz,DMSO-d6) δ / ppm: 12.64 (br s,1H),8.06-7.97 (m,2H),7.93-7.86 (m,1H),7.85-7.78 (m,1H),6.67 (s,1H),4.66 (s,2H),4.51-4.43 (m,2H),3.71-3.62 (m,2H),1.97-1.87 (m,2H).

[0248] Step E, N,N-dimethyl-5-(2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide To a solution of 5-(2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (6.50 g, 17.7 mmol) and TBTU (6.27 g, 19.5 mmol) in DMF (70 mL) was added diisopropylethylamine (12.4 mL, 71.0 mmol) at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 15 minutes. Dimethylamine hydrochloride (1.74 g, 21.3 mmol) was added, and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with water (1000 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (200 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure to give N,N-dimethyl-5-(2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (7.30 g, 15.8 mmol, 88% yield) as a yellow oil, which was used in the next reaction without further purification. LC-MS (ES + ,Method 3): 1.27 min,m / z 394.1 [M+H] + 1 H NMR (400 MHz,DMSO-d6) δ / ppm: 8.02-7.96 (m,2H),7.91-7.85 (m,1H),7.84-7.77 (m,1H),6.52 (s,1H),4.66 (s,2H),4.46-4.38 (m,2H),3.71-3.63 (m,2H),3.21 (s,3H),2.94 (s,3H),1.95-1.87 (m,2H) ppm.

[0249] Step F, N,N-Dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (I-3) To a solution of N,N-dimethyl-5-(2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (7.30 g, 18.6 mmol) and CsCO (12.1 g, 37.1 mmol) in MeCN (150 mL) was added thiophenol (3.8 mL, 37.1 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was directly purified by silica gel chromatography (eluting with MeOH / DCM 1 / 10) to give N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (2.80 g, 12.1 mmol, 65% yield) as a yellow solid. UPLC-MS (ES + , Method 2): 0.34 min, m / z 209.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ / ppm: 6.35 (s, 1H), 5.76 (s, 1H), 4.32 (m, 2H), 3.78 (s, 2H), 3.25 (s, 3H), 3.01 (m, 2H), 2.93 (s, 3H), 1.70 (m, 2H).

[0250] Intermediate I-4, 6-chloro-N,N-bis[(4-methoxyphenyl)methyl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine [ka]

[0251] Intermediate I-4 was prepared according to the route described in Scheme 4. [ka] Step A, 6-chloro-5-iodo-4-methyl-pyridin-2-amine To a solution of 6-chloro-4-methyl-2-pyridinamine (1.00 g, 7.01 mmol) in MeCN (16 mL) was added N-iodosuccinimide (1.89 g, 8.42 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to dryness and partitioned with DCM and brine. The organic material was extracted, passed through a layer-separating filter paper, and concentrated under reduced pressure. The crude product was purified by column chromatography (eluting with 10–100% EtOAc / petroleum ether). The desired fractions were combined and concentrated to dryness to give 6-chloro-5-iodo-4-methyl-pyridin-2-amine (1.52 g, 5.66 mmol, 81% yield) as an orange solid. UPLC-MS (ES + , Method 2): 1.76 min, m / z 268.8 / 270.8 [M+H] +

[0252] Step B, 6-chloro-5-iodo-N,N-bis[(4-methoxyphenyl)methyl]-4-methyl-pyridin-2-amine To a solution of 6-chloro-5-iodo-4-methyl-pyridin-2-amine (1.50 g, 5.59 mmol) in DMF (20 mL) was added 4-methoxybenzyl chloride (2.3 mL, 16.8 mmol) and sodium hydride (60% dispersion in mineral oil) (536 mg, 22.4 mmol), and the reaction was stirred at room temperature for 16 hours. The reaction mixture was partitioned between EtOAc and water. The organic layer was separated, and the aqueous layer was washed three times with EtOAc. The combined organic washes were washed with brine, passed through a layer-separating filter paper, and concentrated to dryness. The crude product was then purified by column chromatography (eluting with 10% EtOAc / petroleum ether to 100% EtOAc). The desired fractions were combined and concentrated under reduced pressure to give 6-chloro-5-iodo-N,N-bis[(4-methoxyphenyl)methyl]-4-methyl-pyridin-2-amine (2.83 g, 5.56 mmol, 100% yield) as a yellow solid. UPLC-MS (ES + , Method 2): 2.59 minutes, m / z 509.0 [M+H] +

[0253] Step C, 6-chloro-N,N-bis[(4-methoxyphenyl)methyl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine (I-4) To a solution of 6-chloro-5-iodo-N,N-bis[(4-methoxyphenyl)methyl]-4-methyl-pyridin-2-amine (1.00 g, 1.97 mmol) in DMF (10 mL) was added copper(I) iodide (749 mg, 3.93 mmol) and methyl-2,2-difluoro-2-(fluorosulfonyl)acetate (0.5 mL, 3.93 mmol), and the reaction was heated to 90 °C for 16 h. The reaction was diluted with EtOAc and water, and the organic material was extracted, passed through a layer-separating filter paper, and concentrated to dryness. The crude product was then purified by flash column chromatography (eluting with 0–60% EtOAc / petroleum ether). The desired fractions were combined and concentrated under reduced pressure to give 6-chloro-N,N-bis[(4-methoxyphenyl)methyl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine (563 mg, 1.2487 mmol, 63.53% yield) as an orange oil that solidified to a white solid on standing. UPLC-MS (ES + , Method 2): 2.51 min, m / z 451.1 [M+H] +

[0254] Intermediate I-5, [8-ethyl-7-fluoro-3-(methoxymethyloxy)-1-naphthyl]-1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate [ka]

[0255] Intermediate I-5 was prepared according to the route described in Scheme 5. The preparation of I-1 is described in Scheme 1. [ka] [8-Ethyl-7-fluoro-3-(methoxymethyloxy)-1-naphthyl]-1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (I-5) A round-bottom flask was charged with 8-ethyl-7-fluoro-3-(methoxymethyloxy)naphthalen-1-ol (3.50 g, 14.0 mmol), reagent-grade DCM (117 mL), and N,N-diisopropylethylamine (7.3 mL, 42.0 mmol) and cooled to 0 °C. Perfluorobutanesulfonyl fluoride (3.8 mL, 21.0 mmol) was added dropwise over 5 minutes, and the reaction was stirred at 0 °C for 30 minutes. The cooling bath was removed, and the reaction was stirred at 25 °C for an additional 46 hours. The reaction was quenched with water (75 mL). The organic layer was separated, and the aqueous layer was extracted with DCM (2 × 75 mL). The combined organic layers were dried over NaSO, filtered, silica was added, and the solvent was evaporated under reduced pressure. Purification by flash column chromatography (SiO, 80 g, petroleum ether / EtOAc gradient 0–10%) gave [8-ethyl-7-fluoro-3-(methoxymethyloxy)-1-naphthyl]1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (6.17 g, 11.6 mmol, 83% yield) as a yellow oil that turned to a gray solid after storage in the freezer for more than a week. UPLC-MS (ES-, Method 1): 5.97 min m / z 531.3 [MH] _ 1 H NMR (400 MHz,DMSO-d6) δ / ppm: 7.95 (dd,J = 8.9,5.6 Hz,1H),7.73 (d,J = 2.2 Hz,1H),7.58-7.52 (m,1H),7.36 (d,J = 2.2 Hz,1H),5.36 (s,2H),3.44 (s,3H),3.21-3.13 (m,2H),1.16 (t,J = 7.5 Hz,3H).

[0256] Intermediate I-6, [1-(1-piperidylmethyl)cyclopropyl]methanol [ka]

[0257] Intermediate I-6 was prepared according to the route described in Scheme 6. [ka] Step A, Methyl 1-(piperidine-1-carbonyl)cyclopropanecarboxylate To a solution of cyclopropane-1,1-dicarboxylic acid methyl ester (400 mg, 2.78 mmol) and N,N-dimethylformamide (0.002 mL, 0.0300 mmol) in DCM (1.7 mL) was added oxalyl chloride (0.3 mL, 3.55 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure to give a yellow oily residue, which was redissolved in THF (1.7 mL), cooled to 0 °C, and piperidine (1.2 mL, 2.39 mmol, 2M in THF) was slowly added. The resulting suspension was stirred at room temperature for 2 h. The reaction mixture was diluted with EtOAc, and the organic layer was washed twice with brine. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give methyl 1-(piperidine-1-carbonyl)cyclopropanecarboxylate (496 mg, 2.35 mmol, 85% yield) as a yellow oil. UPLC-MS (ES + ,Method 2): 1.38 min,m / z 212.1 [M+H] + 1 H NMR (400 MHz,DMSO-d6) δ / ppm: 3.65 (s,3H),3.46-3.40 (m,2H),3.40-3.34 (m,2H),1.61-1.53 ​​(m,3H),1.52-1.39 (m,3H),1.35-1.31 (m,2H),1.25-1.20 (m,2H).

[0258] Step B, [1-(1-piperidylmethyl)cyclopropyl]methanol (I-6) To a solution of methyl 1-(piperidine-1-carbonyl)cyclopropanecarboxylate (496 mg, 2.35 mmol) in anhydrous THF (1.9 mL) was slowly added lithium aluminum hydride (5.2 mL, 5.17 mmol, 1M / THF) at 0 °C. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled to 0 °C and quenched with 2 M HCl. The precipitate was filtered, and the filtrate was loaded onto an SCX cartridge (5 g, pre-washed with MeOH). The crude product was washed with MeOH followed by 1 M NH3 / MeOH. The ammonia fraction was evaporated under reduced pressure to give [1-(1-piperidylmethyl)cyclopropyl]methanol (134 mg, 0.792 mmol, 34%) as a pale yellow oil. 1 H NMR (400 MHz,DMSO-d6) δ / ppm: 4.68-4.57 (m,1H),2.40-2.27 (m,4H),2.22 (s,2H),1.52-1.49 (m,5H),1.41-1.29 (m,3H),0.42-0.37 (m,2H),0.23-0.17 (m,2H).

[0259] Intermediate I-7, [1-(diethylaminomethyl)cyclopropyl]methanol [ka]

[0260] Intermediate I-7 was prepared according to the route described in Scheme 7. [ka] Step A, 1-(diethylcarbamoyl)cyclopropanecarboxylate To a solution of cyclopropane-1,1-dicarboxylic acid methyl ester (400 mg, 2.78 mmol) and N,N-dimethylformamide (0.002 mL, 0.03 mmol) in DCM (1.7 mL) was added oxalyl chloride (0.3 mL, 3.55 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was evaporated under reduced pressure to give a yellow oily residue, which was redissolved in THF (1.7 mL) and cooled to 0 °C. Diethylamine (0.9 mL, 1.79 mmol, 2 M in THF) was added, and the resulting suspension was stirred at room temperature for 2 h. The reaction mixture was diluted with EtOAc and washed twice with brine. The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to give 1-(diethylcarbamoyl)cyclopropanecarboxylate (235 mg, 1.18 mmol, 57% yield) as a yellow oil. 1 H NMR (400 MHz,DMSO-d6) δ / ppm: 3.64 (s,3H),3.36-3.23 (m,4H),1.33-1.29 (m,2H),1.23-1.20 (m,2H),1.08 (t,J = 7.1 Hz,3H),1.01 (t,J = 7.1 Hz,3H).

[0261] Step B, [1-(diethylaminomethyl)cyclopropyl]methanol (I-7) To a solution of methyl 1-(diethylcarbamoyl)cyclopropanecarboxylate (235 mg, 1.18 mmol) in anhydrous THF (1.9 mL) was added lithium aluminum hydride (2.6 mL, 2.59 mmol, 1M / THF) at 0 °C. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with 2 M HCl at 0 °C. The solid was filtered and washed with MeOH. The filtrate was loaded onto an SCX cartridge (2 g) equilibrated with MeOH and washed with MeOH, followed by 1 M NH3 / MeOH. The ammonia fraction was evaporated under reduced pressure to give [1-(diethylaminomethyl)cyclopropyl]methanol as a colorless oil (93.0 mg, 0.591 mmol, 50% yield). 1H NMR (400 MHz,DMSO-d6) δ / ppm: 5.40-4.65 (m,1H),3.17 (d,J = 4.9 Hz,2H),2.57-2.51 (m,4H),2.42 (s,2H),0.95 (t,J = 7.1 Hz,6H),0.41-0.36 (m,2H),0.27-0.22 (m,2H).

[0262] Intermediate I-8, [1-(morpholinomethyl)cyclopropyl]methanol [ka]

[0263] Intermediate I-8 was prepared according to the route described in Scheme 8. [ka] Step A, Methyl 1-(morpholine-4-carbonyl)cyclopropanecarboxylate To a solution of cyclopropane-1,1-dicarboxylic acid methyl ester (400 mg, 2.78 mmol) and N,N-dimethylformamide (0.002 mL, 0.03 mmol) in DCM (1.7 mL) was added oxalyl chloride (0.30 mL, 3.55 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated under reduced pressure to give a yellow semi-solid residue, which was redissolved in THF (1.7 mL) and cooled to 0 °C. Morpholine (1.2 mL, 2.39 mmol, 2M in THF) was added, and the resulting suspension was stirred at room temperature for 2 h. The reaction mixture was diluted with EtOAc, and the organic layer was washed twice with brine. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give methyl 1-(morpholine-4-carbonyl)cyclopropanecarboxylate (496 mg, 2.33 mmol, 84% yield) as a yellow oil. UPLC-MS (ES + ,Method 2): 1.03 min,m / z 214.0 [M+H] + 1H NMR (400 MHz,DMSO-d6) δ / ppm: 3.66 (s,3H),3.59-3.52 (m,4H),3.49-3.38 (m,4H),1.37-1.32 (m,2H),1.29-1.24 (m,2H).

[0264] Step B, [1-(morpholinomethyl)cyclopropyl]methanol (I-8) To a solution of methyl 1-(morpholinomethyl)cyclopropanecarboxylate (483 mg, 2.27 mmol) in anhydrous THF (1.9 mL) was slowly added lithium aluminum hydride (5.0 mL, 4.98 mmol, 1 M in THF) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was cooled to 0 °C and quenched with 2 M HCl. The solid was filtered, and the filtrate was loaded onto an SCX cartridge (5 g, pre-washed with MeOH) and washed with MeOH, followed by 1 M NH3 / MeOH. The ammonia fraction was evaporated under reduced pressure to give [1-(morpholinomethyl)cyclopropyl]methanol (221 mg, 1.29 mmol, 57% yield) as a colorless oil. 1 H NMR (400 MHz,DMSO-d6) δ / ppm: 4.83-4.30 (m,1H),3.64-3.53 (m,5H),2.49-2.21 (m,7H),0.44-0.39 (m,2H),0.27-0.19 (m,2H).

[0265] Intermediate I-9, N,N-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide trifluoroacetic acid [ka]

[0266] Intermediate I-9 was prepared according to the route described in Scheme 9. [ka] Step A, tert-butyl 3-(dimethylcarbamoyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate A solution of 5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylic acid (100 mg, 0.370 mmol), dimethylamine (0.24 mL, 0.490 mmol, 2M in THF), and propylphosphonic anhydride (0.33 mL, 0.560 mmol, 50% in EtOAc) in ethyl acetate (4 mL) was heated to 65 °C overnight. The reaction mixture was diluted with EtOAc and saturated aqueous NaHCO3. The organic layer was extracted, passed through a layer-separating filter paper, and concentrated to dryness. The crude product was purified by column chromatography to give tert-butyl 3-(dimethylcarbamoyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (75.0 mg, 0.255 mmol, 68% yield) as an off-white solid. UPLC-MS (ES + ,Method 2): 1.42 min,m / z 295.1 [M+H] + 1 H NMR (400 MHz,DMSO-d6) δ / ppm: 7.77 (s,1H),4.70 (s,2H),4.11 (t,J = 5.6 Hz,2H),3.81 (t,J = 5.3 Hz,2H),3.27-2.83 (m,6H),1.43 (s,9H).

[0267] Step B, N,N-Dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide; 2,2,2-trifluoroacetic acid (I-9) To a solution of tert-butyl 3-(dimethylcarbamoyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-5-carboxylate (75.0 mg, 0.250 mmol) in DCM (4 mL) was added trifluoroacetic acid (0.20 mL, 2.55 mmol), and the reaction mixture was stirred at room temperature for 90 minutes. The reaction mixture was concentrated under reduced pressure to give N,N-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide; 2,2,2-trifluoroacetic acid (78.0 mg, 0.253 mmol, 99% yield) as an orange oil. UPLC-MS (ES + ,Method 1): 0.25 min,m / z 195.1 [M+H] + 1 H NMR (400 MHz,DMSO-d6) δ / ppm: 9.40 (s,2H),7.89 (s,1H),4.53 (s,2H),4.38-4.29 (t,J = 5.8 Hz,1H),3.69 (t,J = 5.9 Hz,2H),3.57 (s,1H),3.26-2.87 (m,6H).

[0268] Intermediate I-10, 1-bromo-N,N-bis[(4-methoxyphenyl)methyl]isoquinolin-3-amine [ka]

[0269] Intermediate I-10 was prepared according to the route described in Scheme 10. [ka] 1-Bromo-N,N-bis[(4-methoxyphenyl)methyl]isoquinolin-3-amine, (I-10) To a solution of 3-amino-1-bromoisoquinoline (300 mg, 1.34 mmol) in THF (5 mL) were added 4-methoxybenzyl chloride (0.55 mL, 4.03 mmol) and sodium hydride (215 mg, 5.38 mmol, 60% dispersion in mineral oil), and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was partitioned between EtOAc and water. The organic layer was separated, and the aqueous layer was washed three times with EtOAc. The combined organic layers were washed with brine, passed through a layer-separating filter paper, and concentrated to dryness. The crude product was purified by column chromatography (eluting with 10% EtOAc / petroleum ether to 100% EtOAc). The major fractions were combined and concentrated under reduced pressure to give 1-bromo-N,N-bis[(4-methoxyphenyl)methyl]isoquinolin-3-amine (401 mg, 0.865 mmol, 64% yield) as a yellow solid, which was used without further analysis.

[0270] Intermediate I-11, tert-butyl 2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-4-hydroxy-5-oxo-7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate [ka]

[0271] Intermediate I-11 was prepared according to the route described in Scheme 11. [ka] Step A, tert-butyl 4-benzyloxy-2-chloro-5,7-dihydropyrrolo[3,4-d]pyrimidine-6-carboxylate To a solution of tert-butyl 2,4-dichloro-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (500 mg, 1.72 mmol) and benzyl alcohol (0.20 mL, 1.90 mmol) in DCM (10 mL) was added potassium tert-butoxide (212 mg, 1.90 mmol) at 25 °C, and the reaction mixture was stirred for 2 h. The reaction mixture was washed with saturated NH4Cl solution, and the layers were separated. The organic layer was passed through a layer-separating filter paper and concentrated to dryness. The crude product was purified by column chromatography (eluting with 20% EtOAc / petroleum ether to 100% EtOAc). The desired fractions were combined and concentrated under reduced pressure to give tert-butyl 4-benzyloxy-2-chloro-5,7-dihydropyrrolo[3,4-d]pyrimidine-6-carboxylate (623 mg, 1.72 mmol, 100% yield) as a pale yellow solid. UPLC-MS (ES + ,Method 2): 2.22 min,m / z 362.1 [M+H] + 1 H NMR (400 MHz,CDCl3) δ / ppm: 7.51-7.36 (m,4H),7.26-7.19 (m,1H),4.69-4.46 (m,6H),1.49-1.42 (m,9H).

[0272] Step B, tert-butyl 4-benzyloxy-2-chloro-5-oxo-7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate To a solution of tert-butyl 4-benzyloxy-2-chloro-5,7-dihydropyrrolo[3,4-d]pyrimidine-6-carboxylate (623 mg, 1.72 mmol) and ruthenium chloride (53.6 mg, 0.260 mmol) in ethyl acetate (10 mL) and water (10 mL) was added sodium periodate (1.10 g, 5.17 mmol), and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with EtOAc and water and passed through a Celite pad. The organic layer was separated, passed through a layer-separating filter paper, and concentrated to dryness. The crude product was then purified by column chromatography (eluting with 10% EtOAc / petroleum ether to 50% EtOAc / petroleum ether). The desired fractions were combined and concentrated to dryness under reduced pressure to give tert-butyl 4-benzyloxy-2-chloro-5-oxo-7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (265 mg, 0.705 mmol, 41% yield) as a pale yellow oil. UPLC-MS (ES + ,Method 2): 2.03 min,m / z 398.0 [M+Na] +

[0273] Step C, tert-butyl 4-benzyloxy-5-oxo-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate To a solution of tert-butyl 4-benzyloxy-2-chloro-5-oxo-7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (4.03 g, 10.7 mmol) and ((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methanol (1.88 g, 11.8 mmol) in 1,4-dioxane (50 mL) was added potassium carbonate (2.96 g, 21.5 mmol), and the reaction mixture was stirred at 100 °C for 4 h. The reaction mixture was diluted with EtOAc, passed through a layer-separating filter paper, and concentrated to dryness. The crude product was then purified by column chromatography (eluting with 100% DCM to 20% MeOH / DCM). The desired fractions were combined and concentrated under reduced pressure to give tert-butyl 4-benzyloxy-5-oxo-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (2.38 g, 4.78 mmol, 45% yield) as a yellow solid. UPLC-MS (ES + ,Method 2): 1.56 min,m / z 499.4 [M+H] +

[0274] Step D, tert-butyl 2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-4-hydroxy-5-oxo-7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (I-11) To a solution of tert-butyl 4-benzyloxy-5-oxo-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (2.38 g, 4.38 mmol) in ethyl acetate (30 mL) was added anhydrous palladium (233 mg, 0.220 mmol, 10 wt% on carbon powder) under nitrogen. The reaction was purged with hydrogen (×3) and stirred at 25° C. for 16 h. The reaction mixture was passed through a pad of Celite and washed with EtOAc. The organic layer was concentrated under reduced pressure to give tert-butyl 2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-4-hydroxy-5-oxo-7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (1.78 g, 4.36 mmol, 99% yield) as an orange solid. UPLC-MS (ES + ,Method 2): 1.25 min,m / z 409.2 [M+H] +

[0275] Intermediate I-12, tert-butyl 2-chloro-4-(1,4-oxazepan-4-yl)-5-oxo-7h-pyrrolo[3,4-d]pyrimidine-6-carboxylate [ka]

[0276] Intermediate I-12 was prepared according to the route described in Scheme 12. [ka] Step A, tert-butyl 2,4-dichloro-5-oxo-7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate To a solution of tert-butyl 2,4-dichloro-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (2.00 g, 6.89 mmol) and ruthenium chloride (214 mg, 1.03 mmol) in ethyl acetate (20 mL) and water (20 mL) was added sodium periodate (4.42 g, 20.7 mmol), and the reaction was stirred at room temperature overnight. The reaction was diluted and partitioned between EtOAc (50 mL) and water (50 mL), filtered through a plug of Celite, and the plug was washed with ethyl acetate (2 × 50 mL). The filtrate was collected, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (50 mL), and the combined organic layers were washed with saturated brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by flash column silica gel chromatography (eluting with 0–60% ethyl acetate / petroleum) afforded tert-butyl 2,4-dichloro-5-oxo-7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate as a colorless oil (1.75 g, 5.76 mmol, 84% yield) as part of a mixture containing another product where oxidation occurs at the other benzylic methylene of the pyrrole ring, which was used in Step B without further purification. UPLC-MS (ES + ,Method 2): 1.72 min,m / z 326.0 [M+Na] + .

[0277] Step B, tert-butyl 2-chloro-4-(1,4-oxazepan-4-yl)-5-oxo-7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (I-12) To a solution of tert-butyl 2,4-dichloro-5-oxo-7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (2.00 g, 6.58 mmol) and N,N-diisopropylethylamine (1.7 mL, 9.86 mmol) in DCM (26 mL) was added [1,4]oxazepane (0.7 mL, 6.25 mmol) at 0 °C. The reaction mixture was stirred for 30 min and then concentrated under reduced pressure. Purification by flash column chromatography on silica gel (eluting with 20–60% ethyl acetate / petrol) afforded tert-butyl 2-chloro-4-(1,4-oxazepan-4-yl)-5-oxo-7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (504 mg, 1.37 mmol, 21% yield) as a colorless oil. UPLC-MS (ES + ,Method 2): 1.77 min,m / z 369.1 [M+H] + . 1 H NMR (400 MHz,CDCl3) δ / ppm: 4.56 (s,2H),4.40-4.31 (m,2H),4.07-3.96 (m,2H),3.91-3.85 (m,2H),3.78-3.71 (m,2H),2.11-2.02 (m,2H),1.57 (s,9H).

[0278] Intermediates I-13 to I-16 were prepared according to Scheme 13. [ka] Step A, Ethyl 4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carboxylate To a solution of diisopropylamine (55.7 mL, 397 mmol) in THF (1000 L) at −78° C., n-butyllithium (37.43 mL, 397 mmol) was added dropwise. After the addition, the solution was stirred at room temperature for 1 hour and then cooled to −78° C. again. 4,6-Dichloro-2-methylthiopyrimidine (50 g, 256 mmol) was added dropwise, and the mixture was stirred at −78° C. for 1 hour. Ethyl chloroformate (73.5 mL, 769 mmol) was added, and the resulting solution was allowed to warm to room temperature and stirred for 2 hours. The mixture was quenched with saturated aqueous ammonium chloride and diluted with EtOAc. The layers were separated, and the organic layer was washed with water and brine, dried over sodium sulfate, and concentrated in vacuo to give crude ethyl 4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carboxylate (56 g) as a black solid, which was used without purification. UPLC-MS (ES + ,Method 4): 1.09 min,m / z 267.0 [M+H] + .

[0279] Step B, Ethyl 4-chloro-2-methylsulfanyl-6-(1,4-oxazepan-4-yl)pyrimidine-5-carboxylate A solution of 4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carboxylate (60 g, 225 mmol) and EtN (68.2 g, 674 mmol) in DMF (250 mL) was stirred at 0 °C under a N atmosphere for 5 min. 1,4-Oxazepane hydrochloride (30.91 g, 225 mmol) was added, and the mixture was stirred at 0 °C for 30 min, warmed to room temperature, and stirred for an additional 3 h. The mixture was poured into water (3000 mL) and extracted with EtOAc (400 mL × 4). The combined organic layers were washed with brine (1500 mL × 3), dried over NaSO, and concentrated in vacuo. The crude product was purified by silica gel flash column chromatography (1% to 20% EtOAc / petroleum ether) to afford ethyl 4-chloro-2-methylsulfanyl-6-(1,4-oxazepan-4-yl)pyrimidine-5-carboxylate (50 g, 67%) as a yellow solid. UPLC-MS (ES+ ,Method 4): 0.48 min,m / z 332.1 [M+H] + .

[0280] Step C, Ethyl 4-cyano-2-methylsulfanyl-6-(1,4-oxazepan-4-yl)pyrimidine-5-carboxylate A mixture of ethyl 4-chloro-2-methylsulfanyl-6-(1,4-oxazepan-4-yl)pyrimidine-5-carboxylate (33 g, 99 mmol), Pd(PPh) (11.49 g, 9.95 mmol), and Zn(CN) (17.52 g, 149 mmol) in DMF (120 mL) was heated at 120 °C under a N atmosphere for 4 h. After cooling to ambient temperature, the mixture was filtered through Celite, and the filtrate was concentrated in vacuo. The crude product was purified by silica gel chromatography (eluting with 10 / 1 EtOAc / petroleum ether) to give ethyl 4-cyano-2-methylsulfanyl-6-(1,4-oxazepan-4-yl)pyrimidine-5-carboxylate (14.0 g, 44%) as a yellow solid. UPLC-MS (ES + ,Method 3): 1.77 min,m / z 323.1 [M+H] + .

[0281] Step D, 2-methylsulfanyl-4-(1,4-oxazepan-4-yl)-6,7-dihydropyrrolo[3,4-d]pyrimidin-5-one (I-13) To a solution of ethyl 4-cyano-2-methylsulfanyl-6-(1,4-oxazepan-4-yl)pyrimidine-5-carboxylate (5 g, 15.5 mmol) in methanol (120 mL) was added cobalt chloride hexahydrate (11.1 g, 47 mmol) dropwise at −78° C., and the resulting mixture was stirred at this temperature for an additional 30 min. This was then added dropwise to a stirred solution of NaBH (2.93 g, 78 mmol), stirred at −78° C. for 1 h, heated to 50° C., and stirred for an additional 3 h. The reaction mixture was quenched with saturated aqueous NH Cl, filtered through Celite, and the filtrate was concentrated under reduced pressure, diluted with water (700 mL), and extracted with EtOAc (150 mL × 3). The combined organic layers were washed with brine (500 mL × 3), dried over NaSO, concentrated, and purified by silica gel column chromatography (2% DCM / MeOH) to give 2-methylsulfanyl-4-(1,4-oxazepan-4-yl)-6,7-dihydropyrrolo[3,4-d]pyrimidin-5-one (I-13) (1.8 g, 41%) as a yellow solid. UPLC-MS (ES + ,Method 3): 1.41 min,m / z 281.2 [M+H] + . 1 H NMR (400 MHz,DMSO-d6) δ / ppm: 8.29 (s,1H),4.47 (s,2H),4.17 (d,J = 1.2 Hz,2H),3.91 (s,2H),3.70 (s,2H),3.61 (t,J = 5.6 Hz,2H),2.47 (s,3H),1.89 (s,2H).

[0282] Step E, 6-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-2-methylsulfanyl-4-(1,4-oxazepan-4-yl)-7H-pyrrolo[3,4-d]pyrimidin-5-one (I-14) A mixture of 2-methylsulfanyl-4-(1,4-oxazepan-4-yl)-6,7-dihydropyrrolo[3,4-d]pyrimidin-5-one (750 mg, 2.68 mmol), [8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]trifluoromethanesulfonate (1.23 g, 3.21 mmol), Pd(dba) (490 mg, 0.54 mmol), Xantphos (310 mg, 0.54 mmol), and CsCO (2.61 g, 8.03 mmol) in 1,4-dioxane (20 mL) was stirred at 100 °C under a N atmosphere for 3 h. The reaction mixture was concentrated and purified by silica gel column (eluted with 20% EtOAc / petroleum ether) to give 6-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-2-methylsulfanyl-4-(1,4-oxazepan-4-yl)-7H-pyrrolo[3,4-d]pyrimidin-5-one (I-14) (420 mg, 30.63%) as a green solid. UPLC-MS (ES + ,Method 4): 1.30 min,m / z 513.2 [M+H] + .

[0283] Step F, 6-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-2-methylsulfonyl-4-(1,4-oxazepan-4-yl)-7H-pyrrolo[3,4-d]pyrimidin-5-one (I-15) A mixture of 6-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-2-methylsulfanyl-4-(1,4-oxazepan-4-yl)-7H-pyrrolo[3,4-d]pyrimidin-5-one (420 mg, 0.82 mmol) and m-CPBA (424.19 mg, 2.46 mmol) in DCM (20 mL) was stirred for 2 hours at 25° C. The reaction was quenched with saturated sodium sulfate solution (40 mL) and washed with saturated sodium carbonate solution (10 mL×2). The organic layers were combined, washed with brine (400 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 6-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-2-methylsulfonyl-4-(1,4-oxazepan-4-yl)-7H-pyrrolo[3,4-d]pyrimidin-5-one (I-15) (420 mg, 94%). UPLC-MS (ES + ,Method 3): 2.09 min,m / z 545.2 [M+H] + .

[0284] Step G, 6-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-4-(1,4-oxazepan-4-yl)-2-prop-2-ynoxy-7H-pyrrolo[3,4-d]pyrimidin-5-one (I-16) To a solution of propargyl alcohol (49 mg, 0.88 mmol) in THF (40 mL) was added NaH (35.26 mg, 0.88 mmol) slowly over 30 min under N2 at 0° C. 6-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-2-methylsulfonyl-4-(1,4-oxazepan-4-yl)-7H-pyrrolo[3,4-d]pyrimidin-5-one (320 mg, 0.59 mmol) was added, and the mixture was stirred at room temperature for 1 h. The mixture was concentrated under vacuum and purified by silica gel column chromatography (eluting with 33% EtOAc / petroleum ether) to give 6-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-4-(1,4-oxazepan-4-yl)-2-prop-2-ynoxy-7H-pyrrolo[3,4-d]pyrimidin-5-one (I-16) as a yellow solid (73 mg, 23.8%). UPLC-MS (ES + , Method 4): 0.99 min, m / z 521.2 [M+H] + . 1 H NMR (400 MHz,DMSO-d6) δ / ppm: 7.86 (dd,J = 9.1,5.9 Hz,1H),7.60 (d,J = 2.7 Hz,1H),7.46 - 7.38 (m,2H),5.35 - 5.31 (m,2H),5.03 (s,2H),4.80 - 4.67 (m,2H),4.63 - 3.82 (m,5H),3.65 (s,3H),3.56 (t,J = 2.4 Hz,1H),3.43 (s,3H),2.96 - 2.75 (m,2H),1.90 (d,J = 84.4 Hz,2H),1.04 (t,J = 7.4Hz,3H).

[0285] Intermediate I-17 was prepared according to the route described in Scheme 14. [ka] Step A, 2-chloro-4-(1,4-oxazepan-4-yl)-6,7-dihydropyrrolo[3,4-d]pyrimidin-5-one To a solution of tert-butyl 2-chloro-4-(1,4-oxazepan-4-yl)-5-oxo-7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (3.28 g, 8.9 mmol) in DCM (15 mL) was added trifluoroacetic acid (6.82 mL, 89.01 mmol), and the reaction was stirred at room temperature for 1 hour. The reaction was concentrated under reduced pressure, basified with saturated sodium bicarbonate solution, filtered through filter paper, and the filter paper was washed with ethyl acetate (×2). The resulting solid was collected, and the residual solvent was removed under reduced pressure to give 2-chloro-4-(1,4-oxazepan-4-yl)-6,7-dihydropyrrolo[3,4-d]pyrimidin-5-one as a yellow solid (2.705 g, 100% yield). UPLC-MS (ES + ,Method 4): 1.44 min,m / z 269.0 [M+H] + .

[0286] Step B, 2-chloro-6-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-4-(1,4-oxazepan-4-yl)-7H-pyrrolo[3,4-d]pyrimidin-5-one (I-17) To a solution of 2-chloro-4-(1,4-oxazepan-4-yl)-6,7-dihydropyrrolo[3,4-d]pyrimidin-5-one (600 mg, 2.23 mmol), cesium carbonate (1455 mg, 4.47 mmol), and [8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]trifluoromethanesulfonate (1024.48 mg, 2.68 mmol) in toluene (degassed with N) (15 mL) was added Xantphos Pd G3 (211.76 mg, 0.22 mmol). The reaction was evacuated and refilled with N (×3) and heated to 110 °C for 3.5 h. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate, and filtered through a Celite plug, washing the plug with ethyl acetate. The filtrate was collected and concentrated under reduced pressure. Purification by flash column chromatography on a 40 g silica cartridge (wet load in 10:1 DCM:ethyl acetate) (eluting with 20–60% ethyl acetate / petroleum) afforded 2-chloro-6-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-4-(1,4-oxazepan-4-yl)-7H-pyrrolo[3,4-d]pyrimidin-5-one (I-17) as a yellow gum (296 mg, 26.5% yield). UPLC-MS (ES + ,Method 4): 2.34 min,m / z 501.1 [M+H] + .

[0287] Intermediates synthesized following a similar procedure to I-3 (Scheme 13), replacing dimethylamine hydrochloride in step C with the appropriate building block, are listed in Table 3. [Table 4]

[0288] Intermediates synthesized following a similar procedure to I-2 (Scheme 2), replacing 4-bromonaphthalen-2-ol with the appropriate building block, are listed in Table 4. [Table 5] [Table 6]

[0289] I-23, [7,8-difluoro-3-(methoxymethoxy)-1-naphthyl]trifluoromethanesulfonate [ka] Step A, 7,8-difluoro-3-(methoxymethoxy)naphthalen-1-ol To a solution of 7,8-difluoronaphthalene-1,3-diol (204 mg, 1.04 mmol) and N,N-diisopropylethylamine (0.36 mL, 2.08 mmol) in DCM (10.4 mL) was added bromomethyl methyl ether (0.07 mL, 0.83 mmol) at -40 °C. The mixture was stirred at that temperature for 30 minutes and then partitioned between ethyl acetate (20 mL) and aqueous solution (20 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (20 mL). The combined organic layers were washed with saturated brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by flash column silica gel chromatography (eluting with 0–50% ethyl acetate / petrol) afforded 7,8-difluoro-3-(methoxymethoxy)naphthalen-1-ol (26.8 mg, 0.11 mmol, 11% yield) as a brown oil. UPLC-MS (ES + ,Method 2): 1.63 min,m / z 240.9 [M+H] + .

[0290] Step B, [7,8-difluoro-3-(methoxymethoxy)-1-naphthyl]trifluoromethanesulfonate Trifluoromethanesulfonic anhydride (0.02 mL, 0.13 mmol) was added to a solution of N,N-diisopropylethylamine (0.06 mL, 0.33 mmol) and 7,8-difluoro-3-(methoxymethoxy)naphthalen-1-ol (26.8 mg, 0.11 mmol) in DCM (0.75 mL) at -40 °C. The mixture was then stirred at that temperature for 15 minutes. The mixture was partitioned between an ethyl acetate layer (20 mL) and an aqueous layer (20 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (20 mL). The combined organic layers were washed with saturated brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by flash column silica gel chromatography (0-50% ethyl acetate / petroleum) gave [7,8-difluoro-3-(methoxymethoxy)-1-naphthyl]trifluoromethanesulfonate (15.4 mg, 0.041 mmol, 37% yield) as a colorless oil. UPLC-MS (ES + ,Method 2): 2.07 min,m / z 372.9 [M+H] + . 1 H NMR (400 MHz,CDCl3) δ / ppm: 7.54 (ddd,J = 9.2,4.6,1.9 Hz,1H),7.45-7.42 (m,1H),7.41-7.35 (m,1H),7.28 (d,J = 2.1 Hz,1H),5.29 (s,2H),3.52 (s,3H).

[0291] I-30, 3,8-diazabicyclo[3.2.1]octan-8-yl-(2,2-difluorocyclopropyl)methanone; 2,2,2-trifluoroacetic acid [ka] Step A, tert-butyl 8-(2,2-difluorocyclopropanecarbonyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate HATU (1.07 g, 2.83 mmol) was added to a stirred solution of 3-boc-3,8-diazabicyclo[3.2.1]octane (500 mg, 2.36 mmol), triethylamine (0.66 mL, 4.71 mmol), 2,2-difluorocyclopropanecarboxylic acid (431 mg, 3.53 mmol), and DCM (10 mL) at room temperature under a nitrogen atmosphere. The reaction was left stirring at this temperature for 1 hour. The reaction mixture was poured into water (100 mL) and extracted with DCM (3 x 100 mL). The combined organic layers were filtered through layer-separating filter paper and concentrated under vacuum. The residue was subjected to silica gel column chromatography (eluent: 0-100% EtOAc / petroleum ether) to give crude tert-butyl 8-(2,2-difluorocyclopropanecarbonyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (861 mg, 2.72 mmol, 100% yield) as a colorless film.

[0292] Step B: 3,8-diazabicyclo[3.2.1]octan-8-yl-(2,2-difluorocyclopropyl)methanone; 2,2,2-trifluoroacetic acid To a solution of tert-butyl 8-(2,2-difluorocyclopropanecarbonyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (861 mg, 2.72 mmol) in DCM (14 mL) was added trifluoroacetic acid (2.08 mL, 27.22 mmol), and the reaction was stirred at room temperature for 90 min. The reaction was concentrated under reduced pressure and subjected to flash column chromatography (eluting with 0-20% MeOH / DCM) to afford the crude product (735 mg, 2.25 mmol, 81.77% yield) of 3,8-diazabicyclo[3.2.1]octan-8-yl-(2,2-difluorocyclopropyl)methanone; 2,2,2-trifluoroacetic acid as a foamy white solid.

[0293] I-31, N,N-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamide; 2,2,2-trifluoroacetic acid [ka] I-31 was prepared by a method similar to I-9 (Scheme 9), replacing 5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylic acid with 5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylic acid in step A. UPLC-MS (ES + ,Method 2): 0.29 min,m / z 195.1 [M+H] + .

[0294] I-32, 1-[(4-methoxyphenyl)methyl]-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine [ka] Step A, tert-butyl 1-[(4-methoxyphenyl)methyl]-6,7-dihydro-4H-pyrazolo[4,5-c]pyridine-5-carboxylate To a solution of tert-butyl 6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (500 mg, 2.24 mmol) in DMF (10 mL) was added 4-methoxybenzyl chloride (0.33 mL, 2.46 mmol) and potassium carbonate (371.39 mg, 2.69 mmol) at room temperature. The mixture was heated to 70 °C and stirred at that temperature overnight. The mixture was cooled to room temperature and partitioned with EtOAc and water. The organic layer was washed with brine, passed through a phase separator, and concentrated. The crude product was purified by flash chromatography (eluting with 0% to 100% EtAc / petroleum ether). The desired fractions were combined and concentrated to give tert-butyl 2-[(4-methoxyphenyl)methyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (563 mg, 1.64 mmol, 73% yield) as a colorless oil. UPLC-MS (ES + ,Method 2): 1.98 min,m / z 344.2 [M+H] + .

[0295] Step B, 1-[(4-methoxyphenyl)methyl]-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine To a solution of tert-butyl 2-[(4-methoxyphenyl)methyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate (563 mg, 1.64 mmol) in DCM (7 mL) was added trifluoroacetic acid (0.19 mL, 2.46 mmol), and the reaction was stirred at room temperature for 90 min. More trifluoroacetic acid (0.19 mL, 2.46 mmol) was added to the reaction and stirred for an additional 1 h. The reaction was concentrated under reduced pressure and purified by flash column chromatography (KP Amino-D column, 0–20% MeOH / DCM). The desired fractions were combined and concentrated to give 1-[(4-methoxyphenyl)methyl]-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine (314 mg, 1.29 mmol, 79% yield) as a colorless oil. UPLC-MS (ES + ,Method 2): 1.21 min,m / z 244.1 [M+H] + (33%)

[0296] I-33, 2-[[3-bromo-4-(trifluoromethoxy)phenyl]methoxy]tetrahydropyran [ka] 3,4-Dihydro-2H-pyran (0.16 mL, 1.77 mmol) and p-toluenesulfonic acid monohydrate (28.07 mg, 0.15 mmol) were added to a stirred solution of (3-bromo-4-(trifluoromethoxy)phenyl)methanol (400 mg, 1.48 mmol) in DCM (15 mL). The reaction mixture was stirred at room temperature overnight. Water and DCM were added to the reaction, and the layers were separated. The aqueous layer was extracted with additional DCM. The organic fraction was collected and washed with saturated NaHCO3 solution and brine, then passed through a phase separator and the solvent was reduced under reduced pressure. The crude product was purified by flash column chromatography (eluting with 0–40% EtOAc / petroleum ether) to give 2-[[3-bromo-4-(trifluoromethoxy)phenyl]methoxy]tetrahydropyran (420 mg, 1.18 mmol, 80% yield) as a colorless, watery oil.

[0297] I-34, tert-butyl N-(4-bromo-1,3-benzothiazol-2-yl)carbamate [ka] A solution of 4-bromobenzo[d]thiazol-2-amine (500 mg, 2.18 mmol), 4-dimethylaminopyridine, DMAP (26.66 mg, 0.22 mmol), and di-tert-butyl dicarbonate (571.58 mg, 2.62 mmol) in DCM (18 mL) was stirred at 25 °C for 16 h. After completion of the reaction, the mixture was washed with HO (15 mL) and brine (15 mL), and the organic layer was filtered through a layer separation cartridge and concentrated under reduced pressure. The residue was purified by flash chromatography (0–40% EA / petroleum ether) to afford tert-butyl N-(4-bromo-1,3-benzothiazol-2-yl)carbamate (628 mg, 1.91 mmol, 87% yield) as a crystalline white solid. UPLC-MS (ES + ,Method 2): 1.95 min,m / z 329.0 & 330.9 [M+H] + .

[0298] I-35, tert-butyl N-[1-(hydroxymethyl)cycloheptyl]carbamate [ka] Step A, Methyl 1-(tert-butoxycarbonylamino)cycloheptanecarboxylate To a solution of 1-(boc-amino)cycloheptanecarboxylic acid (300 mg, 1.17 mmol) in anhydrous THF (3 mL) was added a 2.0 M (trimethylsilyl)diazomethane solution (1.17 mL, 2.33 mmol) in hexane and stirred at room temperature for 16 hours. The solvent was evaporated under reduced pressure, and the residue was partitioned between EtOAc and saturated aqueous Na2CO3. The organic layers were washed with water and brine, combined, dried over Na2SO4, filtered, and evaporated to give methyl 1-(tert-butoxycarbonylamino)cycloheptanecarboxylate (316 mg, 1.16 mmol, 100% yield) as a yellow solid.

[0299] Step B, tert-butyl N-[1-(hydroxymethyl)cycloheptyl]carbamate To a solution of methyl 1-(tert-butoxycarbonylamino)cycloheptanecarboxylate (316 mg, 1.16 mmol) in anhydrous THF (7 mL) was added lithium borohydride (0.11 mL, 5.82 mmol) at 0 °C, and the reaction was stirred overnight. The reaction was quenched with saturated NH4Cl solution at 0 °C, and the aqueous layer was extracted with EtOAc. The organic layers were combined, dried over Na2SO4, filtered, and the filtrate was evaporated under reduced pressure. The crude product was purified by flash column chromatography (eluting with 0–60% EA / petroleum ether) to give tert-butyl N-[1-(hydroxymethyl)cycloheptyl]carbamate (176 mg, 0.72 mmol, 62% yield) as a white solid. 1H NMR (400 MHz,CDCl3) δ / ppm: 4.60 (s,1H),4.30 (s,1H),3.60 (d,J=6.2 Hz,2H),1.78 - 1.71 (m,2H),1.67 - 1.59 (m,2H),1.59 - 1.53 (m,4H),1.53 - 1.47 (m,4H),1.43 (s,9H).

[0300] I-36, 3-(2-bromo-4-methoxy-phenyl)benzonitrile [ka] To a solution of 2-bromo-1-iodo-4-methoxybenzene (500 mg, 1.6 mmol), 3-cyanophenylboronic acid (214.92 mg, 1.46 mmol), and potassium carbonate (673.82 mg, 4.88 mmol) in 1,4-dioxane (degassed with N) (9.32 mL) and water (1.33 mL) was added tetrakis(triphenylphosphine)palladium(0) (93.9 mg, 0.08 mmol), and the reaction was heated to 90 °C for 3 h. The reaction was concentrated and purified by column chromatography (eluting with 0–100% ethyl acetate / petroleum) to give 3-(2-bromo-4-methoxy-phenyl)benzonitrile (178 mg, 0.62 mmol, 39% yield) as a brown solid. UPLC-MS (ES + ,Method 2): 2.05 min,m / z 289.9 [M+H] + . 1 H NMR (400 MHz,DMSO-d6) δ / ppm: 7.87-7.84 (m,2H),7.74-7.71 (m,1H),7.65 (dt,J = 0.56,8.0 Hz,1H),7.39-7.33 (m,2H),7.07 (dd,J = 2.5,8.6 Hz,1H) 3.83 (s,3H)

[0301] I-37, 4-bromo-2-(methoxymethoxy)-1-methyl-naphthalene [ka] Step A, 4-bromo-1-iodo-naphthalen-2-ol To a solution of 1-bromo-3-hydroxynaphthalene (1000 mg, 4.48 mmol) in MeCN (45 mL) was added N-iodosuccinimide (1.08 g, 4.48 mmol) and the reaction was stirred for 18 h at 25 °C. The reaction was concentrated to dryness and purified by column chromatography (0-50% ethyl acetate / petroleum ether) to give 4-bromo-1-iodo-naphthalen-2-ol (843 mg, 2.42 mmol, 54% yield) as a brown solid. UPLC-MS (ES + ,Method 2): 1.96 min,m / z 349.9 [M+H] + . 1 H NMR (400 MHz,DMSO-d6) δ / ppm: 11.04 (s,1H),8.04 (q,J = 6.7,8.2 Hz ,2H),7.66-7.62 (m,1H),7.60 (s,1H),7.54-7.49 (m,1H).

[0302] Step B, 4-bromo-1-iodo-2-(methoxymethoxy)naphthalene To a solution of 4-bromo-1-iodo-naphthalen-2-ol (583 mg, 1.67 mmol) and N,N-diisopropylethylamine (0.87 mL, 5.01 mmol) in DCM (14.32 mL) was added chloromethyl methyl ether (175 mg, 2.17 mmol) at 0 °C and stirred for 2 h. The reaction was partitioned with ethyl acetate (20 mL) and water (10 mL). The aqueous layer was extracted with ethyl acetate (3 × 20 mL). The organic layer was dried over Na SO and concentrated to give 4-bromo-1-iodo-2-(methoxymethoxy)naphthalene (719 mg, 1.82 mmol, 100% yield) as a yellow solid. UPLC-MS (ES + ,Method 2): 2.26 min,m / z 393.8 [M+H] + . 1H NMR (400 MHz,DMSO-d6) δ / ppm: 8.17 (d,J = 7.9 Hz,1H),8.09 (d,J = 7.6 Hz,1H),7.88 (s,1H),7.72-7.68 (m,1H),7.65-7.60 (m,1H),5.46 (s,2H),3.46 (s,3H).

[0303] Step C, 4-bromo-2-(methoxymethoxy)-1-methyl-naphthalene To a solution of 4-bromo-1-iodo-2-(methoxymethoxy)naphthalene (200 mg, 0.51 mmol), cesium carbonate (497.41 mg, 1.53 mmol) in 1,4-dioxane (degassed with N) (6 mL) and water (1.2 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium II (75 mg, 0.1 mmol) and 2,4,6-trimethylboroxine (0.11 mL, 0.76 mmol), and the reaction was heated to 60 °C for 16 h. The reaction was concentrated to dryness and purified by column chromatography (eluting with 0–40% ethyl acetate / petroleum ether) to give 4-bromo-2-(methoxymethoxy)-1-methyl-naphthalene (102 mg, 0.36 mmol, 71% yield) as a yellow oil. UPLC-MS (ES + ,Method 2): 2.22 min,m / z 282.7 [M+H] + . 1 H NMR (400 MHz,CDCl3) δ / ppm: 8.20-8.14 (m,1H),7.94 (d,J = 8.4 Hz,1H),7.53-7.43 (m,3H),5.24 (s,2H),3.53 (s,3H),2.53 (s,3H).

[0304] I-38, 1-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclopropanamine [ka] Step A, tert-butyl N-[1-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclopropyl]carbamate To a solution of boc-1-aminocyclopropylmethanol (200 mg, 1.07 mmol) and tert-butyl(chloro)diphenylsilane (0.31 mL, 1.17 mmol) in DCM (3 mL) was added imidazole (160 mg, 2.35 mmol) at 0 °C under N 2 , and the reaction mixture was stirred overnight. The mixture was partitioned between DCM (10 mL) and HO (10 mL). The aqueous layer was further washed with DCM. The combined organic layers were further washed with saturated NaHCO 3 and brine, passed through a phase separator, and concentrated. The residue was purified by column chromatography (eluting with 0–80% EtOAc / petroleum ether) to afford tert-butyl N-[1-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclopropyl]carbamate (412 mg, 0.97 mmol, 91% yield) as a colorless oil. UPLC-MS (ES + ,Method 2): 2.62 min,m / z 448.2 [M+Na] + .

[0305] Step B, 1-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclopropanamine To a solution of tert-butyl N-[1-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclopropyl]carbamate (220 mg, 0.52 mmol) in DCM (3 mL) was added trifluoroacetic acid (0.2 mL, 2.58 mmol), and the reaction was stirred at room temperature for 90 min. The reaction was concentrated under reduced pressure and purified by flash column chromatography (KP Amino-D column, 0-20% MeOH / DCM) to afford 1-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclopropanamine (126 mg, 0.39 mmol, 75% yield) as a colorless oil. UPLC-MS (ES + , Method 2): 1.87 min, m / z 326.1 [M+H] + .

[0306] I-39, 4-bromo-1-fluoro-2-(methoxymethoxy)naphthalene [ka] Step A, 4-bromo-1-fluoro-naphthalen-2-ol To a solution of 1-bromo-3-hydroxynaphthalene (500 mg, 2.24 mmol) in MeCN (20 mL) at 0 °C was added Selectfluor (794 mg, 2.24 mmol) and the reaction was stirred overnight. The reaction was quenched with sodium bicarbonate solution and extracted three times with DCM. The combined organic layers were filtered through a phase separator cartridge and concentrated to dryness to give 4-bromo-1-fluoro-naphthalen-2-ol (540 mg, 2.24 mmol, 100% yield) as a yellow oil. UPLC-MS (ES-, Method 2): 2.02 min, m / z 238.9 & 240.9 [MH] - .

[0307] Step B, 4-bromo-1-fluoro-2-(methoxymethoxy)naphthalene To a solution of 4-bromo-1-fluoro-naphthalen-2-ol (101 mg, 0.26 mmol) and N,N-diisopropylethylamine (0.09 mL, 0.52 mmol) in DCM (2.5 mL) at 0 °C, bromomethyl methyl ether (0.02 mL, 0.29 mmol) was added, and the reaction was stirred at 0 °C for 1 h. The reaction mixture was quenched with water and extracted three times with DCM. The combined organic extracts were filtered through a layer separator cartridge and concentrated to dryness. The residue was purified by column chromatography (0–20% EtOAc / petroleum ether) to give 4-bromo-1-fluoro-2-(methoxymethoxy)naphthalene (41 mg, 0.14 mmol, 55% yield) as an orange oil. UPLC-MS (ES + ,Method 2): 2.23 min, no mass ions were detected

[0308] I-40, 3-[2-bromo-4-(methoxymethoxy)phenyl]benzonitrile [ka] Step A, 3-(2-bromo-4-hydroxy-phenyl)benzonitrile To a solution of 3-bromo-4-iodophenol (400 mg, 1.34 mmol), 3-cyanophenylboronic acid (180 mg, 1.22 mmol), and potassium carbonate (564.34 mg, 4.08 mmol) in 1,4-dioxane (degassed with N) (9.3 mL) and water (1.3 mL) was added tetrakis(triphenylphosphine)palladium(0) (169 mg, 0.15 mmol). The reaction was heated to 90 °C for 3 h. The reaction was concentrated and purified by column chromatography (eluting with 0–100% ethyl acetate / petroleum ether) to give 3-(2-bromo-4-hydroxyphenyl)benzonitrile (209 mg, 0.76 mmol, 57% yield) as a brown solid. UPLC-MS (ES + ,Method 2): 1.75 min,m / z 275.9 [M+H] + . 1 H NMR (400 MHz,DMSO-d6) δ / ppm: 10.11 (s,1H),7.85 - 7.81 (m,2H),7.70 (dt,J = 1.7,8.1 Hz,1H),7.63 (t,J = 7.9 Hz,1H) 7.26 (d,J = 8.4 Hz,1H),7.13 (d,J = 2.4 Hz, 1H),6.88 (dd,J = 2.4,8.4 Hz,1H).

[0309] Step B, 3-[2-bromo-4-(methoxymethoxy)phenyl]benzonitrile 3-[2-Bromo-4-(methoxymethoxy)phenyl]benzonitrile (I-40) was synthesized following a similar procedure to I-2 (Scheme 2), replacing 4-bromonaphthalen-2-ol with 3-(2-bromo-4-hydroxy-phenyl)benzonitrile. UPLC-MS (ES + ,Method 2): 2.15 min,m / z 320.0 [M+H]+ . 1 H NMR (400 MHz,DMSO-d6) δ / ppm: 7.88-7.85 (m,2H),7.73 (dt,J = 1.36,7.90 Hz,1H),7.66 (dt,J = 0.84,7.60 Hz,1H),7.42 (d,J = 2.48 Hz,1H),7.39 (d,J = 8.52 Hz,1H),7.15 (dd,J = 2.52,8.52 Hz,1H),5.28 (s,2H),3.41 (s,3H).

[0310] I-41, Azetidin-3-yl 2,2-dimethylpropanoate; 2,2,2-trifluoroacetic acid [ka] Step A, tert-butyl 3-(2,2-dimethylpropanoyloxy)azetidine-1-carboxylate To a solution of 1-N-boc-3-hydroxyazetidine (500 mg, 2.89 mmol) in pyridine (11 mL) was added trimethylacetyl chloride (0.71 mL, 5.77 mmol) dropwise, and the mixture was stirred overnight at 25° C. The reaction was concentrated to dryness, and the crude product was purified by column chromatography (EtOAc / petroleum ether 0–100%) to afford tert-butyl 3-(2,2-dimethylpropanoyloxy)azetidine-1-carboxylate (254 mg, 0.99 mmol, 34% yield) as a colorless oil.

[0311] Step B, Azetidin-3-yl 2,2-dimethylpropanoate; 2,2,2-trifluoroacetic acid To a solution of tert-butyl 3-(2,2-dimethylpropanoyloxy)azetidine-1-carboxylate (250 mg, 0.97 mmol) in EtOAc (9 mL) was added trifluoroacetic acid (5.95 mL, 77.72 mmol), and the mixture was stirred at 25° C. for 24 hours. The reaction was concentrated to dryness to afford azetidin-3-yl 2,2-dimethylpropanoate; 2,2,2-trifluoroacetic acid (218 mg, 0.80 mmol, 83% yield) as a colorless oil. 1 H NMR (400 MHz,CDCl3) δ / ppm: 9.76 (s br,2H),5.28 (m,1H),4.42 (m,2H),4.11 (m,2H),1.22 (s,9H).

[0312] I-42, Azetidin-3-ylmethyl 2,2-dimethylpropanoate; 2,2,2-trifluoroacetic acid [ka] Intermediate 42 (I-42) was prepared by a method similar to intermediate 41 (I-41), replacing 1-N-boc-3-hydroxyazetidine with tert-butyl 3-(2,2-dimethylpropanoyloxymethyl)azetidine-1-carboxylate in step A. 1 H NMR (400 MHz,CDCl3) δ / ppm: 9.87 (s br,1H),9.40 (s br,1H),4.20 (d,J = 5.4 Hz,2H),4.11 (m,2H),4.00 (m,2H),3.32 (m,1H),1.23 (s,9H).

[0313] I-43, Morpholin-2-ylmethyl 2,2-dimethylpropanoate; 2,2,2-trifluoroacetic acid [ka] Intermediate 43 (I-43) was prepared by a method similar to intermediate 41 (I-41), replacing 1-N-boc-3-hydroxyazetidine with tert-butyl 2-(2,2-dimethylpropanoyloxymethyl)morpholine-4-carboxylate in step A. 1 H NMR (400 MHz,CDCl3) δ / ppm: 4.10 (dd,J=5.6,11.5 Hz,1H),4.03 (dd,J=5.0,11.6 Hz,1H),3.93 - 3.86 (m,1H),3.71 - 3.57 (m,2H),2.94 - 2.79 (m,3H),2.69 - 2.63 (m,1H),1.21 (s,9H). [Example]

[0314] Example 1, 6-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-4-(1,4-oxazepan-4-yl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one Example 1 was prepared according to the route described in Scheme 15. [ka]

[0315] Step A, tert-butyl 4-(1,4-oxazepan-4-yl)-5-oxo-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate A solution of tert-butyl 2-chloro-4-(1,4-oxazepan-4-yl)-5-oxo-7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (504 mg, 1.37 mmol), ((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methanol (544 mg, 3.42 mmol) and potassium carbonate (378 mg, 2.74 mmol) in 1,4-dioxane (6.8 mL) was heated to 100° C. overnight. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate (10 mL), filtered through a hydrophobic frit, the frit washed with ethyl acetate (2×20 mL), and the filtrate collected and concentrated under reduced pressure. Purification by flash column chromatography on silica gel (eluting with 0–16% MeOH / DCM) afforded tert-butyl 4-(1,4-oxazepan-4-yl)-5-oxo-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (723 mg, 1.47 mmol, 100% yield) as a brown oil. UPLC-MS (ES + ,Method 2): 1.24 min,m / z 492.4 [M+H] +

[0316] Step B, 4-(1,4-oxazepan-4-yl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-6,7-dihydropyrrolo[3,4-d]pyrimidin-5-one To a solution of tert-butyl 4-(1,4-oxazepan-4-yl)-5-oxo-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (672 mg, 1.37 mmol) in DCM (1.8 mL) was added trifluoroacetic acid (1.05 mL, 13.7 mmol) and the reaction was stirred at room temperature for 90 minutes. The reaction was concentrated under reduced pressure and purified by flash column chromatography (KP Amino-D silica column 0-15% MeOH / DCM) to give the TFA salt of 4-(1,4-oxazepan-4-yl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-6,7-dihydropyrrolo[3,4-d]pyrimidin-5-one (527 mg, 1.04 mmol, 76% yield) as a brown oil. UPLC-MS (ES + , short-term acidic): 1.01 min, m / z 392.3 [M-TFA+H] + .

[0317] Step C, 6-[8-ethyl-7-fluoro-3-(methoxymethyloxy)-1-naphthyl]-4-(1,4-oxazepan-4-yl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one To a solution of intermediate I-1a (85.5 mg, 0.220 mmol), cesium carbonate (104 mg, 0.320 mmol), and 4-(1,4-oxazepan-4-yl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-6,7-dihydropyrrolo[3,4-d]pyrimidin-5-one (50.0 mg, 0.130 mmol) in degassed toluene (1.3 mL) was added 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (14.8 mg, 0.0300 mmol) and tris(dibenzylideneacetone)dipalladium(0) (11.7 mg, 0.0100 mmol). The reaction mixture was heated to 110 °C for 2 h. The reaction mixture was allowed to cool to room temperature. The reaction mixture was then diluted with EtOAc (10 mL) and passed through a layer separator frit. The frit was washed with ethyl acetate (2 × 10 mL), and the filtrate was collected and concentrated to dryness. The crude product was then purified by flash column chromatography (KP-Amino D silica column, eluted with 0–80% ethyl acetate / petrol) to afford 6-[8-ethyl-7-fluoro-3-(methoxymethyloxy)-1-naphthyl]-4-(1,4-oxazepan-4-yl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one (35.9 mg, 0.0600 mmol, 45% yield) as a colorless oil. UPLC-MS (ES + ,Method 2): 1.52 min,m / z 624.4 [M+H] + .

[0318] Step D, 6-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-4-(1,4-oxazepan-4-yl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one (Example 1) Trifluoroacetic acid (0.22 mL, 2.88 mmol) was added to a solution of triethylsilane (0.05 mL, 0.290 mmol) and 6-[8-ethyl-7-fluoro-3-(methoxymethyloxy)-1-naphthyl]-4-(1,4-oxazepan-4-yl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one (35.9 mg, 0.0600 mmol) in DCM (0.38 mL). The reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. Purification by reverse-phase chromatography (eluting with 5–40% MeCN (0.1% formic acid) / water (0.1% formic acid)) and isolation of product-containing fractions by SCX (methanol washes (×2) followed by 1 M NH3 / MeOH (×2)) afforded Example 1, 6-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-4-(1,4-oxazepan-4-yl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one (16.9 mg, 0.0300 mmol, 51% yield), as an off-white solid. UPLC-MS (ES + ,Method 1): 3.03 min,m / z 580.4 [M+H] + . 1 H NMR (400 MHz,DMSO-d6) δ / ppm: 9.93 (s,1H),7.73 (dd,J = 9.1,6.0 Hz,1H),7.36 - 7.31 (m,1H),7.26 (d,J = 2.6 Hz,1H),7.15 (d,J = 2.5 Hz,1H),5.39-5.17 (m,1H),4.73-4.46 (m,3H),4.41-4.15 (m,1H),4.15-3.92 (m,3H),3.92-3.53 (m,5H),3.17-2.96 (m,3H),2.95-2.78 (m,2H),2.77-2.66 (m,1H),2.19-1.69 (m,8H),1.02 (t,J = 7.4 Hz,3H).

[0319] Examples synthesized according to the same procedure as in Example 1 (Scheme 15), replacing ((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methanol in Step A and / or I-1a in Step C with appropriate building blocks, are listed in Table 5. When the building blocks in Step A or Step C did not have protecting groups, Step D was not necessary. [Table 7] [Table 8] [Table 9] [Table 10] [Table 11] [Table 12] [Table 13] [Table 14] [Table 15] [Table 16] [Table 17] [Table 18] [Table 19]

[0320] Example 2, 6-(5,6-dimethyl-1H-indazol-4-yl)-4-(1,4-oxazepan-4-yl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one Example 2 was prepared according to the method described in Scheme 16. [ka] The synthesis of 4-(1,4-oxazepan-4-yl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-6,7-dihydropyrrolo[3,4-d]pyrimidin-5-one was described in Scheme 15 for the preparation of Example 1.

[0321] Step A, 6-(5,6-dimethyl-1-tetrahydropyran-2-yl-indazol-4-yl)-4-(1,4-oxazepan-4-yl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one 4-Bromo-5,6-dimethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (145 mg, 0.470 mmol), cesium carbonate (191 mg, 0.590 mmol), and 4-(1,4-oxazepan-4-yl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-6,7-dihydropyrrolo[3,4 To a solution of the TFA salt of [-d]pyrimidin-5-one (119 mg, 0.230 mmol) in toluene (degassed with nitrogen) (2.3 mL) was added tris(dibenzylideneacetone)dipalladium(0) (21.5 mg, 0.0200 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (27.1 mg, 0.0500 mmol), and the reaction was heated to 110 °C for 3 h. The reaction mixture was allowed to cool to room temperature. The reaction was then diluted with ethyl acetate and passed through a phase separator frit, and the filtrate was collected and concentrated to dryness. The crude product was then purified by flash column chromatography (KP-Amino D silica column, eluted with 0-70% ethyl acetate / petroleum) to give 6-(5,6-dimethyl-1-tetrahydropyran-2-yl-indazol-4-yl)-4-(1,4-oxazepan-4-yl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one (40.5 mg, 0.0700 mmol, 28% yield) as a colorless oil. UPLC-MS (ES + ,Method 2): 1.41 min,m / z 620.5 [M+H] + .

[0322] Step B. 6-(5,6-dimethyl-1H-indazol-4-yl)-4-(1,4-oxazepan-4-yl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one (Example 2) Hydrogen chloride (0.33 mL, 1.31 mmol) (4N / dioxane) was added to a solution of 6-(5,6-dimethyl-1-tetrahydropyran-2-yl-indazol-4-yl)-4-(1,4-oxazepan-4-yl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one (40.5 mg, 0.0700 mmol) in methanol (0.66 mL). The mixture was stirred at room temperature overnight and concentrated under reduced pressure. Purification by reverse-phase chromatography (eluting with 5–40% MeCN (0.1% formic acid) / water (0.1% formic acid)) and isolation of the product-containing fractions by SCX (methanol washes (×2) followed by 1 M NH3 / MeOH (×2)) afforded 6-(5,6-dimethyl-1H-indazol-4-yl)-4-(1,4-oxazepan-4-yl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one (12.2 mg, 0.0200 mmol, 35% yield) as a white solid. UPLC-MS (ES + ,Method 1): 2.58 min,m / z 536.4 [M+H] + . 1 H NMR (400 MHz,DMSO-d6) δ / ppm: 12.98 (s,1H),7.92-7.88 (m,1H),7.38 (s,1H),5.40-5.17 (m,1H),4.76 (dd,J = 18.4,2.5 Hz,1H),4.59-4.33 (m,3H),4.17-3.84 (m,4H),3.84-3.58 (m,4H),3.17-2.94 (m,3H),2.90-2.79 (m,1H),2.40 (s,3H),2.16-1.69 (m,11H).

[0323] Example 4, 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-6-(3-hydroxy-1-naphthyl)-7H-pyrrolo[3,4-d]pyrimidin-5-one Example 4 was prepared according to the route described in Scheme 17. [ka]

[0324] Step A, tert-butyl 4-(8-tert-butoxycarbonyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-chloro-5-oxo-7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate To a solution of tert-butyl 2,4-dichloro-5-oxo-7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (135 mg, 0.440 mmol) in DCM (5 mL) was added 8-Boc-3,8-diazabicyclo[3.2.1]octane (188 mg, 0.890 mmol) and N,N-diisopropylethylamine (0.31 mL, 1.78 mmol), and the reaction was stirred at room temperature for 2 h. The reaction was concentrated to dryness under reduced pressure, and the crude product was then purified by column chromatography (eluting with 10–100% EtOAc / petroleum ether). The desired fractions were concentrated to dryness under reduced pressure to give tert-butyl 4-(8-tert-butoxycarbonyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-chloro-5-oxo-7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (213 mg, 0.440 mmol, 100% yield) as a pale yellow oil. UPLC-MS (ES + ,Method 2): 2.20 minutes, m / z 480.2 [M+H] + .

[0325] Step B, tert-butyl 4-(8-tert-butoxycarbonyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-5-oxo-7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate A solution of tert-butyl 4-(8-tert-butoxycarbonyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-chloro-5-oxo-7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (230 mg, 0.480 mmol), (tetrahydro-1H-pyrrolidin-7a(5H)-yl)methanol (203 mg, 1.44 mmol), and potassium carbonate (132 mg, 0.960 mmol) in 1,4-dioxane (4 mL) was heated to 100 °C overnight. The reaction was diluted with EtOAc, passed through a layer-separating filter paper, and concentrated to dryness. The crude product was then purified by silica column chromatography (eluting with 100% DCM to 20% MeOH / DCM). The desired fractions were concentrated to dryness under reduced pressure to afford tert-butyl 4-(8-tert-butoxycarbonyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-5-oxo-7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (229 mg, 0.390 mmol, 82% yield) as an orange oil. UPLC-MS (ES + ,Method 2): 1.68 min,m / z 585.4 [M+H] + .

[0326] Step C, tert-butyl 3-[2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-5-oxo-6,7-dihydropyrrolo[3,4-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate To a solution of tert-butyl 4-(8-tert-butoxycarbonyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-5-oxo-7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (210 mg, 0.360 mmol) in MeCN (2 mL) was added magnesium perchlorate (16.0 mg, 0.0700 mmol) and the reaction was stirred overnight at 60° C. The reaction was concentrated to dryness and the crude product was purified by silica column chromatography (eluting with 100% DCM to 20% MeOH / DCM). The desired fractions were collected and concentrated under reduced pressure to give tert-butyl 3-[2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-5-oxo-6,7-dihydropyrrolo[3,4-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (174 mg, 0.360 mmol, 100% yield) as a yellow oil.

[0327] Step D, tert-butyl 3-[2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-6-[3-(methoxymethyloxy)-1-naphthyl]-5-oxo-7H-pyrrolo[3,4-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate 1-Bromo-3-(methoxymethyloxy)naphthalene (216 mg, 0.810 mmol), cesium carbonate (264 mg, 0.810 mmol), and tert-butyl 3-[2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-5-oxo-6,7-dihydropyrrolo[3,4-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octadecanoate To a solution of benzophenone-8-carboxylate (196 mg, 0.400 mmol) in 1,4-dioxane (degassed) (2 mL), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (23.4 mg, 0.0400 mmol) and tris(dibenzylideneacetone)dipalladium(0) (18.5 mg, 0.0200 mmol) were added, and the reaction was heated to 100 °C for 4 h. The reaction was then diluted with EtOAc, passed through a layer-separating filter paper, and concentrated to dryness. The crude product was then purified by column chromatography (KP-NH modified silica column, eluting with 100% DCM to 20% MeOH / DCM). The desired fractions were concentrated to dryness under reduced pressure to afford tert-butyl 3-[2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-6-[3-(methoxymethyloxy)-1-naphthyl]-5-oxo-7H-pyrrolo[3,4-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (77.0 mg, 0.110 mmol, 28% yield) as a yellow oil. UPLC-MS (ES + ,Method 2): 1.94 min,m / z 671.4 [M+H] + .

[0328] Step E, 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-6-(3-hydroxy-1-naphthyl)-7H-pyrrolo[3,4-d]pyrimidin-5-one (Example 4) To a solution of tert-butyl 3-[2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-6-[3-(methoxymethyloxy)-1-naphthyl]-5-oxo-7H-pyrrolo[3,4-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (77.0 mg, 0.110 mmol) in 1,4-dioxane (2 mL) and methanol (1 mL) was added hydrogen chloride (4 M in dioxane) (0.29 mL, 1.15 mmol), and the reaction was stirred overnight at 25° C. The reaction was loaded onto an SCX column (the column was washed with MeOH, and then the product was eluted with 1 M NH3 / MeOH). The ammonia washes were concentrated to dryness, and the crude product was purified by column chromatography (KP-NH-modified silica column, eluting with 100% DCM to 20% MeOH / DCM). The desired fractions were concentrated to dryness under reduced pressure to give 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(1,2,3,5,6,7-hexahydropyrrolidin-8-ylmethoxy)-6-(3-hydroxy-1-naphthyl)-7H-pyrrolo[3,4-d]pyrimidin-5-one (39.0 mg, 0.0700 mmol, 65% yield) as a pale yellow solid. UPLC-MS (ES + ,Method 1): 2.20 min,m / z 527.3 [M+H] + . 1 H NMR (400 MHz,DMSO-d6) δ / ppm: 9.95 (br s,1H),7.77 (d,J = 8.2 Hz,1H),7.54 (d,J = 8.6 Hz,1H),7.45-7.41 (m,1H),7.30-7.25 (m,1H),7.19-7.16 (m,2H),4.71 (s,2H),4.01 (s,2H),3.47-3.39 (m,2H),3.15-3.03 (m,2H),2.96-2.90 (m,2H),2.58-2.54 (m,2H),1.90-1.69 (m,8H),1.66-1.51 (m,6H).

[0329] Prepare the following examples (Table 6) by methods analogous to Example 4 (Scheme 17), substituting components in steps A, B and D, where necessary, as indicated in the table. [Table 20] [Table 21] [Table 22] [Table 23] [Table 24] [Table 25] [Table 26] [Table 27] [Table 28] [Table 29] [Table 30] [Table 31] [Table 32] [Table 33] [Table 34] [Table 35] [Table 36] [Table 37] [Table 38]

[0330] Example 49, 6-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-4-(1,4-oxazepan-4-yl)-2-(pyrrolidin-3-ylmethoxy)-7H-pyrrolo[3,4-d]pyrimidin-5-one Example 49 was prepared according to the route described in Scheme 18. [ka]

[0331] Step A, tert-butyl 2-[(1-tert-butoxycarbonylpyrrolidin-3-yl)methoxy]-4-(1,4-oxazepan-4-yl)-5-oxo-7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate To a degassed toluene (2 mL) solution of tert-butyl 2-chloro-4-(1,4-oxazepan-4-yl)-5-oxo-7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (20 mg, 0.540 mmol), tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate (218 mg, 1.08 mmol), and cesium carbonate (530 mg, 1.63 mmol) was added (+ / -)-BINAP (67.5 mg, 0.110 mmol) and palladium(II) acetate (12.2 mg, 0.0500 mmol). The reaction mixture was stirred at 110 °C for 1 hour. The reaction mixture was diluted with EtOAc and passed through a layer-separating filter paper. The filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography (eluting with 0–100% EtOAc / petroleum ether followed by 0–100% MeOH (as a 20% solution in DCM)) to afford tert-butyl 2-[(1-tert-butoxycarbonylpyrrolidin-3-yl)methoxy]-4-(1,4-oxazepan-4-yl)-5-oxo-7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (45.0 mg, 0.0843 mmol, 16% yield) as a yellow solid. UPLC-MS (ES + ,Method 2): 2.02 min,m / z 534.3 [M+H] +

[0332] Step B, tert-butyl 3-[[4-(1,4-oxazepan-4-yl)-5-oxo-6,7-dihydropyrrolo[3,4-d]pyrimidin-2-yl]oxymethyl]pyrrolidine-1-carboxylate To a solution of tert-butyl 2-[(1-tert-butoxycarbonylpyrrolidin-3-yl)methoxy]-4-(1,4-oxazepan-4-yl)-5-oxo-7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (45.0 mg, 0.0800 mmol) in MeCN (1 mL) was added magnesium perchlorate (3.8 mg, 0.0200 mmol), and the reaction mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash column chromatography (eluting with 0–100% MeOH (as a 20% solution in DCM)) to afford tert-butyl 3-[[4-(1,4-oxazepan-4-yl)-5-oxo-6,7-dihydropyrrolo[3,4-d]pyrimidin-2-yl]oxymethyl]pyrrolidine-1-carboxylate (15.0 mg, 0.0346 mmol, 41% yield) as a waxy colorless solid. UPLC-MS (ES + ,Method 2): 1.64 min,m / z 434.2 [M+H] +

[0333] Step C, tert-butyl 3-[[6-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-4-(1,4-oxazepan-4-yl)-5-oxo-7H-pyrrolo[3,4-d]pyrimidin-2-yl]oxymethyl]pyrrolidine-1-carboxylate To a degassed solution of tert-butyl 3-[[4-(1,4-oxazepan-4-yl)-5-oxo-6,7-dihydropyrrolo[3,4-d]pyrimidin-2-yl]oxymethyl]pyrrolidine-1-carboxylate (25.0 mg, 0.0600 mmol), [8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]trifluoromethanesulfonate (38.6 mg, 0.100 mmol), and cesium carbonate (47.0 mg, 0.140 mmol) in toluene (1 mL) was added 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (6.7 mg, 0.0100 mmol) and tris(dibenzylideneacetone)dipalladium(0) (5.3 mg, 0.0100 mmol). The reaction mixture was stirred at 110 °C for 2 h. The reaction mixture was diluted with EtOAc and passed through a layer-separating filter paper. The filtrate was concentrated under reduced pressure, and the residue was purified by flash column chromatography (eluting with 0-100% EtOAc / petroleum ether) to give tert-butyl 3-[[6-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-4-(1,4-oxazepan-4-yl)-5-oxo-7H-pyrrolo[3,4-d]pyrimidin-2-yl]oxymethyl]pyrrolidine-1-carboxylate (10.0 mg, 0.0150 mmol, 26% yield) as a yellow residue. UPLC-MS (ES + ,Method 2): 2.33 min, m / z 666.3 [M+H] +

[0334] Step D, 6-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-4-(1,4-oxazepan-4-yl)-2-(pyrrolidin-3-ylmethoxy)-7H-pyrrolo[3,4-d]pyrimidin-5-one (Example 49) To a solution of tert-butyl 3-[[6-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-4-(1,4-oxazepan-4-yl)-5-oxo-7H-pyrrolo[3,4-d]pyrimidin-2-yl]oxymethyl]pyrrolidine-1-carboxylate (10.0 mg, 0.0200 mmol) in DCM (0.5 mL) was added triethylsilane (0.02 mL, 0.150 mmol) and trifluoroacetic acid (0.12 mL, 1.50 mmol). The reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography (eluting with 0–100% MeOH (as a 20% solution in DCM)) to afford 6-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-4-(1,4-oxazepan-4-yl)-2-(pyrrolidin-3-ylmethoxy)-7H-pyrrolo[3,4-d]pyrimidin-5-one (1.8 mg, 0.00340 mmol, 23% yield) as a white solid. UPLC-MS (ES + ,Method 1): 2.97 min,m / z 522.5 [M+H] + . 1 H NMR (400 MHz,DMSO-d6) δ / ppm: 7.73 (dd,J = 9.0,5.9 Hz,1H),7.37 - 7.29 (m,1H),7.27 (d,J = 2.4 Hz,1H),7.16 (d,J = 2.1 Hz,1H),4.72 - 4.48 (m,3H),4.31 - 4.21 (m,3H),4.01 - 3.76 (m,3H),3.65 (s,3H),2.96 - 2.70 (m,6H),2.65 - 2.55 (m,2H),2.03 - 1.83 (m,4H),1.48 - 1.39 (m,1H),1.02 (t,J = 7.5 Hz,3H).

[0335] Prepare the examples listed in Table 7 below by a method similar to Example 49 (Scheme 18), replacing tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate in Step A with the appropriate building blocks listed in the table. [Table 39] [Table 40] [Table 41] [Table 42] [Table 43] [Table 44]

[0336] Example 63, 6-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-4-(1,4-oxazepan-4-yl)-7H-pyrrolo[3,4-d]pyrimidin-5-one Example 63 was prepared according to the route described in Scheme 19. [ka]

[0337] 6-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-4-(1,4-oxazepan-4-yl)-7H-pyrrolo[3,4-d]pyrimidin-5-one (Example 63) A solution of formaldehyde (36.5-38%) in water (0.01 mL, 0.110 mmol) was added to a solution of Example 60, 6-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-2-[[(2S,4R)-4-fluoropyrrolidin-2-yl]methoxy]-4-(1,4-oxazepan-4-yl)-7H-pyrrolo[3,4-d]pyrimidin-5-one (38.0 mg, 0.0700 mmol) in methanol (1.5 mL), and the mixture was stirred at 25°C under nitrogen for 90 minutes. Sodium triacetoxyborohydride (44.8 mg, 0.210 mmol) was added, and stirring was continued for 1 hour. The mixture was diluted with methanol (10 mL) and allowed to stand at room temperature overnight. The solvent was removed under reduced pressure, and the resulting solid was suspended in DCM (2 mL). The suspension was purified by flash chromatography (using a 5.9 g irregular NH silica cartridge, eluting with 0–15% MeOH / DCM). The product-containing fractions were concentrated under reduced pressure, and the resulting solid was transferred to a tared vial containing methanol (1 mL). The solvent was removed using a Smart Evaporator, and the vial was dried in a vacuum oven at 50 °C for 3 h to afford 6-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-2-[[(2S,4R)-4-fluoro-1-methyl-pyrrolidin-2-yl]methoxy]-4-(1,4-oxazepan-4-yl)-7H-pyrrolo[3,4-d]pyrimidin-5-one (15.3 mg, 0.0280 mmol, 39% yield) as a pale yellow solid. UPLC-MS (ES + ,Method 1): 3.02 min,m / z 554.4 [M+H] + . 1H NMR (400 MHz,DMSO-d6) δ / ppm: 9.96 (br s,1H),7.73 (dd,J = 8.7,5.9 Hz,1H),7.39 - 7.29 (m,1H),7.26 (d,J = 2.5 Hz,1H),7.16 (d,J = 2.5 Hz,1H),5.29 - 5.10 (m,1H),4.72 - 4.51 (m,3H),4.44 - 4.23 (m,3H),4.08 - 3.76 (m,3H),3.72 - 3.60 (m,3H),3.50 - 3.40 (m,1H),2.98 - 2.83 (m,2H),2.77 - 2.68 (m,1H),2.56 - 2.43 (m,1H),2.41 (d,J = 1.1 Hz,3H),2.19 - 2.08 (m,1H),2.02 - 1.72 (m,3H),1.02 (t,J = 7.3 Hz,3H).

[0338] The examples listed in Table 8 below were made by a method similar to Example 63 (Scheme 19), substituting the listed example for Example 60 as the precursor. [Table 45] [Table 46] [Table 47]

[0339] Example 64, 6-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-4-(1,4-oxazepan-4-yl)-2-[[1-(4-piperidyl)triazol-4-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one Example 64 was prepared according to the route described in Scheme 20. [ka]

[0340] Step A, tert-butyl 4-[4-[[6-[8-ethyl-7-fluoro-3-(methoxymethyloxy)-1-naphthyl]-4-(1,4-oxazepan-4-yl)-5-oxo-7H-pyrrolo[3,4-d]pyrimidin-2-yl]oxymethyl]triazol-1-yl]piperidine-1-carboxylate To a mixture of (+)-sodium L-ascorbate (28.7 mg, 0.140 mmol), 1-boc-4-azidopiperidine (9.8 mg, 0.0400 mmol), 6-[8-ethyl-7-fluoro-3-(methoxymethyloxy)-1-naphthyl]-4-(1,4-oxazepan-4-yl)-2-prop-2-ynoxy-7H-pyrrolo[3,4-d]pyrimidin-5-one (15.0 mg, 0.0300 mmol), and copper(II) sulfate pentahydrate (14.4 mg, 0.0600 mmol) in tert-butanol (0.25 mL) was added water (0.25 mL), and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with water and DCM, stirred for 5 min, and passed through a hydrophobic frit. The solvent was removed under reduced pressure to give tert-butyl 4-[4-[[6-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-4-(1,4-oxazepan-4-yl)-5-oxo-7H-pyrrolo[3,4-d]pyrimidin-2-yl]oxymethyl]triazol-1-yl]piperidine-1-carboxylate (46.0 mg, 0.0277 mmol, 96% yield) as a yellow gum. UPLC-MS (ES + ,Method 2): 2.20 min,m / z 747.4 [M+H] +

[0341] Step B. 6-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-4-(1,4-oxazepan-4-yl)-2-[[1-(4-piperidyl)triazol-4-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one (Example 64) Trifluoroacetic acid (0.12 mL, 1.54 mmol) was added to a solution of triethylsilane (0.02 mL, 0.150 mmol) and tert-butyl 4-[4-[[6-[8-ethyl-7-fluoro-3-(methoxymethyloxy)-1-naphthyl]-4-(1,4-oxazepan-4-yl)-5-oxo-7H-pyrrolo[3,4-d]pyrimidin-2-yl]oxymethyl]triazol-1-yl]piperidine-1-carboxylate (46.0 mg, 0.0300 mmol) in DCM (1 mL). The reaction mixture was stirred at room temperature for 4.5 hours, and the mixture was concentrated under reduced pressure. The mixture was dissolved in DMSO:MeCN:HO (1 mL, 2:1:1, v / v) and filtered. The resulting solution was purified by preparative LC to give 6-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-4-(1,4-oxazepan-4-yl)-2-[[1-(4-piperidyl)triazol-4-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one (2.9 mg, 0.00480 mmol, 16% yield) as a pale yellow solid. UPLC-MS (ES + ,Method 1): 2.91 min,m / z 603.4 [M+H] + 1 H NMR (400 MHz,MeOH-d4) δ / ppm: 8.52 (br s,1H),8.20 (s,1H),7.67 (dd,J = 9.0,5.8 Hz,1H),7.12 (d,J = 2.6 Hz,1H),7.29-7.22 (m,2H),5.76-5.44 (m,2H),4.76-4.60 (m,3H),4.51-3.95 (m,3H),3.93-3.70 (m,4H),3.65-3.43 (m,2H),3.27-3.17 (m,2H),3.11-2.97 (m,1H),2.88-2.71 (m,1H),2.51-2.39 (m,2H),2.39-2.25 (m,2H),2.16-1.83 (m,2H),1.40-1.26 (m,2H),1.12 (t,J = 7.4 Hz,3H).

[0342] Example 65, 4-(1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5-yl)-6-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one Example 65 was prepared according to the route described in Scheme 21. [ka]

[0343] Step A, tert-butyl 4-(1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5-yl)-5-oxo-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate To a solution of tert-butyl 4-hydroxy-5-oxo-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (100 mg, 0.240 mmol), HATU (130 mg, 0.340 mmol), and hexahydro-1H-furo[3,4-c]pyrrole hydrochloride (51.3 mg, 0.340 mmol) in THF (10 mL) was added N,N-diisopropylethylamine (0.17 mL, 0.980 mmol), and the reaction was stirred at 65 °C for 4 h. The reaction was concentrated to dryness under reduced pressure and purified by column chromatography (eluting with 100% DCM to 20% MeOH / DCM). The desired fractions were combined and concentrated to dryness to give tert-butyl 4-(1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5-yl)-5-oxo-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (123 mg, 0.244 mmol, 100% yield) as a yellow oil. UPLC-MS (ES + ,Method 2): 1.42 min,m / z 504.2 [M+H] +

[0344] Step B, 4-(1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5-yl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-6,7-dihydropyrrolo[3,4-d]pyrimidin-5-one To a solution of tert-butyl 4-(1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5-yl)-5-oxo-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (123 mg, 0.240 mmol) in DCM (6 mL) was added trifluoroacetic acid (0.19 mL, 2.44 mmol), and the reaction was stirred at room temperature for 90 min. The reaction was concentrated under reduced pressure and purified by flash column chromatography (eluting with 100% DCM to 20% MeOH / DCM). The desired fractions were combined and concentrated under reduced pressure to give 4-(1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5-yl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-6,7-dihydropyrrolo[3,4-d]pyrimidin-5-one (20.0 mg, 0.0496 mmol, 20% yield) as an orange oil. UPLC-MS (ES + ,Method 2): 1.26 min,m / z 404.2 [M+H] +

[0345] Step C, 4-(1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5-yl)-6-[8-ethyl-7-fluoro-3-(methoxymethyloxy)-1-naphthyl]-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one 4-(1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5-yl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-6,7-dihydropyrrolo[3,4-d]pyrimidin-5-one (20.0 mg, 0.0500 mmol), cesium carbonate (40.4 mg, 0.120 mmol), and [8-ethyl-7-fluoro To a solution of [2-(3-(methoxymethyloxy)-1-naphthyl]trifluoromethanesulfonate (28.4 mg, 0.0700 mmol) in toluene (degassed with N) (2 mL) was added 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (5.7 mg, 0.0100 mmol) and tris(dibenzylideneacetone)dipalladium(0) (4.54 mg, 0.00500 mmol). The reaction flask was evacuated, refilled with N, and heated to 110 °C for 2 h. The reaction was diluted with EtOAc, passed through a layer-separating filter paper, and concentrated to dryness. The crude product was then purified by column chromatography (KP-NH column, eluting with 100% DCM to 20% MeOH / DCM) to give 4-(1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5-yl)-6-[8-ethyl-7-fluoro-3-(methoxymethyloxy)-1-naphthyl]-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one (13.0 mg, 0.0204 mmol, 41% yield) as a yellow oil. UPLC-MS (ES + ,Method 2): 1.80 min,m / z 636.3 [M+H] +

[0346] Step D, 4-(1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5-yl)-6-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one (Example 65) To a solution of 4-(1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5-yl)-6-[8-ethyl-7-fluoro-3-(methoxymethyloxy)-1-naphthyl]-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one (13.0 mg, 0.0200 mmol) in DCM (2 mL) and methanol (1 mL) was added hydrogen chloride (4 M in dioxane) (0.05 mL, 0.200 mmol) and the reaction was stirred overnight at 25° C. The reaction was diluted with MeOH and loaded onto an SCX column (the column was washed with MeOH, then the product was eluted with 1 M NH3 / MeOH). The ammonia washes were concentrated to dryness, and the crude product was purified by column chromatography (KP-NH modified column, eluting with DCM to 10% MeOH / DCM). The desired fractions were combined and concentrated to dryness under reduced pressure to give 4-(1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5-yl)-6-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one (3.0 mg, 0.00510 mmol, 25% yield) as an orange solid. UPLC-MS (Method 1): 2.95,2.97 min,m / z 592.5 [M+H] + (5.6%) and 2.99, 3.01 min, m / z 592.6 [M+H] + (33,53%). 1H NMR (400 MHz,DMSO-d6) δ / ppm: 9.93 (s,1H),7.75 - 7.70 (m,1H),7.35 - 7.30 (m,1H),7.27 - 7.25 (m,1H),7.16 - 7.14 (m,1H),5.37 - 5.19 (m,1H),4.70 - 4.59 (m,2H),4.12 - 3.96 (m,2H),3.93 - 3.73 (m,4H),3.61 - 3.46 (m,2H),3.14 - 2.79 (m,7H),2.75 - 2.69 (m,1H),2.14 - 1.75 (m,6H),1.06 - 1.00 (m,3H).

[0347] The following examples (Table 9) were made by a method similar to Example 65 (Scheme 21), replacing hexahydro-1H-furo[3,4-c]pyrrole hydrochloride in Step A with the listed building blocks. [Table 48] [Table 49] [Table 50] [Table 51] [Table 52] [Table 53] [Table 54] [Table 55] [Table 56] [Table 57] [Table 58] [Table 59] [Table 60] [Table 61]

[0348] Example 69, 6-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-4-[methyl(4-piperidyl)amino]-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one Example 69 was prepared according to the route described in Scheme 22. [ka]

[0349] Step A, Ethyl 4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carboxylate To a solution of diisopropylamine (55.7 mL, 397 mmol) in THF (100 mL) was added dropwise a solution of n-butyllithium (159 mL, 397 mmol) and 4,6-dichloro-2-methylthiopyrimidine (50.0 g, 256 mmol) in THF (200 mL) at −78° C. The reaction mixture was stirred at −78° C. for 1 hour. Ethyl chloroformate (73.5 mL, 769 mmol) was added dropwise, and the reaction mixture was stirred at 0° C. for 30 minutes. The reaction mixture was quenched with saturated aqueous NH4Cl solution, and the layers were separated. The aqueous layer was extracted with EtOAc (500 mL × 3). The combined organic layers were washed with brine (2000 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by flash chromatography (PE / EtOAc=1 / 0 to PE / EtOAc=100 / 1, v / v) to give ethyl 4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carboxylate (40.0 g, 44.9 mmol, 18% yield) as a pale yellow solid. LC-MS (ES + ,Method 4) 1.09 min,m / z 267.0 / 269.0 [M+H] +

[0350] Step B, Ethyl 4-[(1-tert-butoxycarbonyl-4-piperidyl)-methyl-amino]-6-chloro-2-methylsulfanyl-pyrimidine-5-carboxylate A solution of ethyl 4,6-dichloro-2-(methylthio)pyrimidine-5-carboxylate (30.0 g, 67.4 mmol), N-boc-4-(methylamino)piperidine (14.4 g, 67.4 mmol), and triethylamine (28.2 mL, 202 mmol) in DMF (300 mL) was stirred at room temperature under nitrogen for 3 hours. The reaction mixture was diluted with water (3000 mL), and the layers were separated. The aqueous layer was extracted with EtOAc (800 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by silica gel chromatography (eluting with 20% EtOAc / petroleum ether) to give ethyl 4-[(1-tert-butoxycarbonyl-4-piperidyl)-methyl-amino]-6-chloro-2-methylsulfanyl-pyrimidine-5-carboxylate (25.0 g, 56.2 mmol, 83% yield) as a yellow solid. LC-MS (ES + ,Method 4): 2.32 min,m / z 445.1 [M+H] +

[0351] Step C, Ethyl 4-[(1-tert-butoxycarbonyl-4-piperidyl)-methyl-amino]-6-cyano-2-methylsulfanyl-pyrimidine-5-carboxylate A solution of ethyl 4-[(1-tert-butoxycarbonyl-4-piperidyl)-methyl-amino]-6-chloro-2-methylsulfanyl-pyrimidine-5-carboxylate (13.0 g, 29.2 mmol), Zn(CN) (51.5 g, 43.8 mmol), and tetrakis(triphenylphosphine)palladium (33.8 g, 2.92 mmol) in DMF (20 mL) was stirred at 120 °C for 16 h. The reaction mixture was diluted with water (500 mL), and the layers were separated. The aqueous layer was extracted with EtOAc (200 mL × 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated in vacuo. The crude product was purified by silica gel chromatography (eluting with 1 / 3 EtOAc / petroleum ether) to give ethyl 4-[(1-tert-butoxycarbonyl-4-piperidyl)-methyl-amino]-6-cyano-2-methylsulfanyl-pyrimidine-5-carboxylate (12.0 g, 27.6 mmol, 94% yield) as a yellow solid. LC-MS (ES + ,Method 4): 2.17 min,m / z 436.2 [M+H] +

[0352] Step D, tert-butyl 4-[methyl-(2-methylsulfanyl-5-oxo-6,7-dihydropyrrolo[3,4-d]pyrimidin-4-yl)amino]piperidine-1-carboxylate A solution of ethyl 4-[(1-tert-butoxycarbonyl-4-piperidyl)-methyl-amino]-6-cyano-2-methylsulfanyl-pyrimidine-5-carboxylate (6.00 g, 13.8 mmol), CoCl2-6H2O (11.5 g, 41.3 mmol), and sodium borohydride (2.61 g, 68.9 mmol) in methanol (300 mL) was stirred at -78 °C under nitrogen for 45 minutes. The reaction mixture was heated to 50 °C for 4 hours. The reaction mixture was diluted with water (3000 mL) and extracted with EtOAc (1000 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel chromatography (1 / 10 EtOAc / petroleum ether) to give tert-butyl 4-[methyl-(2-methylsulfanyl-5-oxo-6,7-dihydropyrrolo[3,4-d]pyrimidin-4-yl)amino]piperidine-1-carboxylate (817 mg, 2.08 mmol, 15% yield) as a yellow solid. LC-MS (ES + ,Method 4): 1.97 min,m / z 392.2 [M+H] +

[0353] Step E, tert-butyl 4-[methyl-(2-methylsulfonyl-5-oxo-6,7-dihydropyrrolo[3,4-d]pyrimidin-4-yl)amino]piperidine-1-carboxylate A solution of ethyl 4-[(1-tert-butoxycarbonyl-4-piperidyl)-methyl-amino]-6-cyano-2-methylsulfonyl-pyrimidine-5-carboxylate (100 mg, 0.214 mmol) and Ni (500 mg, 0.214 mmol) in IPA (2 mL) was stirred for 3 h at 70° C. The reaction mixture was concentrated under reduced pressure and used in the next step without further purification. LC-MS (ES + ,Method 4): 1.55 min,m / z 426.2 [M+H] +

[0354] Step F, tert-butyl 4-[[6-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-2-methylsulfonyl-5-oxo-7H-pyrrolo[3,4-d]pyrimidin-4-yl]-methyl-amino]piperidine-1-carboxylate To a solution of tert-butyl 4-[[6-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-2-methylsulfanyl-5-oxo-7H-pyrrolo[3,4-d]pyrimidin-4-yl]-methyl-amino]piperidine-1-carboxylate (290 mg, 0.460 mmol) in DCM (8 mL) was added m-CPBA (240 mg, 1.39 mmol) at 0 °C under N2 conditions. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (100 mL) and the layers were separated. The aqueous layer was extracted with DCM (30 mL × 3). The combined organic layers were washed with brine, dried over Na2SO4, concentrated in vacuo, and the residue was purified by silica gel chromatography (eluting with 1 / 2 EtOAc / petroleum ether) to give tert-butyl 4-[[6-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-2-methylsulfonyl-5-oxo-7H-pyrrolo[3,4-d]pyrimidin-4-yl]-methyl-amino]piperidine-1-carboxylate (260 mg, 0.395 mmol, 85% yield) as a yellow solid. LC-MS (ES + ,Method 3): 2.35 min,m / z 658.2 [M+H] + .

[0355] Step G, tert-butyl 4-[[6-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-5-oxo-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-4-yl]-methyl-amino]piperidine-1-carboxylate A solution of tert-butyl 4-[[6-[8-ethyl-7-fluoro-3-(methoxymethyloxy)-1-naphthyl]-2-methylsulfonyl-5-oxo-7H-pyrrolo[3,4-d]pyrimidin-4-yl]-methyl-amino]piperidine-1-carboxylate (20.0 mg, 0.0300 mmol), ((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methanol (7.3 mg, 0.0500 mmol), and t-BuOK (10.2 mg, 0.0900 mmol) in DMF (3 mL) was stirred at 40° C. for 3 hours. The reaction mixture was concentrated under reduced pressure and used in the next step without further purification. LC-MS (ES + ,Method 3): 1.80 min,m / z 769.30 [M+Na] +

[0356] Step H, 6-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-4-[methyl(4-piperidyl)amino]-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one (Example 69) A solution of tert-butyl 4-[[6-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-5-oxo-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-4-yl]-methyl-amino]piperidine-1-carboxylate (65.0 mg, 0.0900 mmol) and HCl / dioxane (3 mL) in DCM (3 mL) was stirred at room temperature for 30 minutes. The reaction mixture was adjusted to pH 8 with saturated aqueous Na2CO3. The layers were separated, and the aqueous layer was extracted with EtOAc (20 mL x 3), dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was purified by preparative HPLC to give 6-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-4-[methyl(4-piperidyl)amino]-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one (5.2 mg, 0.00880 mmol, 10% yield) as a white solid. LC-MS (ES + ,Method 4): 1.30 min,m / z 593.3 [M+H] + 1H NMR (400 MHz,DMSO-d6) δ / ppm: 11.26-10.94 (m,1H),10.26-9.94 (m,1H),8.75-8.34 (m,2H),7.75 (dd,J = 8.9,6.0 Hz,1H),7.38-7.31 (m,1H),7.30-7.28 (m,1H),7.21-7.15 (m,1H),5.59 (br d,J = 52.6 Hz,1H),4.79-4.65 (m,2H),4.63-4.48 (m,2H),4.01-3.65 (m,3H),3.34-3.26 (m,3H),3.20-3.01 (m,2H),2.96-2.81 (m,2H),2.75-2.61 (m,2H),2.59-2.53 (m,1H),2.39-2.27 (m,1H),2.25-2.13 (m,2H),2.12-1.99 (m,3H),1.96-1.86 (m,2H),1.03 (t,J = 7.3 Hz,3H).

[0357] Examples synthesized following a procedure similar to that of Example 69 (Scheme 22), replacing N-Boc-4-(methylamino)piperidine in Step B with the appropriate building blocks, are listed in Table 10. [Table 62] [Table 63] [Table 64] [Table 65] [Table 66] [Table 67] [Table 68] [Table 69] [Table 70] [Table 71] [Table 72] [Table 73]

[0358] Example 74, 6-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-4-(1,4-oxazepan-4-yl)-2-[[(2S,4R)-4-methoxypyrrolidin-2-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one Example 74 was prepared according to the route described in Scheme 23. [ka]

[0359] Step A, tert-butyl (2S,4R)-2-[[6-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-4-(1,4-oxazepan-4-yl)-5-oxo-7H-pyrrolo[3,4-d]pyrimidin-2-yl]oxymethyl]-4-methoxy-pyrrolidine-1-carboxylate To a solution of 2-chloro-6-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-4-(1,4-oxazepan-4-yl)-7H-pyrrolo[3,4-d]pyrimidin-5-one (30 mg, 0.06 mmol), tert-butyl (2S,4R)-2-(hydroxymethyl)-4-methoxy-pyrrolidine-1-carboxylate (20.78 mg, 0.09 mmol), and cesium carbonate (58.54 mg, 0.18 mmol) in toluene (1 mL) (degassed with N), (+ / -)-BINAP (7.46 mg, 0.01 mmol) and palladium(II) acetate (1.34 mg, 0.01 mmol) were added. The mixture was stirred at 110 °C for 1 hour. The mixture was diluted with ethyl acetate, passed through a layer-separating filter paper, and the filtrate was evaporated under reduced pressure to give a brown residue. The crude material was purified by flash column chromatography (4 g Biotage KP-NH column, wet load with minimal DCM, elution with 0–100% ethyl acetate / petroleum ether), and the desired fractions were combined and evaporated under reduced pressure to give tert-butyl (2S,4R)-2-[[6-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-4-(1,4-oxazepan-4-yl)-5-oxo-7H-pyrrolo[3,4-d]pyrimidin-2-yl]oxymethyl]-4-methoxy-pyrrolidine-1-carboxylate as a waxy yellow solid (25 mg, 60.0% yield). UPLC-MS (ES + ,Method 4): 2.32 min,m / z 696.3 [M+H] + .

[0360] Step B. 6-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-4-(1,4-oxazepan-4-yl)-2-[[(2S,4R)-4-methoxypyrrolidin-2-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one (Example 74) To a solution of tert-butyl (2S,4R)-2-[[6-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-4-(1,4-oxazepan-4-yl)-5-oxo-7H-pyrrolo[3,4-d]pyrimidin-2-yl]oxymethyl]-4-methoxy-pyrrolidine-1-carboxylate (25 mg, 0.04 mmol) in DCM (1 mL) was added triethylsilane (0.06 mL, 0.36 mmol) and trifluoroacetic acid (0.28 mL, 3.59 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was evaporated under reduced pressure to give a yellow residue. The material was purified by flash column chromatography (4 g Biotage KP-NH column, wet-loaded with minimal DCM) (eluting with 0–100% MeOH (as a 10% solution in DCM) / DCM). The desired fractions were combined and passed through an SCX cartridge (pre-equilibrated with 1 g MeOH) (washed first with MeOH, followed by 1 M NH3 / MeOH). The ammoniacal fraction was evaporated under reduced pressure to give a white solid. The material was transferred to a tared vial containing MeOH, evaporated using a smart evaporator, and dried overnight in a vacuum oven to give 6-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-4-(1,4-oxazepan-4-yl)-2-[[(2S,4R)-4-methoxypyrrolidin-2-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one as a white solid (4 mg, 20.2% yield). UPLC-MS (ES + ,Method 1): 2.92 min,m / z 552.5 [M+H] + . 1H NMR (400 MHz,DMSO-d6,) δ / ppm: 9.93 (s,1H),7.73 (dd,J=6.3,9.1 Hz,1H),7.32 (t,J=10.0 Hz,1H),7.26 (d,J=2.4 Hz,1H),7.16 (d,J=2.4 Hz,1H),4.66 (d,J=2.8 Hz,2H),4.21 - 4.17 (m,3H),3.90 - 3.87 (m,2H),3.67 - 3.62 (m,3H),3.54 (t,J=6.9 Hz,1H),3.20 (s,3H),2.97 - 2.82 (m,3H),2.79 - 2.67 (m,1H),2.48 - 2.40 (m,3H),2.02 - 1.89 (m,3H),1.60 - 1.52 (m,1H),1.02 (t,J=7.7 Hz,3H).

[0361] The examples listed in Table 11 below were prepared by a method similar to Example 74 (Scheme 23), replacing tert-butyl (2S,4R)-2-(hydroxymethyl)-4-methoxy-pyrrolidine-1-carboxylate with the appropriate building blocks in Step A. [Table 74] [Table 75] [Table 76] [Table 77] [Table 78] [Table 79] [Table 80] [Table 81] [Table 82] [Table 83]

[0362] Example 84, 6-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-4-(1,4-oxazepan-4-yl)-2-[[(2S,4R)-4-hydroxypyrrolidin-2-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one Example 84 was prepared according to the route described in Scheme 24. [ka]

[0363] Step A, 6-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-2-[2-(1-methylimidazol-2-yl)ethoxy]-4-(1,4-oxazepan-4-yl)-7H-pyrrolo[3,4-d]pyrimidin-5-one A solution of 2-chloro-6-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-4-(1,4-oxazepan-4-yl)-7H-pyrrolo[3,4-d]pyrimidin-5-one (58 mg, 0.12 mmol), 2-(1-methyl-1H-imidazol-2-yl)ethanol (36.52 mg, 0.29 mmol), and potassium carbonate (48 mg, 0.35 mmol) in 1,4-dioxane (1.5 mL) was stirred at 100° C. under nitrogen for 18 hours. The mixture was diluted with water and ethyl acetate, and the layers were separated. The organic layer was washed with water and brine and passed through a hydrophobic frit. The solvent was removed under reduced pressure. The crude residue was purified by flash chromatography (4 g KP-Amino, wet load, 30–100% EA / PE, then 0–20% MeOH / DCM) to give 6-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-2-[2-(1-methylimidazol-2-yl)ethoxy]-4-(1,4-oxazepan-4-yl)-7H-pyrrolo[3,4-d]pyrimidin-5-one as a yellow solid (19.5 mg, 28.5% yield). UPLC-MS (ES + ,Method 4): 1.46 min,m / z 591.4 [M+H] + .

[0364] Step B. 6-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-2-[2-(1-methylimidazol-2-yl)ethoxy]-4-(1,4-oxazepan-4-yl)-7H-pyrrolo[3,4-d]pyrimidin-5-one (Example 84) Trifluoroacetic acid (0.25 mL, 3.3 mmol) and triethylsilane (0.05 mL, 0.33 mmol) were added to a solution of 6-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-2-[2-(1-methylimidazol-2-yl)ethoxy]-4-(1,4-oxazepan-4-yl)-7H-pyrrolo[3,4-d]pyrimidin-5-one (19.5 mg, 0.03 mmol) in DCM (0.5 mL). The mixture was stirred at room temperature for 3 h. All volatiles were removed under reduced pressure. The crude residue was purified by flash chromatography (4 g KP-amino, wet load DCM, 0-20% MeOH / DCM). Relevant fractions were pooled, reduced under reduced pressure, and further dried to give 6-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-2-[2-(1-methylimidazol-2-yl)ethoxy]-4-(1,4-oxazepan-4-yl)-7H-pyrrolo[3,4-d]pyrimidin-5-one as a pink / off-white solid (11.7 mg, 64.8% yield). UPLC-MS (ES + ,Method 1): 2.88 min,m / z 547.7 [M+H] + . 1 H NMR (400 MHz,DMSO-d6) δ / ppm: 9.99 (s,1H),7.75-7.71 (m,1H),7.34-7.30 (m,1H),7.27-7.26 (m,1H),7.05-7.04 (m,1H),6.77-6.76 (m,1H),4.69-4.59 (m,4H),4.59-4.40 (m,1H),4.38-4.16 (m,1H),4.09-3.91 (m,1H),3.90-3.72 (m,2H),3.73 (s,2H),3.64 (s,3H),3.11 (t,J = 7.1Hz,2H),2.93-2.82 (m,1H),2.76-2.64 (m,1H),2.03-1.31 (br. m,3H),1.02 (t,J = 7.1Hz,3H).

[0365] The following examples were prepared by a method analogous to Example 84 (Scheme 23), replacing 2-(1-methyl-1H-imidazol-2-yl)ethanol with the appropriate building block in Step A. Example 100, 2-[2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-3-yl)ethoxy]-6-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-4-(1,4-oxazepan-4-yl)-7H-pyrrolo[3,4-d]pyrimidin-5-one [ka] Example 100 was prepared by a method similar to Example 84 (Scheme 23), replacing 2-(1-methyl-1H-imidazol-2-yl)ethanol with 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-3-yl)ethanol in Step A. UPLC-MS (ES + ,Method 1): 3.00 min,m / z 573.5 [M+H] + . 1 H NMR (400 MHz,DMSO-d6) δ / ppm: 9.33 (s,1H),7.75-7.71 (m,1H),7.35-7.31 (m,1H),7.27-7.26 (m,1H),7.16-7.15 (m,1H),6.49-6.46 (m,1H),4.67 (s,2H),4.62-5.48 (m,2H),3.95 (t,J = 7.3Hz,2H),3.71-3.59 (m,4H),3.09-3.04 (m,2H),2.75-2.71 (m,4H),2.01-1.91 (m,4H),1.29-1.20 (m,4H),1.00 (t,J = 7.2Hz,3H),0.82 (s,2H).

[0366] Example 188, 2-benzyloxy-6-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-4-(1,4-oxazepan-4-yl)-7H-pyrrolo[3,4-d]pyrimidin-5-one [ka] Example 188 was prepared in a similar manner to Example 84 (Scheme 24) using benzyl alcohol, replacing 2-(1-methyl-1H-imidazol-2-yl)ethanol with 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-3-yl)ethanol in Step A. UPLC-MS (ES + ,Method 1): 4.64 min,m / z 529.4 [M+H] + . 1 H NMR (400 MHz,DMSO-d6,) δ / ppm: 9.94 (s,1H),7.73 (dd,J=6.7,9.2 Hz,1H),7.48 - 7.39 (m,4H),7.37 - 7.30 (m,2H),7.26 (d,J=3.7 Hz,1H),7.17 (d,J=2.0 Hz,1H),5.43 (s,2H),4.73 - 3.79 (m,4H),3.75 - 3.56 (m,3H),3.25 - 2.84 (m,3H),1.94 - 1.71 (m,4H),1.02 (t,J=7.3 Hz,3H).

[0367] Example 133, 6-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-2-[(6-methylene-2,3,5,7-tetrahydro-1H-pyrrolidin-8-yl)methoxy]-4-(1,4-oxazepan-4-yl)-7H-pyrrolo[3,4-d]pyrimidin-5-one [ka] Example 133 was prepared by a method similar to Example 84 (Scheme 24), replacing 2-(1-methyl-1H-imidazol-2-yl)ethanol with (6-methylene-2,3,5,7-tetrahydro-1H-pyrrolidin-8-yl)methanol in Step A. UPLC-MS (ES + ,Method 1): 2.91 min,m / z 574.7 [M+H] + . 1H NMR (400 MHz,DMSO-d6) δ / ppm: 9.93 (s,1H),7.73 (dd,J=6.2,9.2 Hz,1H),7.33 (t,J=9.2 Hz,1H),7.26 (d,J=3.0 Hz,1H),7.16 (d,J=2.0 Hz,1H),4.91 (s,2H),4.66 (d,J=1.6 Hz,2H),4.36 - 4.20 (m,1H),4.01 (s,3H),3.87 - 3.77 (m,1H),3.65 (s,3H),3.56 (d,J=15.1 Hz,1H),3.20 (d,J=15.3Hz,1H),3.02 - 2.97 (m,1H),2.91 - 2.70 (m,3H),2.61 - 2.55 (m,3H),2.36 (d,J=14.0 Hz,1H),1.98 - 1.65 (m,6H),1.02 (t,J=7.5 Hz,3H).

[0368] Example 99, 1-[4-(1,4-oxazepan-4-yl)-5-oxo-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-6-yl]-2H-isoquinolin-3-one [ka] 6-(3-chloro-1-isoquinolyl)-4-(1,4-oxazepan-4-yl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one (87 mg, 0.16 mmol) and potassium hydroxide (26 mg, 0.47 mmol) in 1,4-dioxane (N To a solution of 2 mL of hexane (degassed with 2) and water (0.3 mL) was added bis(1,1-dimethylethyl)[2',4',6'-tris(1-methylethyl)[1,1'-biphenyl]-2-yl]-phosphine (13 mg, 0.03 mmol) and tris(dibenzylideneacetone)dipalladium(0) (14 mg, 0.02 mmol), and the mixture was heated to 100 °C for 2 h. The reaction was concentrated under reduced pressure and purified by column chromatography to give a pale yellow oil. This was purified by reverse-phase column chromatography (eluting with 0-45% acetonitrile / water (0.1% formic acid)), and the appropriate fractions were passed through an SCX column, which was washed with 1 M ammonia / methanol, and the ammonia-containing fractions were concentrated to give 1-[4-(1,4-oxazepan-4-yl)-5-oxo-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-6-yl]-2H-isoquinolin-3-one (26.8 mg, 0.046 mmol, 29% yield) as a yellow solid. UPLC-MS (ES + ,Method 1): 2.62 min,m / z 535.3 [M+H] + . 1 H NMR (400 MHz,DMSO-d6,) δ / ppm: 10.77 (s,1H),7.81-7.77 (m,2H),7.62-7.58 (m,1H),7.33-7.30 (m,1H),6.95 (s,1H),5.28 (d,J = 53.7 Hz,1H),4.92 (s,2H),4.41 (s,2H),4.11-3.64 (m,8H),3.14-3.09 (m,2H),3.01 (s,1H),2.87-2.81 (m,1H),2.14-1.73 (m,8H).

[0369] Example 108, 6-[2-(hydroxymethyl)-1-naphthyl]-4-(1,4-oxazepan-4-yl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one [ka] PI-1 was synthesized according to a similar procedure to Example 1 (Scheme 15), replacing I-1a with methyl 1-bromonaphthalene-2-carboxylate in step C. Step D was not performed. UPLC-MS (ES + ,Method 2): 1.56 min, m / z 576.2 [M+H] + .

[0370] Step A 6-[2-(hydroxymethyl)-1-naphthyl]-4-(1,4-oxazepan-4-yl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one A stirred solution of methyl 1-[4-(1,4-oxazepan-4-yl)-5-oxo-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-6-yl]naphthalene-2-carboxylate (65 mg, 0.11 mmol) in THF (1 mL) was cooled to 0 °C, and a solution of lithium aluminum hydride in THF (0.11 mL, 0.11 mmol) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 4 hours. The reaction was quenched with 2 M aqueous HCl. The reaction was basified and extracted with EtOAc. The organic fraction was collected, passed through a layer-separating filter paper, and the solvent was reduced under reduced pressure. The crude product was purified by reverse-phase chromatography (0–50% acetonitrile (0.1% formic acid) / water (0.1% formic acid) elution). The product-containing fractions were loaded onto a pre-equilibrated SCX-2 column (2 g, washed with MeOH, eluted with 1N NH3 / MeOH) to afford the desired product, 6-[2-(hydroxymethyl)-1-naphthyl]-4-(1,4-oxazepan-4-yl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one (7.5 mg, 0.0137 mmol, 12.129% yield), as an off-white solid. The product was isolated as a mixture of atropisomers. UPLC-MS (ES + ,Method 1): 2.61 min,m / z 548.6 [M+H] + ,2.64 min,m / z 548.6 [M+H] + . 1H NMR (400 MHz,DMSO-d6,) δ / ppm: 8.05 - 7.97 (m,2H),7.35 (d,J = 8.6 Hz,1H),7.65 - 7.59 (m,1H),7.57 - 7.49 (m,2H),5.29 (t,J = 5.26 Hz,1H),5.29 (d,J = 54.5 Hz,1H),4.64 (s,2H),4.61 - 4.28 (m,4H),4.18 - 3.58 (m,8H),3.18 - 2.98 (m,3H),2.91 - 2.78 (m,1H),2.20 - 1.69 (m,8H).

[0371] Example 110, 6-[5-(hydroxymethyl)-2-(trifluoromethoxy)phenyl]-4-(1,4-oxazepan-4-yl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one [ka] PI-2 was synthesized according to a similar procedure to Example 1 (Scheme 15), except that I-1a was replaced with 2-[[3-bromo-4-(trifluoromethoxy)phenyl]methoxy]tetrahydropyran I-33 in Step C. Step D was not performed. Hydrogen chloride (4N / dioxane) (0.17 mL, 0.68 mmol) was added to a stirred solution of 4-(1,4-oxazepan-4-yl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-6-[5-(tetrahydropyran-2-yloxymethyl)-2-(trifluoromethoxy)phenyl]-7H-pyrrolo[3,4-d]pyrimidin-5-one (180 mg, 0.27 mmol) in methanol (4 mL). The reaction mixture was warmed to 40 °C and stirred overnight. The solvent was removed under reduced pressure, and the crude product was purified by reverse-phase chromatography (eluting with 0–40% acetonitrile (0.1% formic acid) / water (0.1% formic acid)). The product-containing fractions were loaded onto a pre-equilibrated SCX-2 column (2 g, washed with MeOH, eluted with 1 N NH3 / MeOH) to give 6-[5-(hydroxymethyl)-2-(trifluoromethoxy)phenyl]-4-(1,4-oxazepan-4-yl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one (19 mg, 0.03 mmol, 12% yield) as an off-white solid. UPLC-MS (ES + ,Method 1): 2.67 min,m / z 582.8 [M+H] + . 1 H NMR (400 MHz,DMSO-d6,) δ / ppm: 7.57 (d,J = 1.5 Hz,1H),7.48 - 7.39 (m,2H),5.39 (t,J = 5.7 Hz,1H),5.28 (d,J = 53.7 Hz,1H),4.64 (s,2H),4.55 (d,J = 5.6 Hz,2H), 4.53 - 4.29 (m,2H),4.13 - 3.59 (m,8H),3.15 - 2.96 (m,3H),2.88 - 2.79 (m,1H),2.18 - 1.68 (m,8H).

[0372] Example 119, 6-(2-amino-1,3-benzothiazol-4-yl)-4-(1,4-oxazepan-4-yl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one [ka] The synthesis of the starting material, 4-(1,4-oxazepan-4-yl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-6,7-dihydropyrrolo[3,4-d]pyrimidin-5-one, is detailed in Scheme 15 (Steps A and B) for the preparation of Example 1.

[0373] Step A, tert-butyl N-[4-[4-(1,4-oxazepan-4-yl)-5-oxo-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-6-yl]-1,3-benzothiazol-2-yl]carbamate To a solution of 4-(1,4-oxazepan-4-yl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-6,7-dihydropyrrolo[3,4-d]pyrimidin-5-one (30 mg, 0.08 mmol), cesium carbonate (74.91 mg, 0.23 mmol), tbuBrettPhos (7.43 mg, 0.02 mmol), and tert-butyl N-(4-bromo-1,3-benzothiazol-2-yl)carbamate (I-34) (30.28 mg, 0.09 mmol) in 1,4-dioxane (degassed with N) (0.7 mL) was added BrettPhos Pd G1 MTBE adduct (12.24 mg, 0.02 mmol). The reaction was evacuated, backfilled with N2, and heated in a microwave to 130°C for 1 hour. The crude reaction was filtered through hydrophobic filter paper and rinsed thoroughly with EtOAc. The filtrate was concentrated. The residue was purified by acidic reverse-phase flash chromatography (20 g column, gradient 0–50% MeCN / water, 0.1% HCOH) and the product was recovered by SCX (2× methanol washes, followed by 2× 1 M NH / MeOH washes) to give tert-butyl N-[4-[4-(1,4-oxazepan-4-yl)-5-oxo-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-6-yl]-1,3-benzothiazol-2-yl]carbamate (31 mg, 0.05 mmol, 63% yield) as an orange oil. UPLC-MS (ES + ,Method 2): 1.71 min,m / z 640.3 [M+H] + .

[0374] Step B, 6-(2-amino-1,3-benzothiazol-4-yl)-4-(1,4-oxazepan-4-yl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one Trifluoroacetic acid (0.5 mL, 6.53 mmol) was added to a solution of tert-butyl N-[4-[4-(1,4-oxazepan-4-yl)-5-oxo-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-6-yl]-1,3-benzothiazol-2-yl]carbamate (31 mg, 0.05 mmol) in DCM (0.5 mL), and the mixture was stirred at 25° C. for 2 h. The residue was purified by reverse-phase flash chromatography (12 g column, gradient 0–20% MeCN / water, 0.1% HCOH) and the product was recovered by SCX (2× methanol washes followed by 2× 1 M NH / MeOH washes) to give 6-(2-amino-1,3-benzothiazol-4-yl)-4-(1,4-oxazepan-4-yl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one (17 mg, 0.032 mmol, 65% yield) as an off-white solid. UPLC-MS (ES + ,Method 1): 2.41 min,m / z 540.3 [M+H] + . 1 H NMR (400 MHz,DMSO-d6,) δ / ppm: 7.67 (s,2H),7.63 (dd,J = 7.8,1.2 Hz,1H),7.31 (dd,J = 7.8,1.2 Hz,1H),7.06 (t,J = 7.8 Hz,1H),5.27 (d,J = 53.7 Hz,1H),4.88 (s,2H),4.58-4.25 (m,2H),4.14-3.85 (m,4H),3.82-3.60 (m,4H),3.13-2.98 (m,3H),2.87-2.79 (m,1H),2.14-1.71 (m,8H).

[0375] Example 120, 6-(3-hydroxy-1-naphthyl)-7-methyl-4-(1,4-oxazepan-4-yl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one [ka]

[0376] Step A, Ethyl 4-chloro-2-methylsulfanyl-6-(1,4-oxazepan-4-yl)pyrimidine-5-carboxylate A solution of ethyl 4,6-dichloro-2-(methylthio)pyrimidine-5-carboxylate (4.8 g, 17.9 mmol) and EtN (5.4 g, 53.9 mmol) in anhydrous DMF (20 mL) was added to a stirred solution of 1,4-oxazepane hydrochloride (2.4 g, 17.9 mmol) in anhydrous DMF (10 mL) while cooling in an ice bath. After the addition was complete, the reaction mixture was stirred overnight at room temperature. The mixture was quenched with water (300 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine, dried over NaSO, concentrated in vacuo, and purified by silica gel chromatography (eluting with 20 / 1 petroleum ether / EtOAc) to give ethyl 4-chloro-2-methylsulfanyl-6-(1,4-oxazepan-4-yl)pyrimidine-5-carboxylate as a yellow solid (5.5 g, 92% yield). UPLC-MS (ES + ,Method 4):0.55 min,m / z 332.1 [M+H] + . 1 H NMR (400 MHz,DMSO-d6,) δ / ppm: 4.28 - 4.25 (q,2H),3.79 - 3.56 (m,8H),2.48 (s,3H),1.88 - 1.81 (m,2H),1.27 - 1.25 (t,3H).

[0377] Step B, Ethyl 4-(1-ethoxyvinyl)-2-methylsulfanyl-6-(1,4-oxazepan-4-yl)pyrimidine-5-carboxylate A mixture of ethyl 4-chloro-2-methylsulfanyl-6-(1,4-oxazepan-4-yl)pyrimidine-5-carboxylate (20 g, 60.27 mmol), Pd(PPh)Cl (4.23 g, 6.03 mmol), and tributyl(1-ethoxyvinyl)tin (30.55 mL, 90.41 mmol) in 1,4-dioxane (150 mL) was stirred at 80 °C under N for 4 h. The mixture was quenched with water (1000 mL) and extracted with EtOAc (300 mL × 3), and the combined organic layers were washed with brine, dried over Na2SO4, concentrated in vacuo, and purified by silica gel chromatography (eluted with 4 / 1 petroleum ether / EtOAc) to give ethyl 4-(1-ethoxyvinyl)-2-methylsulfanyl-6-(1,4-oxazepan-4-yl)pyrimidine-5-carboxylate as a yellow oil (42 g, 91% yield). UPLC-MS (ES + ,Method 4):1.83 min,m / z 368.10 [M+H] + .

[0378] Step C, Ethyl 4-acetyl-2-methylsulfanyl-6-(1,4-oxazepan-4-yl)pyrimidine-5-carboxylate A mixture of ethyl 4-(1-ethoxyvinyl)-2-(methylthio)-6-(1,4-oxazepan-4-yl)pyrimidine-5-carboxylate (1.75 g, 4.76 mmol) and 2.5 M HCl (15 mL) in acetone (36 mL) was stirred at room temperature under N2 overnight. The mixture was concentrated in vacuo and purified by silica gel column (10 / 1 to 2 / 1 petroleum ether / EtOAc) to give ethyl 4-acetyl-2-methylsulfanyl-6-(1,4-oxazepan-4-yl)pyrimidine-5-carboxylate (23 g, 65% yield). UPLC-MS (ES + ,Method 4):1.70 min,m / z 340.10 [M+H] +

[0379] Step D, 4-Ethanimidoyl-2-methylsulfanyl-6-(1,4-oxazepan-4-yl)pyrimidine-5-carboxylic acid A mixture of ethyl 4-acetyl-2-methylsulfanyl-6-(1,4-oxazepan-4-yl)pyrimidine-5-carboxylate (20 g, 58.93 mmol) and titanium(IV) isopropoxide (34.89 mL, 117.85 mmol) in 7N NH₃MeOH (100 mL) was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure, and the crude product, 4-ethanimidoyl-2-methylsulfanyl-6-(1,4-oxazepan-4-yl)pyrimidine-5-carboxylic acid, was used directly in the next step. UPLC-MS (ES + ,Method 4): 1.06 min,m / z 311.05 [M+H] + .

[0380] Step E, 7-methyl-2-methylsulfanyl-4-(1,4-oxazepan-4-yl)-6,7-dihydropyrrolo[3,4-d]pyrimidin-5-one A mixture of 4-ethanimidoyl-2-methylsulfanyl-6-(1,4-oxazepan-4-yl)pyrimidine-5-carboxylic acid (20 g, 64.44 mmol) in NH3 (7N) / MeOH (50 mL) was cooled to 0 °C, and NaBH4 (7.3 g, 193.32 mmol) was added. The resulting mixture was allowed to warm to room temperature and stirred overnight. The mixture was quenched with water, extracted with EtOAc, dried over Na2SO4, filtered, concentrated in vacuo, and purified by silica gel column (DCM / MeOH, 80 / 1 to 20 / 1) to give 7-methyl-2-methylsulfanyl-4-(1,4-oxazepan-4-yl)-6,7-dihydropyrrolo[3,4-d]pyrimidin-5-one (1.7 g, 9% yield) as a yellow oil. UPLC-MS (ES + ,Method 4): 1.278 min,m / z 295.10 [M+H] + .

[0381] Step F, 6-[3-(methoxymethoxy)-1-naphthyl]-7-methyl-2-methylsulfanyl-4-(1,4-oxazepan-4-yl)-7H-pyrrolo[3,4-d]pyrimidin-5-one A mixture of 1-bromo-3-(methoxymethoxy)naphthalene (272.23 mg, 1.02 mmol), 7-methyl-2-methylsulfanyl-4-(1,4-oxazepan-4-yl)-6,7-dihydropyrrolo[3,4-d]pyrimidin-5-one (200 mg, 0.68 mmol), CsCO (663.7 mg, 2.04 mmol), t-BuBrettPhos (72.94 mg, 0.14 mmol), and BrettPhos Pd G1 (108.55 mg, 0.14 mmol) in 1,4-dioxane (30 mL) was stirred at 100 °C overnight. The mixture was quenched with water (150 mL) and extracted with EtOAc (50 mL × 3), and the combined organic layers were washed with brine, dried over NaSO, concentrated in vacuo, and purified by silica gel chromatography (eluting with 30 / 1 DCM / MeOH) to give 6-[3-(methoxymethoxy)-1-naphthyl]-7-methyl-2-methylsulfanyl-4-(1,4-oxazepan-4-yl)-7H-pyrrolo[3,4-d]pyrimidin-5-one (140 mg, 43% yield) as a yellow solid. UPLC-MS (ES + ,Method 3): 1.969 min,m / z 481.2[M+H] + .

[0382] Step G, 6-[3-(methoxymethoxy)-1-naphthyl]-7-methyl-2-methylsulfonyl-4-(1,4-oxazepan-4-yl)-7H-pyrrolo[3,4-d]pyrimidin-5-one A mixture of 6-[3-(methoxymethoxy)-1-naphthyl]-7-methyl-2-methylsulfanyl-4-(1,4-oxazepan-4-yl)-7H-pyrrolo[3,4-d]pyrimidin-5-one (110 mg, 0.23 mmol) in DCM (15 mL) was cooled to 0 °C, m-chloroperbenzoic acid (118.49 mg, 0.69 mmol) was added, and the mixture was stirred at room temperature for 2 h. Saturated aqueous NaSO (30 mL) was added. After stirring for 15 min, the mixture was diluted with DCM (50 mL), the layers were separated, and the organic layer was washed with saturated aqueous bicarbonate (2 × 50 mL) and brine (300 mL). The combined organic layers were dried over sodium sulfate, concentrated in vacuo, and purified by silica gel chromatography (eluting with 50 / 1 DCM / MeOH) to give 6-[3-(methoxymethoxy)-1-naphthyl]-7-methyl-2-methylsulfonyl-4-(1,4-oxazepan-4-yl)-7H-pyrrolo[3,4-d]pyrimidin-5-one (100 mg, 85% yield) as a pale yellow solid. UPLC-MS (ES + ,Method 3): 2.09 min,m / z 513.2 [M+H] + .

[0383] Step H, 6-[3-(methoxymethoxy)-1-naphthyl]-7-methyl-4-(1,4-oxazepan-4-yl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one A mixture of ((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methanol (46.59 mg, 0.29 mmol) and NaH (23.41 mg, 0.59 mmol) in THF (12 mL) was stirred at 0 °C under N2 for 30 min, and 6-[3-(methoxymethoxy)-1-naphthyl]-7-methyl-2-methylsulfonyl-4-(1,4-oxazepan-4-yl)-7H-pyrrolo[3,4-d]pyrimidin-5-one (100 mg, 0.2 mmol) was added and stirred at room temperature for 1 h. The reaction mixture was poured into saturated ammonium chloride solution at 0 °C, diluted with water (100 mL), and extracted with DCM (30 mL × 3). The combined organic layers were washed with brine, dried over sodium sulfate, concentrated in vacuo, and purified by silica gel column chromatography (DCM / MeOH 30 / 1) to give 6-[3-(methoxymethoxy)-1-naphthyl]-7-methyl-4-(1,4-oxazepan-4-yl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one (40 mg, 34% yield) as a white solid. UPLC-MS (ES + ,Method 4): 1.247 Method,m / z 592.2 [M+H] + .

[0384] Step I, 6-(3-hydroxy-1-naphthyl)-7-methyl-4-(1,4-oxazepan-4-yl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one (Example 120) A mixture of 6-[3-(methoxymethoxy)-1-naphthyl]-7-methyl-4-(1,4-oxazepan-4-yl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one (35 mg, 0.06 mmol) and HCl (4N) in dioxane (1.5 mL) in methanol (1 mL) was stirred at room temperature for 1 hour. The pH of the resulting mixture was adjusted to 8 with saturated sodium carbonate solution and extracted with EtOAc (20 mL × 3). The combined organic layers were washed with brine, dried over NaSO, and concentrated under reduced pressure to give the crude product, which was purified by preparative HPLC to give 6-(3-hydroxy-1-naphthyl)-7-methyl-4-(1,4-oxazepan-4-yl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one (7 mg, 21% yield) as a white solid. UPLC-MS (ES + ,Method 4): 0.97 min,m / z 548.3 [M+H] + . 1 H NMR (400 MHz,DMSO-d6,) δ / ppm: 10.79 (s,1H),7.78 (dd,J = 18.1,8.4 Hz,1H),7.62 - 7.38 (m,2H),7.31 - 6.97 (m,3H),5.59 (d,J = 52.3 Hz,1H),4.91 (dd,J = 115.2,7.1 Hz,1H),4.62 - 4.46 (m,2H),4.07 - 3.62 (m,10H),3.33 (s,3H),2.69 - 2.53 (m,1H),2.41 - 1.70 (m,7H),1.28 (dd,J = 49.7,7.1 Hz,3H).

[0385] Example 166, 6-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-4-(1,4-oxazepan-4-yl)-2-prop-2-ynoxy-7H-pyrrolo[3,4-d]pyrimidin-5-one [ka] Example 166 was synthesized according to the reaction conditions of Step D of Example 1 (Scheme 15), replacing I-16 with 6-[8-ethyl-7-fluoro-3-(methoxymethyloxy)-1-naphthyl]-4-(1,4-oxazepan-4-yl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one. UPLC-MS (ES + ,Method 1): 3.68 min,m / z 477.7 [M+H] + . 1 H NMR (400 MHz,DMSO-d6,) δ / ppm: 9.94 (br. s,1H),7.73 (dd,J=6.0,9.1 Hz,1H),7.33 (t,J=9.4 Hz,1H),7.26 (d,J=2.6 Hz,1H),7.17 (d,J=2.6 Hz,1H),5.03 (br. s,2H),4.74 - 4.53 (m,3H),4.42 - 4.21 (m,1H),4.10 - 3.75 (m,3H),3.71 - 3.60 (m,3H),3.56 (t,J=2.4 Hz,1H),2.93 - 2.83 (m,1H),2.76 - 2.66 (m,1H),2.07 - 1.76 (m,2H),1.02 (t,J=7.4 Hz,3H).

[0386] Example 172, 6-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-4-phenyl-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one [ka]

[0387] Step A, tert-butyl 2-chloro-4-phenyl-5,7-dihydropyrrolo[3,4-d]pyrimidine-6-carboxylate To a solution of tert-butyl 2,4-dichloro-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (500 mg, 1.72 mmol), 4,4,5,5-tetramethyl-2-phenyl-1,3,2-dioxaborolane (386.86 mg, 1.9 mmol), and potassium phosphate, tribasic acid (1097.37 mg, 5.17 mmol) in 1,4-dioxane (degassed) (3.6 mL) and water (0.4 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride dichloromethane complex (140.73 mg, 0.17 mmol). The reaction was evacuated, refilled with nitrogen, and heated to 100 °C for 4 h. The reaction was diluted with EtOAc, passed through a layer-separating filter paper, and concentrated to dryness. The crude product was then purified by column chromatography (eluting with 100% petroleum ether to 100% EtOAc) to give tert-butyl 2-chloro-4-phenyl-5,7-dihydropyrrolo[3,4-d]pyrimidine-6-carboxylate (349 mg, 1.05 mmol, 61% yield) as a white solid. UPLC-MS (ES + ,Method 2): 2.24 min,m / z 332.2 [M+H] + .

[0388] Step B, tert-butyl 2-chloro-5-oxo-4-phenyl-7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate To a solution of tert-butyl 2-chloro-4-phenyl-5,7-dihydropyrrolo[3,4-d]pyrimidine-6-carboxylate (349 mg, 1.05 mmol) and sodium periodate (674.93 mg, 3.16 mmol) in ethyl acetate (30 mL) and water (30 mL) was added ruthenium chloride (32.73 mg, 0.16 mmol), and the reaction was stirred for 4 hours. The reaction was filtered through a pad of Celite, washed with EtOAc, and the layers were separated. The organic layer was passed through a layer-separating filter paper and concentrated to dryness. The crude product was then purified by column chromatography (eluting with 100% petroleum ether to 50% EtOAc / petroleum ether) to give tert-butyl 2-chloro-5-oxo-4-phenyl-7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (147 mg, 0.43 mmol, 40% yield) as a white solid. UPLC-MS (ES + ,Method 2): 2.04 min,m / z 368.0 [M+Na] + .

[0389] Step C, tert-butyl 5-oxo-4-phenyl-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate To a solution of tert-butyl 2-chloro-5-oxo-4-phenyl-7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (147 mg, 0.4 mmol) and ((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methanol (135.36 mg, 0.85 mmol) in 1,4-dioxane (20 mL) was added potassium carbonate (117.51 ​​mg, 0.85 mmol) and the reaction was stirred at 100° C. for 4 hours. The reaction was diluted with EtOAc, passed through layer-separating filter paper, and concentrated to dryness. The crude product was then purified by column chromatography (eluting with 100% DCM to 20% MeOH / DCM) to give tert-butyl 5-oxo-4-phenyl-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (176 mg, 0.38 mmol, 88% yield) as a yellow solid. UPLC-MS (ES + ,Method 2): 1.53 min,m / z 469.2 [M+H] + .

[0390] Step D, 4-phenyl-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-6,7-dihydropyrrolo[3,4-d]pyrimidin-5-one To a solution of tert-butyl 5-oxo-4-phenyl-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (176 mg, 0.38 mmol) in DCM() was added trifluoroacetic acid (0.29 mL, 3.76 mmol) and the reaction was stirred at room temperature for 90 minutes. The reaction was concentrated under reduced pressure and purified by flash column chromatography (KP-NH column, eluting with 100% DCM to 20% MeOH / DCM) to afford 4-phenyl-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-6,7-dihydropyrrolo[3,4-d]pyrimidin-5-one (95 mg, 0.26 mmol, 69% yield) as an orange oil. UPLC-MS (ES + ,Method 2): 1.23 min,m / z 369.1 [M+H] + .

[0391] Step E, 6-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-4-phenyl-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one To a solution of 4-phenyl-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-6,7-dihydropyrrolo[3,4-d]pyrimidin-5-one (95 mg, 0.26 mmol), cesium carbonate (168.04 mg, 0.52 mmol), and [8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]trifluoromethanesulfonate (138.03 mg, 0.36 mmol) in toluene (degassed with N) (4 mL) was added Xantphos Pd G3 (24.45 mg, 0.03 mmol), and the reaction was heated to 110 °C for 4 h. The reaction was diluted with EtOAc, passed through a layer-separating filter paper, and concentrated. The crude product was then purified by column chromatography (eluting with 100% petroleum ether to 100% DCM and to 20% MeOH / DCM) to give 6-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-4-phenyl-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one (72 mg, 0.12 mmol, 46% yield) as an orange oil. UPLC-MS (ES + ,Method 2): 1.79 min,m / z 601.3 [M+H] + .

[0392] Step F, 6-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-4-phenyl-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one To a solution of 6-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-4-phenyl-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one (72 mg, 0.12 mmol) in DCM (2 mL) was added triethylsilane (0.1 mL, 0.6 mmol) and trifluoroacetic acid (0.46 mL, 5.99 mmol), and the reaction was stirred at 25 °C for 4 h. The reaction was diluted with MeOH, loaded onto an SCX cartridge, washed with MeOH, and eluted with 1 M NH3 / MeOH. The eluted washes were concentrated to dryness. This was then purified by column chromatography (KP-NH column, eluted with 100% DCM to 10% MeOH / DCM) to give 6-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-4-phenyl-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one (47 mg, 0.08 mmol, 70% yield) as a beige solid. UPLC-MS (ES + ,Method 1): 2.80 min,m / z 557.6 [M+H] + . 1 H NMR (400 MHz,DMSO-d6,) δ / ppm: 9.98 (s,1H),8.25 - 8.22 (m,2H),7.78 - 7.73 (m,1H),7.61 - 7.49 (m,3H),7.38 - 7.26 (m,3H),5.40 - 5.23 (m,1H),4.93 (s,2H),4.32 - 4.19 (m,2H),3.18 - 3.03 (m,3H),2.94 - 2.82 (m,2H),2.76 - 2.65 (m,1H),2.26 - 2.01 (m,3H),1.92 - 1.77 (m,3H),1.03 (t,J=7.5 Hz,3H).

[0393] Example 181, 6-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-2-[[(2S,8R)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-4-(3-oxo-1,4-diazepan-1-yl)-7H-pyrrolo[3,4-d]pyrimidin-5-one [ka] PI-3 was synthesized following a procedure similar to that of Example 69 (Scheme 22), replacing N-Boc-4-(methylamino)piperidine with 1-[(4-methoxyphenyl)methyl]-1,4-diazepan-2-one in Step B. Example 181 was prepared by a method similar to that of Example 176, replacing PI-3 with 6-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-2-[[(2S,8R)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-4-[1-[(4-methoxyphenyl)methyl]-6,7-dihydro-4H-pyrazolo[4,5-c]pyridin-5-yl]-7H-pyrrolo[3,4-d]pyrimidin-5-one (Example 175). UPLC-MS (ES + ,Method 1): 2.53 min,m / z 593.5 [M+H] + . 1 H NMR (400 MHz,DMSO-d6,) δ / ppm: 9.94 (s,1H),7.70-7.77 (m,1H),7.48-7.55 (br s,1H),7.29-7.36 (m,1H),7.25-7.28 (m,1H),7.14-7.18 (m,1H),5.22-5.36 (m,1H),4.61-4.74 (m,2H),4.29-4.49 (m,2H),4.07-4.29 (m,3H),2.98-3.21 (m,5H),2.79-2.98 (m,2H),2.68-2.76 (m,1H),1.69-2.16 (m,9H),0.97-1.06 (m,3H).

[0394] Example 196, 6-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one [ka]

[0395] Step A, tert-butyl 2-chloro-5,7-dihydropyrrolo[3,4-d]pyrimidine-6-carboxylate To a solution of tert-butyl 2,4-dichloro-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (1000 mg, 3.45 mmol) and zinc powder (901.36 mg, 13.79 mmol) in methanol (30 mL) was added acetic acid (1.97 mL, 34.47 mmol), and the reaction was stirred at 65 °C for 2 h. The reaction was cooled, decanted, and concentrated to dryness. The crude product was then stirred in EtOAc:water and filtered through a Celite pad. The organic layer was extracted, passed through a layer-separating filter paper, and concentrated to dryness. The crude product was purified by column chromatography (petroleum ether to EtOAc) to afford tert-butyl 2-chloro-5,7-dihydropyrrolo[3,4-d]pyrimidine-6-carboxylate (251 mg, 0.98 mmol, 28% yield) as an off-white solid. UPLC-MS (ES + ,Method 2): 1.71 min,m / z 256.0 [M+H] + .

[0396] Step B, tert-butyl 2-chloro-5-oxo-7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate To a solution of tert-butyl 2-chloro-5,7-dihydropyrrolo[3,4-d]pyrimidine-6-carboxylate (251 mg, 0.98 mmol) and ruthenium chloride (30.54 mg, 0.15 mmol) in ethyl acetate (6 mL) and water (6 mL), sodium periodate (629.88 mg, 2.94 mmol) was added, and the reaction was stirred at room temperature for 4 hours. The reaction was diluted with EtOAc and filtered through a Celite pad. The organic layer was extracted, passed through a layer-separating filter paper, and concentrated to dryness. The crude product was then purified by column chromatography (petroleum ether to EtOAc) to afford tert-butyl 2-chloro-5-oxo-7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (180 mg, 0.67 mmol, 68% yield) as a white solid. UPLC-MS (ES + ,Method 2): 1.70 min,m / z 291.9 [M+Na] + .

[0397] Step C, tert-butyl 5-oxo-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate To a solution of tert-butyl 2-chloro-5-oxo-7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (90 mg, 0.33 mmol) and ((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methanol (106.26 mg, 0.67 mmol) in 1,4-dioxane (7 mL) was added potassium carbonate (92.25 mg, 0.67 mmol) and the reaction was stirred at 100° C. for 4 hours. The reaction was diluted with EtOAc, passed through layer-separating filter paper, and concentrated to dryness. The crude product was then purified by column chromatography (eluting with 100% DCM to 20% MeOH / DCM) to give tert-butyl 5-oxo-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (113 mg, 0.29 mmol, 86% yield) as a red solid. UPLC-MS (ES + ,Method 2): 1.25 min,m / z 393.2 [M+H] + .

[0398] Step D, 2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-6,7-dihydropyrrolo[3,4-d]pyrimidin-5-one To a solution of tert-butyl 5-oxo-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (113 mg, 0.29 mmol) in DCM (6 mL) was added trifluoroacetic acid (0.22 mL, 2.88 mmol) and the reaction was stirred at room temperature for 90 minutes. The reaction was concentrated under reduced pressure and purified by flash column chromatography (KP-NH column, eluting with 100% DCM to 20% MeOH / DCM) to give 2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-6,7-dihydropyrrolo[3,4-d]pyrimidin-5-one (68 mg, 0.23 mmol, 81% yield) as an orange oil. UPLC-MS (ES + ,Method 2): 0.97 min,m / z 293.0 [M+H] + .

[0399] Step E, 6-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one To a solution of 2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-6,7-dihydropyrrolo[3,4-d]pyrimidin-5-one (42 mg, 0.14 mmol), cesium carbonate (93.63 mg, 0.29 mmol), and [8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]trifluoromethanesulfonate (76.91 mg, 0.2 mmol) in toluene (degassed with N) (4 mL) was added Xantphos Pd G3 (13.63 mg, 0.01 mmol), and the reaction was heated to 110 °C for 4 h. The reaction was diluted with EtOAc, passed through layer-separating filter paper, and concentrated. The crude product was then purified by column chromatography (eluting with 100% petroleum ether to 100% to 20% MeOH / DCM) to give 6-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one (62 mg, 0.12 mmol, 82% yield) as a yellow oil. UPLC-MS (ES + ,Method 2): 1.63 min,m / z 525.2 [M+H] + .

[0400] Step F, 6-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one To a solution of 6-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one (62 mg, 0.12 mmol) in DCM (2 mL) was added triethylsilane (0.09 mL, 0.59 mmol) and trifluoroacetic acid (0.45 mL, 5.91 mmol), and the reaction was stirred for 4 h at 25° C. The reaction was diluted with MeOH and loaded onto an SCX cartridge (washed with MeOH, eluted with 1 M NH3 / MeOH). The eluted wash was concentrated to dryness and purified by column chromatography (KP-NH modified column, eluted with 100% DCM to 10% MeOH / DCM) to give 6-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolidin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one (34 mg, 0.07 mmol, 59.8% yield) as an orange solid. UPLC-MS (ES + ,Method 1): 2.73 min...

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof: 【Chemistry 1】 [In the formula, Z １ are independently —O— and —NR ５ - selected from; Z ２ are independently absent or —O— and —NR ６ - selected from; L １ is a bond and -C(R １８ ) ２ Selected from - X １ is -C(R ３ａ ) ２ and -NR ３ｂ - selected from; R １ is independent, C ０ ~C ３ -Alkylene-R １ａ and C ２ ~C ６ -Alkylene-R １ｂ wherein R １ａ are independently a 4- to 7-membered heterocycloalkyl ring; a phenyl ring; and NR ７ R ８ C optionally substituted with a group ３ ~C ７ -cycloalkyl ring; wherein said heterocycloalkyl ring, said phenyl ring or said cycloalkyl ring is selected from 1 to 4 R ９ optionally substituted with R １ｂ is independent, NR ７ R ８ , OR ８ , S.R. ８ , SOR ８ , S.O. ２ R ８ and SO(NH)R ８ Selected from; Or R １ and R ５ together with the nitrogen to which they are attached, form one to four 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, spirofused or bridged bicyclic 6- to 11-membered heterocyclyl groups, optionally substituted with a group; R ２ is independent, 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 are independently 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; C ３ ~C ７ -cycloalkyl; where R is either heterocycloalkyl or cycloalkyl. ２ａ The group is composed of 1 to 6 R １０ R is optionally substituted with a heteroaryl or phenyl group. ２ａ The group is composed of 1 to 6 R １１ optionally substituted with groups; Here, R ２ｂ is independent, CONR １２ R １２ and CO ２ R １２ Selected from: Here, R ２ｃ is independent, NR １２ R １３ and OR １２ 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, spirofused, or bridged bicyclic 6- to 11-membered heterocycloalkyl groups; said heterocycloalkyl groups being selected from 1 to 6 R １０ optionally substituted with groups; R ３ａ are independently generated for each occurrence, H, C １ ~C ４ -Alkyl, C １ ~C ４ -haloalkyl, NR １２ R １３ C substituted with １ ~C ４ -Alkyl, OR １２ C substituted with １ ~C ４ -Alkyl, C ２ ~C ４ -alkenyl, C ２ ~C ４ -alkynyl, C １ ~C ４ -haloalkyl and cyclopropyl; or wherein two R ３ａ groups, taken together with the carbons to which they are attached, form a spiro-fused cyclopropyl group; R ３ｂ are independently H, C １ ~C ４ -Alkyl, C １ ~C ４ - selected from haloalkyl and cyclopropyl; R ４ is independently phenyl, and said phenyl is optionally C ５ ~C ７ - selected from phenyl optionally fused to a cycloalkyl ring; naphthyl; monocyclic 4- to 7-membered cycloalkyl or heterocycloalkyl; and 5- to 10-membered monocyclic or bicyclic heterocyclyl; wherein R ４ is 1 to 4 R １４ optionally substituted with groups; R ５ , R ６ , R ８ and R １２ are independently expressed as H, C for each occurrence. １ ~C ４ -haloalkyl, cyclopropyl and C １ ~C ４ - selected from alkyl; R ７ and R １３ are independently expressed as H, C for each occurrence. １ ~C ４ -Alkyl, C １ ~C ４ -haloalkyl and C(O)-C １ ~C ４ - selected from alkyl; Or R １２ and R １３ together with the nitrogen to which they are attached form a ring system selected from monocyclic 4- to 7-membered heterocycloalkyl groups; and fused, spirofused, or bridged bicyclic 6- to 11-membered heterocycloalkyl groups; said heterocycloalkyl groups being selected from 1 to 6 R １０ optionally substituted with groups; R ９ independently at each occurrence, represents oxo, halo, cyano, NR １２ R １３ , OR １２ , C.O.R. １２ , CO ２ R １２ , C.O.R. １２ R １２ , C.O.R. １２ R １３ , C １ ~C ４ -Alkyl, NR １２ R １３ C substituted with １ ~C ４ -Alkyl, OR １２ C substituted with １ ~C ４ -C substituted with alkyl, cyano １ ~C ４ -C substituted with alkyl, phenyl １ ~C ４ -Alkyl, C ２ ~C ４ -alkenyl, C ２ ~C ４ -alkynyl, C １ ~C ４ - selected from haloalkyl and cyclopropyl; R １０ independently at each occurrence, represents oxo, halo, cyano, NR １２ R １３ , OR １２ , C.O.R. １２ , CO ２ R １２ , C.O.R. １２ R １２ , C １ ~C ４ -Alkyl, NR １２ R １３ C substituted with １ ~C ４ -Alkyl, OR １２ C substituted with １ ~C ４ -C substituted with alkyl, cyano １ ~C ４ -C substituted with alkyl, phenyl 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 are independently halo, cyano, nitro, NR １２ R １３ , OR １２ , CO ２ R １２ , C.O.R. １２ R １２ , C １ ~C ４ -Alkyl, NR １２ R １３ C substituted with １ ~C ４ -Alkyl, OR １２ C substituted with １ ~C ４ -alkyl, monocyclic 4- to 7-membered cycloalkyl or heterocycloalkyl, C ２ ~C ４ -alkenyl, C ２ ~C ４ -alkynyl, C １ ~C ４ - selected from haloalkyl and cyclopropyl; R １４ independently at each occurrence, H, halo, cyano, nitro, NR １２ R １３ , OR １２ , CO ２ R １２ , C.O.R. １２ R １２ , C １ ~C ４ -Alkyl, NR １２ R １３ C substituted with １ ~C ４ -Alkyl, OR １２ C substituted with １ ~C ４ -Alkyl, C ２ ~C ４ -alkenyl, C ２ ~C ４ -alkynyl, C １ ~C ４ selected from haloalkyl, phenyl and cyclopropyl; R １８ independently at each occurrence, H, halo, cyano, nitro, NR １２ R １３ , OR １２ , CO ２ R １２ , C.O.R. １２ R １２ , C １ ~C ４ -Alkyl, NR １２ R １３ C substituted with １ ~C ４ -Alkyl, OR １２ C substituted with １ ~C ４ -Alkyl, C ２ ~C ４ -alkenyl, C ２ ~C ４ -alkynyl, C １ ~C ４ -haloalkyl and cyclopropyl; or wherein two R １８ groups, taken together with the carbons to which they are attached, form a spiro-fused cyclopropyl group; wherein any of the aforementioned alkyl, alkylene, phenyl or cyclopropyl groups may be optionally substituted, where chemically possible, with from 1 to 5 substituents independently selected at each occurrence from the group consisting of: １ ~C ４ -Alkyl, OR ａ C substituted with １ ~C ４ -Alkyl, halo, nitro, cyano, NR ａ R ｂ , OR ａ , S.R. ａ , CO ２ R ａ , C(O)R ａ , C.O.R. ａ R ａ ; where R ａ are independently generated for each occurrence, H, C １ ~C ４ -Alkyl and C １ ~C ４ -haloalkyl; R ｂ are independently generated for each occurrence, H, C １ ~C ４ -alkyl, C(O)-C １ ~C ４ -Alkyl and S(O) ２ -C １ ~C ４ -alkyl].

2. R １ and R ５ But NR １ R ５ is selected to contain only one amine, which may be a primary, secondary, or tertiary amine.

3. R １ and R ５ together with the nitrogen to which they are attached, form 1 to 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 heterocyclyl group, optionally substituted with a group; and one to four R ９ a bridged bicyclic 6- to 11-membered heterocyclyl group, optionally substituted with a group; １ and R ５ 3. The compound of claim 1 or claim 2, wherein the nitrogen to which is attached is the only nitrogen in the ring system.

4. R １ and R ５ together with the nitrogen to which they are attached, form 1 to 4 R ９ a monocyclic 4- to 7-membered heterocycloalkyl group optionally substituted with a group; ９ 4. The compound according to any one of claims 1 to 3, wherein the compound forms a ring system selected from: a fused or spiro-fused bicyclic 6- to 11-membered heterocycloalkyl group, optionally substituted with a group.

5. R １ and R ５ together with the nitrogen to which they are attached to form the structure: 【Chemistry 2】 The compound of claim 4, which forms a ring system having the formula [In the formula, R ９ａ is NR １２ R １３ , and N.R. １２ R １３ C substituted with １ ~C ４ -alkyl; p1 is selected from 0, 1, 2 and 3, q1 is selected from 0, 1 and 2; r1 is selected from 0, 1, 2 and 3].

6. R １ and R ５ together with the nitrogen to which they are attached to form the structure: 【Transformation 3】 The compound of claim 4, which forms a ring system having the formula [In the formula, Z ６ are independently C(O)NR ９ｂ , N.R. ９ｂ , O, S, S(O) ２ , S(O), S(O)(NR ９ｂ ) and S(O)(NH); R ９ｂ is H and C １ ~C ４ -alkyl; p2 is selected from 2 and 3, q2 is 2; r2 is selected from 0, 1, 2 and 3.

7. R １ and R ５ together with the nitrogen to which they are attached to form the structure: 【Chemistry 4】 The compound of claim 6, which forms a ring system having the formula [In the formula, Z ６ are independently C(O)NR ９ｂ , O, S, S(O) ２ , S(O), S(O)(NR ９ｂ ), S(O)(NH) and NR ９ｂ is selected from: R ９ｂ independently for each occurrence, H and C １ ~C ４ -alkyl; n6 is an integer selected from 0, 1, 2, 3 and 4.

8. Z ６ The compound of claim 7 , wherein

9. R ２ The structure: 【Transformation 5】 The compound according to any one of claims 1 to 8, having the formula [In the formula, R １５ are independently H, C １ ~C ４ -alkyl; where R １６ are independently H, C １ ~C ４ -alkyl and cyclopropyl; or where R １５ and R １６ together with the atoms to which they are attached, form one or two R １０ and y is independently selected from 0, 1, 2, 3, and 4.

10. R ２ The structure: 【Transformation 6】 The compound of claim 9 having the formula: wherein z is independently selected from 0, 1, 2, 3, and 4.

11. L １ The compound of any one of claims 1 to 10, wherein is a bond.

12. L １ -C(R １８ ) ２ The compound according to any one of claims 1 to 10, wherein

13. R １８ 13. The compound of claim 12, wherein each occurrence is H.

14. X １ -C(R ３ａ ) ２ The compound according to any one of claims 1 to 13, wherein

15. R ３ａ independently for each occurrence, H, C １ ~C ４ -Alkyl, C １ ~C ４ -haloalkyl, and cyclopropyl; or two R ３ａ 15. The compound of claim 14, wherein the groups, together with the carbon to which they are attached, form a spiro-fused cyclopropyl group.

16. R ３ａ 15. The compound of claim 13 or 14, wherein each occurrence is H.

17. X １ Ga-NR ３ｂ The compound according to any one of claims 1 to 13, wherein

18. R ３ｂ is H and C １ ~C ４ - alkyl.

19. R ４ is phenyl, and said phenyl is C ５ ~C ７ - optionally fused to a cycloalkyl ring, R ４ 1 to 4 R １４ The compound according to any one of claims 1 to 18, optionally substituted with a group.

20. R ４ The structure: 【Transformation 7】 The compound according to any one of claims 1 to 18, having the formula wherein x is independently selected from 0, 1, 2, 3, and 4.

21. R ４ The structure: 【Transformation 8】 The compound of claim 20 having the formula: [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.

22. R ４ But 1 to 4 R １４ The compound of any one of claims 1 to 18, which is a 5-, 6-, 9- or 10-membered, monocyclic or bicyclic heteroaryl optionally substituted with a group.

23. 10. The compound of claim 1, wherein the compound of formula (I) is selected from the following compounds: 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 [Chemistry 18] 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】

24. A compound according to any one of claims 1 to 23 for pharmaceutical use.

25. A compound according to any one of claims 1 to 23 for use in the treatment of cancer.

26. 26. The use of a compound according to claim 25, 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.

27. 27. The compound for use according to claim 25 or 26, wherein the subject to be treated has a cancer with wild-type KRAS.

28. 27. The compound for use according to claim 25 or 26, wherein the subject to be treated has a cancer with a KRAS mutation selected from KRAS G12D, KRAS G12C, KRAS G12V, KRAS G12A, KRAS G12S, KRAS G13D and KRAS Q61H.

29. A pharmaceutical composition comprising a compound according to any one of claims 1 to 23 and a pharmaceutically acceptable excipient.

Images