Compounds

Abstract

The present invention relates to compounds useful for inhibiting RAS proteins. More specifically, the present invention relates to compounds that inhibit broad spectrum KRAS muteins. Thus, the compounds of the invention are useful in the treatment of conditions mediated by the KRAS protein. For example, these compounds are useful in the treatment of cancer. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to compounds and methods of use thereof. In particular, the compounds of the present invention can be used to inhibit RAS proteins. More specifically, the present invention relates to compounds that inhibit a broad spectrum of KRAS proteins, including mutant and wild-type KRAS. Thus, the compounds of the present invention can be used to treat conditions mediated by KRAS proteins. For example, these compounds can be used to treat cancer. Background Art

[0002] RAS (HRAS, KRAS4A and KRAS4B and NRAS) proteins are a group of closely related monomeric globular proteins that act as molecular switches, cycling between inactive (GDP-bound) and active (GTP-bound) states, transducing upstream cellular signals to downstream effectors to regulate a variety of processes, including cell proliferation. RAS is the most commonly mutated oncogene in cancer (about 30%), and KRAS is the most commonly mutated isoform, accounting for about 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 results in the substitution of glycine (G) for aspartic acid at codon 12 and is the most prevalent, accounting for approximately 26% of all KRAS mutations in cancer. KRAS G12D mutations are present in 36% of pancreatic cancer patients, 13% of colorectal cancer patients, 10% of rectal cancer patients, 6% of endometrial cancer patients, 4% of non-small cell lung cancer patients, 4% of gastric cancer patients, 3% of ovarian cancer patients, and 2% of small cell lung cancer patients (e.g., The AACR Project GENIEConsortium, (2017) Cancer Discovery; 7(8):818-831. Dataset Version 8). Many of these patients with G12D mutations have a high unmet need and few options for effective targeted therapies. For many of these patients, the mainstay of treatment remains combination chemotherapy, which is associated with a high level of side effects and a lack of efficacy.

[0004] Other KRAS missense gains of KRAS functional mutations that result in amino acid substitutions at codons 12, 13, and 61, as well as amplification of KRAS wild-type proteins, also drive carcinogenesis. KRAS alterations are found in approximately one-seventh of cancers (Hoffman et al., Cancer Discovery (2022) 12, 924-937). KRAS activating mutations are very common in solid tumors and are 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 common KRAS mutations and are found in more than half of all KRAS-driven 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 alterations and commonly occurs in ovarian, breast, lung, gastric, uterine, and esophagogastric cancers (reviewed by Hoffman). Pan-KRAS inhibitors have the potential to treat a wider range of patient populations, including cancers harboring KRAS mutations, cancers with KRAS wild-type amplification, and cancers caused by loss of the tumor suppressor NF1. In addition, pan-KRAS inhibitors could potentially be used to treat cancers that have acquired resistance to allele-specific inhibitors, such as KRAS G12C inhibitors.

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

[0006] Compounds capable of modulating G12D mutant KRAS are described in WO2021 / 041671. Compounds capable of modulating multiple RAS isoforms and mutants have also been described (Kessler et al., 2019), however, these compounds are considered to have limited therapeutic benefit due to a lack of sufficient potency and minimal selectivity between KRAS and 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] In addition, certain embodiments of the present invention aim to provide novel compounds for treating conditions regulated by RAS proteins. For example, certain embodiments of the present invention aim to provide compounds for treating cancer. Compared to prior art compounds, the compounds are more selective between KRAS proteins with the G12D mutation and alternative KRAS proteins. Alternatively, the compounds may have broad-spectrum activity against a range of KRAS proteins.

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

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

[0011] Another object of certain embodiments of the present invention is to provide compounds having convenient pharmacokinetic characteristics and suitable duration of action after administration.Another object of certain embodiments of the present invention is to provide compounds wherein the metabolic fragments after drug absorption are GRAS (generally recognized as safe).

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

[0013] According to the present invention, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0014]

[0015] Z 1 Independently selected from -O- and -NR 5 -;

[0016] Z 2 Independently absent or selected from -O- and -NR 6 -;

[0017] L 1 Selected from bonds and -C(R 18 )2-

[0018] X 1 Selected from -C(R 3a )2 and -NR 3b -;

[0019] R 1 Independently selected from C0-C3-alkylene-R 1a and C2-C6-alkylene-R 1b ; where R 1a independently selected from a 4- to 7-membered heterocycloalkyl ring; a benzene ring; and optionally NR 7 R 8 wherein the heterocycloalkyl ring, the benzene ring or the cycloalkyl ring is optionally substituted with 1 to 4 R 9 Group substitution; R 1b Independently selected from the following: NR 7 R 8 , OR 8 SR 8 、SOR 8 、SO2R 8 and SO(NH)R 8 ;

[0020] or R 1 and R 5 Together with the nitrogen to which they are attached, they form a ring system selected from: optionally substituted by 1 to 4 R 9 a monocyclic 4 to 7 membered heterocycloalkyl group substituted with a group; and optionally substituted with 1 to 4 R 9 a substituted fused, spirofused or bridged bicyclic 6- to 11-membered heterocyclyl;

[0021] 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 ;

[0022] R 2a is independently selected from monocyclic 4 to 7 membered heterocycloalkyl; fused, spirofused or bridged bicyclic 6 to 11 membered heterocycloalkyl; 5, 6, 9 or 10 membered monocyclic or bicyclic heteroaryl; phenyl; C3-C7-cycloalkyl; wherein any heterocycloalkyl or cycloalkyl R 2a The group is optionally substituted by 1 to 6 R 10 group substituted, and any heteroaryl or phenyl R 2a The group is optionally substituted by 1 to 6 R 11 group substitution;

[0023] where R 2b Independently selected from CONR 12 R 12 and CO2R 12 ;

[0024] where R 2c Independently selected from NR 12 R 13 and OR 12 ;

[0025] or R 2 and R 6 Together with the nitrogen to which they are attached, they form a ring system selected from the group consisting of: monocyclic 4 to 7 membered heterocycloalkyl; and fused, spirofused or bridged bicyclic 6 to 11 membered heterocycloalkyl; the heterocycloalkyl being optionally substituted by 1 to 6 R 10 group substitution;

[0026] R 3a In each occurrence, independently selected from the group consisting of: H, C1-C4-alkyl, C1-C4-haloalkyl, 12 R 13 Substituted C1-C4-alkyl, 12 Substituted C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl; or two of R 3a The groups, together with the carbon to which they are attached, form a spiro-fused cyclopropyl group;

[0027] R 3b independently selected from H, C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl;

[0028] R 4 independently selected from the group consisting of: 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 Optionally 1 to 4 R 14 group substitution;

[0029] R 5 、R 6 、R 8 and R 12 is independently selected at each occurrence from H, C1-C4-haloalkyl, cyclopropyl and C1-C4-alkyl;

[0030] R 7 and R 13 are independently selected at each occurrence from H, C1-C4-alkyl, C1-C4-haloalkyl and C(O)-C1-C4-alkyl;

[0031] or R 12 and R 13Together with the nitrogen to which they are attached, they form a ring system selected from the group consisting of: monocyclic 4 to 7 membered heterocycloalkyl; and fused, spirofused or bridged bicyclic 6 to 11 membered heterocycloalkyl; the heterocycloalkyl being optionally substituted by 1 to 6 R 10 group substitution;

[0032] R 9 is independently selected at each occurrence from oxo, halogen, cyano, NR 12 R 13 , OR 12 、COR 12 、CO2R 12 、CONR 12 R 12 、CONR 12 R 13 、C1-C4-alkyl、NR 12 R 13 Substituted C1-C4-alkyl, 12 Substituted C1-C4-alkyl, C1-C4-alkyl substituted by cyano, C1-C4-alkyl substituted by phenyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl;

[0033] R 10 is independently selected at each occurrence from the group consisting of: oxo, halogen, cyano, NR 12 R 13 , OR 12 、COR 12 、CO2R 12 、CONR 12 R 12 、C1-C4-alkyl、NR 12 R 13 Substituted C1-C4-alkyl, 12 Substituted C1-C4-alkyl, C1-C4-alkyl substituted by cyano, C1-C4-alkyl substituted by phenyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl;

[0034] R 11 Independently selected from the following: halogen, cyano, nitro, NR 12 R 13 , OR 12 、CO2R 12 、CONR 12 R 12 、C1-C4-alkyl、NR 12 R 13 Substituted C1-C4-alkyl, 12Substituted C1-C4-alkyl, monocyclic 4- to 7-membered cycloalkyl or heterocycloalkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl; R 14 is independently selected at each occurrence from the group consisting of: H, halogen, cyano, nitro, NR 12 R 13 , OR 12 、CO2R 12 、CONR 12 R 12 、C1-C4-alkyl、NR 12 R 13 Substituted C1-C4-alkyl, 12 substituted C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, phenyl and cyclopropyl;

[0035] R 18 is independently selected at each occurrence from the group consisting of: H, halogen, cyano, nitro, NR 12 R 13 , OR 12 、CO2R 12 、CONR 12 R 12 、C1-C4 alkyl、NR 12 R 13 Substituted C1-C4-alkyl, 12 Substituted C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl; or two of R 18 The groups, together with the carbon to which they are attached, form a spiro-fused cyclopropyl group;

[0036] wherein any of the above alkyl, alkylene, phenyl or cyclopropyl groups is optionally substituted, where chemically possible, by 1 to 5 substituents, said substituents being independently selected at each occurrence from the group consisting of: C1-C4-alkyl, substituted by OR a Substituted C1-C4-alkyl, halogen, nitro, cyano, NR a R b , OR a SR 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; and R bis independently selected at each occurrence from H, C1-C4-alkyl, C(O)-C1-C4-alkyl and S(O)2-C1-C4-alkyl.

[0037] According to the present invention, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0038]

[0039] Z 1 Independently selected from -O- and -NR 5 -;

[0040] Z 2 Independently absent or selected from -O- and -NR 6 -;

[0041] L 1 Selected from bonds and -C(R 18 )2-

[0042] X 1 Selected from -C(R 3a )2 and -NR 3b -;

[0043] R 1 Independently selected from C0-C3-alkylene-R 1a and C2-C6-alkylene-R 1b ; where R 1a is independently selected from an oxygen-containing 4- to 7-membered heterocycloalkyl ring, which is a 4- to 7-membered heterocycloalkyl ring; and 7 R 8 wherein the heterocycloalkyl ring or the cycloalkyl ring is optionally substituted with 1 to 4 R 9 Group substitution; R 1b Independently selected from: NR 7 R 8 , OR 8 SR 8 、SOR 8 、SO2R 8 and SO(NH)R 8 ; or R 1 and R 5 Together with the nitrogen to which they are attached, they form a ring system selected from: optionally substituted by 1 to 4 R 9 monocyclic 4 to 7 membered heterocycloalkyl substituted with a group; optionally substituted with 1 to 4 R 9 a substituted fused, spirofused or bridged bicyclic 6- to 11-membered heterocyclyl;

[0044] R 2are independently C1-C6-alkyl, C1-C4-haloalkyl, C0-C4-alkylene-R 2a 、C1-C4-alkylene-R 2b 、C2-C4-alkylene-R 2c ;

[0045] R 2a is independently selected from monocyclic 4 to 7 membered heterocycloalkyl, fused, spirofused or bridged bicyclic 6 to 11 membered heterocycloalkyl; 5, 6, 9 or 10 membered monocyclic or bicyclic heteroaryl; phenyl; C3-C7-cycloalkyl; wherein any heterocycloalkyl or cycloalkyl R 2a The group is optionally substituted by 1 to 6 R 10 group substituted, and any heteroaryl or phenyl R 2a The group is optionally substituted by 1 to 6 R 11 group substitution;

[0046] where R 2b Independently selected from CONR 12 R 12 and CO2R 12 ;

[0047] where R 2c Independently selected from NR 12 R 13 and OR 12 ;

[0048] or R 2 and R 6 Together with the nitrogen to which they are attached, they form a ring system selected from the group consisting of monocyclic 4 to 7 membered heterocycloalkyl, fused, spirofused or bridged bicyclic 6 to 11 membered heterocycloalkyl, optionally substituted by 1 to 6 R 10 group substitution;

[0049] R 3a In each occurrence, independently selected from the group consisting of: H, C1-C4-alkyl, C1-C4-haloalkyl, 12 R 13 Substituted C1-C4-alkyl, 12 Substituted C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl; or two of R 3a The groups, together with the carbon to which they are attached, form a spiro-fused cyclopropyl group;

[0050] R 3b independently selected from H, C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl;

[0051] R 4are independently selected from the group consisting of: 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 Optionally 1 to 4 R 14 group substitution;

[0052] R 5 、R 6 、R 8 and R 12 are independently selected at each occurrence from H, C1-C4-haloalkyl and C1-C4-alkyl;

[0053] R 7 and R 13 are independently selected at each occurrence from H, C1-C4-alkyl, C1-C4-haloalkyl and C(O)-C1-C4-alkyl;

[0054] or R 12 and R 13 Together with the nitrogen to which they are attached, they form a ring system selected from the group consisting of monocyclic 4 to 7 membered heterocycloalkyl, fused, spirofused or bridged bicyclic 6 to 11 membered heterocycloalkyl, optionally substituted by 1 to 6 R 10 group substitution;

[0055] R 9 and R 10 is independently selected at each occurrence from the group consisting of: oxo, halogen, cyano, NR 12 R 13 , OR 12 、CO2R 12 、CONR 12 R 12 、C1-C4-alkyl、NR 12 R 13 Substituted C1-C4-alkyl, 12 Substituted C1-C4-alkyl, C1-C4-alkyl substituted by cyano, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl;

[0056] R 11 Independently selected from the following: halogen, cyano, nitro, NR 12 R 13 , OR 12 、CO2R 12 、CONR 12 R 12 、C1-C4-alkyl、NR 12 R 13 Substituted C1-C4-alkyl, 12Substituted C1-C4-alkyl, monocyclic 4- to 7-membered cycloalkyl or heterocycloalkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl; R 14 is independently selected at each occurrence from the group consisting of: H, halogen, cyano, nitro, NR 12 R 13 , OR 12 、CO2R 12 、CONR 12 R 12 、C1-C4-alkyl、NR 12 R 13 Substituted C1-C4-alkyl, 12 substituted C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl;

[0057] R 18 is independently selected at each occurrence from the group consisting of: H, halogen, cyano, nitro, NR 12 R 13 , OR 12 、CO2R 12 、CONR 12 R 12 、C1-C4 alkyl、NR 12 R 13 Substituted C1-C4-alkyl, 12 Substituted C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl; or two of R 18 The groups, together with the carbon to which they are attached, form a spiro-fused cyclopropyl group;

[0058] wherein any of the above alkyl, alkylene or cyclopropyl groups is optionally substituted, where chemically possible, by 1 to 5 substituents, each of which is independently selected at each occurrence from the group consisting of: C1-C4-alkyl, halogen, nitro, cyano, NR a R b , OR a SR 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; and 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.

[0059] According to the present invention, there is provided a compound of formula (Ia) or a pharmaceutically acceptable salt thereof:

[0060]

[0061] L 1 Selected from bonds and -C(R 18 )2-

[0062] X 1 Selected from -C(R 3a )2 and -NR 3b -;

[0063] R 1 Independently selected from C0-C3-alkylene-R 1a and C2-C6-alkylene-R 1b ; where R 1a independently selected from a 4- to 7-membered heterocycloalkyl ring; a benzene ring; and optionally NR 7 R 8 wherein the heterocycloalkyl ring, the benzene ring or the cycloalkyl ring is optionally substituted with 1 to 4 R 9 Group substitution; R 1b Independently selected from the following: NR 7 R 8 , OR 8 SR 8 、SOR 8 、SO2R 8 and SO(NH)R 8 ;

[0064] or R 1 and R 5 Together with the nitrogen to which they are attached, they form a ring system selected from the group consisting of: optionally substituted by 1 to 4 R 9 monocyclic 4 to 7 membered heterocycloalkyl substituted with a group; optionally substituted with 1 to 4 R 9 a substituted fused, spirofused or bridged bicyclic 6- to 11-membered heterocyclyl;

[0065] 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 ;

[0066] R 2ais independently selected from monocyclic 4 to 7 membered heterocycloalkyl; fused, spirofused or bridged bicyclic 6 to 11 membered heterocycloalkyl; 5, 6, 9 or 10 membered monocyclic or bicyclic heteroaryl; phenyl; C3-C7-cycloalkyl; wherein any heterocycloalkyl or cycloalkyl R 2a The group is optionally substituted by 1 to 6 R 10 group substituted, and any heteroaryl or phenyl R 2a The group is optionally substituted by 1 to 6 R 11 group substitution;

[0067] where R 2b Independently selected from CONR 12 R 12 and CO2R 12 ;

[0068] where R 2c Independently selected from NR 12 R 13 and OR 12 ;

[0069] or R 2 and R 6 Together with the nitrogen to which they are attached, they form a ring system selected from the group consisting of monocyclic 4 to 7 membered heterocycloalkyl, fused, spirofused or bridged bicyclic 6 to 11 membered heterocycloalkyl, optionally substituted by 1 to 6 R 10 group substitution;

[0070] R 3a In each occurrence, independently selected from the group consisting of: H, C1-C4-alkyl, C1-C4-haloalkyl, 12 R 13 Substituted C1-C4-alkyl, 12 Substituted C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl; or two of R 3a The groups, together with the carbon to which they are attached, form a spiro-fused cyclopropyl group;

[0071] R 3b independently selected from H, C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl;

[0072] R 4 independently selected from the group consisting of: 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 Optionally 1 to 4 R 14 group substitution;

[0073] R 5 、R6 、R 8 and R 12 is independently selected at each occurrence from H, C1-C4-haloalkyl, cyclopropyl and C1-C4-alkyl;

[0074] R 7 and R 13 are independently selected at each occurrence from H, C1-C4-alkyl, C1-C4-haloalkyl and C(O)-C1-C4-alkyl;

[0075] or R 12 and R 13 Together with the nitrogen to which they are attached, they form a ring system selected from the group consisting of: monocyclic 4- to 7-membered heterocycloalkyl, fused, spirofused or bridged bicyclic 6- to 11-membered heterocycloalkyl; the heterocycloalkyl being optionally substituted by 1 to 6 R 10 group substitution;

[0076] R 9 and R 10 is independently selected at each occurrence from the group consisting of: oxo, halogen, cyano, NR 12 R 13 , OR 12 、COR 12 、CO2R 12 、CONR 12 R 12 、CONR 12 R 13 、C1-C4-alkyl、NR 12 R 13 Substituted C1-C4-alkyl, 12 Substituted C1-C4-alkyl, C1-C4-alkyl substituted by cyano, C1-C4-alkyl substituted by phenyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl;

[0077] R 11 Independently selected from the following: halogen, cyano, nitro, NR 12 R 13 , OR 12 、CO2R 12 、CONR 12 R 12 、C1-C4-alkyl、NR 12 R 13 Substituted C1-C4-alkyl, 12 Substituted C1-C4-alkyl, monocyclic 4- to 7-membered cycloalkyl or heterocycloalkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl; R 14is independently selected at each occurrence from the group consisting of: H, halogen, cyano, nitro, NR 12 R 13 , OR 12 、CO2R 12 、CONR 12 R 12 、C1-C4-alkyl、NR 12 R 13 Substituted C1-C4-alkyl, 12 substituted C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, phenyl and cyclopropyl;

[0078] R 18 is independently selected at each occurrence from the group consisting of: H, halogen, cyano, nitro, NR 12 R 13 , OR 12 、CO2R 12 、CONR 12 R 12 、C1-C4 alkyl、NR 12 R 13 Substituted C1-C4-alkyl, 12 Substituted C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl; or two of R 18 The groups, together with the carbon to which they are attached, form a spiro-fused cyclopropyl group;

[0079] wherein any of the above alkyl, alkylene, phenyl or cyclopropyl groups is optionally substituted, where chemically possible, by 1 to 5 substituents, said substituents being independently selected at each occurrence from the group consisting of: C1-C4-alkyl, substituted by OR a Substituted C1-C4-alkyl, halogen, nitro, cyano, NR a R b , OR a SR 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; and 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.

[0080] According to the present invention, there is provided a compound of formula (Ia) or a pharmaceutically acceptable salt thereof:

[0081]

[0082] L 1 Selected from bonds and -C(R 18 )2-

[0083] X 1 Selected from -C(R 3a )2 and -NR 3b -;

[0084] R 1 Independently selected from C0-C3-alkylene-R 1a and C2-C6-alkylene-R 1b ; where R 1a are independently selected from the following: an oxygen-containing 4- to 7-membered heterocycloalkyl ring, which is a 4- to 7-membered heterocycloalkyl ring; and 7 R 8 wherein the heterocycloalkyl ring or the cycloalkyl ring is optionally substituted with 1 to 4 R 9 Group substitution; R 1b Independently selected from the following: NR 7 R 8 , OR 8 SR 8 、SOR 8 、SO2R 8 and SO(NH)R 8 ;

[0085] or R 1 and R 5 Together with the nitrogen to which they are attached, they form a ring system selected from: optionally substituted by 1 to 4 R 9 monocyclic 4 to 7 membered heterocycloalkyl substituted with a group; optionally substituted with 1 to 4 R 9 a substituted fused, spirofused or bridged bicyclic 6- to 11-membered heterocyclyl;

[0086] 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 ;

[0087] R 2a is independently selected from the following: monocyclic 4 to 7 membered heterocycloalkyl, fused, spirofused or bridged bicyclic 6 to 11 membered heterocycloalkyl; 5, 6, 9 or 10 membered monocyclic or bicyclic heteroaryl; phenyl; C3-C7-cycloalkyl; any heterocycloalkyl or cycloalkyl R 2aThe group is optionally substituted by 1 to 6 R 10 group substituted, and any heteroaryl or phenyl R 2a The group is optionally substituted by 1 to 6 R 11 group substitution;

[0088] where R 2b Independently selected from CONR 12 R 12 and CO2R 12 ;

[0089] where R 2c Independently selected from NR 12 R 13 OR 12 ;

[0090] or R 2 and R 6 Together with the nitrogen to which they are attached, they form a ring system selected from the group consisting of monocyclic 4 to 7 membered heterocycloalkyl, fused, spirofused or bridged bicyclic 6 to 11 membered heterocycloalkyl, optionally substituted by 1 to 6 R 10 group substitution;

[0091] R 3a In each occurrence, independently selected from the group consisting of: H, C1-C4-alkyl, C1-C4-haloalkyl, 12 R 13 Substituted C1-C4-alkyl, 12 Substituted C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl; or two of R 3a The groups, together with the carbon to which they are attached, form a spiro-fused cyclopropyl group;

[0092] R 3b independently selected from H, C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl;

[0093] R 4 are independently selected from the group consisting of: 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 Optionally 1 to 4 R 14 group substitution;

[0094] R 5 、R 6 、R 8 and R 12 are independently selected at each occurrence from H, C1-C4-haloalkyl and C1-C4-alkyl;

[0095] R 7 and R 13 are independently selected at each occurrence from H, C1-C4-alkyl, C1-C4-haloalkyl and C(O)-C1-C4-alkyl;

[0096] or R 12 and R 13 Together with the nitrogen to which they are attached, they form a ring system selected from the group consisting of monocyclic 4 to 7 membered heterocycloalkyl, fused, spirofused or bridged bicyclic 6 to 11 membered heterocycloalkyl, optionally substituted by 1 to 6 R 10 Group substitution; R 9 and R 10 is independently selected at each occurrence from the group consisting of: oxo, halogen, cyano, NR 12 R 13 , OR 12 、CO2R 12 、CONR 12 R 12 、C1-C4-alkyl、NR 12 R 13 Substituted C1-C4-alkyl, 12 Substituted C1-C4-alkyl, C1-C4-alkyl substituted by cyano, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl;

[0097] R 11 Independently selected from the following: halogen, cyano, nitro, NR 12 R 13 , OR 12 、CO2R 12 、CONR 12 R 12 、C1-C4-alkyl、NR 12 R 13 Substituted C1-C4-alkyl, 12 Substituted C1-C4-alkyl, monocyclic 4- to 7-membered cycloalkyl or heterocycloalkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl; R 14 is independently selected at each occurrence from the group consisting of: H, halogen, cyano, nitro, NR 12 R 13 , OR 12 、CO2R 12 、CONR 12 R 12 、C1-C4-alkyl、NR 12 R 13 Substituted C1-C4-alkyl, 12substituted C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl;

[0098] R 18 is independently selected at each occurrence from the group consisting of: H, halogen, cyano, nitro, NR 12 R 13 , OR 12 、CO2R 12 、CONR 12 R 12 、C1-C4 alkyl、NR 12 R 13 Substituted C1-C4-alkyl, 12 Substituted C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl; or two of R 18 The groups, together with the carbon to which they are attached, form a spiro-fused cyclopropyl group;

[0099] wherein any of the above alkyl, alkylene or cyclopropyl groups is optionally substituted, where chemically possible, by 1 to 5 substituents, each of which is independently selected at each occurrence from the group consisting of: C1-C4-alkyl, halogen, nitro, cyano, NR a R b , OR a SR 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; and 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.

[0100] In one embodiment, the compound of formula (I) is a compound of formula (II):

[0101]

[0102] where R 1 、R 2 、R 14 , L 1 、X 1 , Z 1 and Z 2 As described above for compounds of formula (I); and x is independently selected from 0, 1, 2, 3 and 4. For clarity, throughout the specification, x R 14The group may be attached to any ring of the naphthyl group.

[0103] In one embodiment, the compound of formula (I) is a compound of formula (IIa):

[0104]

[0105] where R 1 、R 2 、R 5 、R 14 , L 1 and X 1 As described above for compounds of formula (I); and x is independently selected from 0, 1, 2, 3 and 4. For clarity, throughout the specification, x R 14 The group may be attached to any ring of the naphthyl group.

[0106] In one embodiment, the compound of formula (I) is a compound of formula (III):

[0107]

[0108] where R 1 、R 4 、R 10 , L 1 、X 1 , Z 1 and Z 2 As described above for compounds of formula (I); and wherein R 15 are independently selected from H, C1-C4-alkyl; wherein R 16 are independently selected from H, C1-C4-alkyl and cyclopropyl; or wherein R 15 and R 16 Together with the atoms to which they are attached, they form a 5- or 6-membered heterocycloalkyl ring, which is optionally substituted by 1 or 2 R 10 and y is independently selected from 0, 1, 2, 3 and 4.

[0109] In one embodiment, the compound of formula (I) is a compound of formula (IIIa):

[0110]

[0111] where R 1 、R 4 、R 10 , L 1 and X 1 As described above for compounds of formula (I); and wherein R 15 are independently selected from H, C1-C4-alkyl; wherein R 16 are independently selected from H, C1-C4-alkyl and cyclopropyl; or wherein R15 and R 16 Together with the atoms to which they are attached, they form a 5- or 6-membered heterocycloalkyl ring, which is optionally substituted by 1 or 2 R 10 and y is independently selected from 0, 1, 2, 3 and 4.

[0112] In one embodiment, the compound of formula (I) is a compound of formula (IV):

[0113]

[0114] where R 1 、R 10 、R 14 , L 1 、X 1 , Z 1 and Z 2 As described above for compounds of formula (I); wherein R 15 are independently selected from H, C1-C4-alkyl; wherein R 16 are independently selected from H, C1-C4-alkyl and cyclopropyl; or wherein R 15 and R 16 Together with the atoms to which they are attached, they form a 5- or 6-membered heterocycloalkyl ring, which is optionally substituted by 1 or 2 R 10 and y is independently selected from 0, 1, 2, 3, and 4.

[0115] In one embodiment, the compound of formula (I) is a compound of formula (IVa):

[0116]

[0117] where R 1 、R 5 、R 10 、R 14 , L 1 and X 1 As described above for compounds of formula (I); wherein R 15 are independently selected from H, C1-C4-alkyl; wherein R 16 are independently selected from H, C1-C4-alkyl and cyclopropyl; or wherein R 15 and R 16 Together with the atoms to which they are attached, they form a 5- or 6-membered heterocycloalkyl ring, which is optionally substituted by 1 or 2 R 10 and y is independently selected from 0, 1, 2, 3, and 4.

[0118] In one embodiment, the compound of formula (I) is a compound of formula (V):

[0119]

[0120] where R 1 、R 4 、R 10 , L 1 、X 1 , Z 1 and Z 2 As described above for compounds of formula (I); and wherein z is independently selected from 0, 1, 2, 3 and 4. For clarity, throughout the specification, z R 10 The group may be attached to either ring of the pyrrolizidinyl group.

[0121] In one embodiment, the compound of formula (I) is a compound of formula (Va):

[0122]

[0123] where R 1 、R 4 、R 5 、R 10 , L 1 and X 1 As described above for compounds of formula (I); and wherein z is independently selected from 0, 1, 2, 3 and 4. For clarity, throughout the specification, z R 10 The group may be attached to any ring of the pyrrolizidinyl group.

[0124] In one embodiment, the compound of formula (I) is a compound of formula (VI):

[0125]

[0126] where R 1 、R 10 、R 14 , L 1 、X 1 , Z 1 and Z 2 As described above for compounds of formula (I); wherein x is independently selected from 0, 1, 2, 3 and 4; and wherein z is independently selected from 0, 1, 2, 3 and 4.

[0127] In one embodiment, the compound of formula (I) is a compound of formula (VIa):

[0128]

[0129] where R 1 、R 5 、R 10 、R14 , L 1 and X 1 As described above for compounds of formula (I); wherein x is independently selected from 0, 1, 2, 3 and 4; and wherein z is independently selected from 0, 1, 2, 3 and 4.

[0130] In one embodiment, the compound of formula (I) or (Ia) is a compound of formula (VII):

[0131]

[0132] where R 1 、R 2 、R 3a 、R 4 and R 5 As described above for compounds of formula (I) or (Ia).

[0133] In one embodiment, the compound of formula (I) or (Ia) is a compound of formula (VIII):

[0134]

[0135] where R 1 、R 2 、R 3a 、R 5 and R 14 As described above for compounds of formula (I) or (Ia); and x is independently selected from 0, 1, 2, 3 and 4.

[0136] In one embodiment, the compound of formula (I) is a compound of formula (IX):

[0137]

[0138] where R 1 、R 2 、R 3a 、R 4 , Z 1 and Z 2 As described above for the compounds of formula (I).

[0139] In one embodiment, the compound of formula (I) or (Ia) is a compound of formula (IXa):

[0140]

[0141] where R 1 、R 2 、R 3a 、R 4 and Z 1 As described above for compounds of formula (I) or (Ia).

[0142] In one embodiment, the compound of formula (I) or (Ia) is a compound of formula (IXb):

[0143]

[0144] where R 1 、R 2 、R 3a 、R 4 , Z 1 and Z 2 As described above for compounds of formula (I) or (Ia).

[0145] In one embodiment, the compound of formula (I) is a compound of formula (X):

[0146]

[0147] where R 1 、R 2 、R 3a 、R 14 , Z 1 and Z 2 As described above for compounds of formula (I); and x is independently selected from 0, 1, 2, 3 and 4. For clarity, throughout the specification, x R 14 The group may be attached to either ring of the naphthyl group.

[0148] In one embodiment, the compound of formula (I) or (Ia) is a compound of formula (Xa):

[0149]

[0150] where R 1 、R 2 、R 3a 、R 5 and R 14 As described above for compounds of formula (I) or (Ia); and x is independently selected from 0, 1, 2, 3 and 4. For clarity, throughout the specification, x R 14 The group may be attached to either ring of the naphthyl group.

[0151] In one embodiment, the compound of formula (I) is a compound of formula (XI):

[0152]

[0153] where R 1 、R 3a 、R 4 、R 10 , Z 1 and Z 2As described above for compounds of formula (I); and wherein R 15 are independently selected from H, C1-C4-alkyl; wherein R 16 are independently selected from H, C1-C4-alkyl and cyclopropyl; or wherein R 15 and R 16 Together with the atoms to which they are attached, they form a 5- or 6-membered heterocycloalkyl ring, which is optionally substituted by 1 or 2 R 10 and y is independently selected from 0, 1, 2, 3 and 4.

[0154] In one embodiment, the compound of formula (I) or (Ia) is a compound of formula (XIa):

[0155]

[0156] where R 1 、R 3a 、R 4 、R 5 and R 10 As described above for compounds of formula (I) or (Ia); and wherein R 15 are independently selected from H, C1-C4-alkyl; wherein R 16 are independently selected from H, C1-C4-alkyl and cyclopropyl; or wherein R 15 and R 16 Together with the atoms to which they are attached, they form a 5- or 6-membered heterocycloalkyl ring, which is optionally substituted by 1 or 2 R 10 and y is independently selected from 0, 1, 2, 3 and 4.

[0157] In one embodiment, the compound of formula (I) is a compound of formula (XII):

[0158]

[0159] where R 1 、R 3a 、R 10 、R 14 , Z 1 and Z 2 As described above for compounds of formula (I); wherein R 15 are independently selected from H, C1-C4-alkyl; wherein R 16 are independently selected from H, C1-C4-alkyl and cyclopropyl; or wherein R 15 and R 16 Together with the atoms to which they are attached, they form a 5- or 6-membered heterocycloalkyl ring, which is optionally substituted by 1 or 2 R 10 and y is independently selected from 0, 1, 2, 3, and 4.

[0160] In one embodiment, the compound of formula (I) or (Ia) is a compound of formula (XIIa):

[0161]

[0162] where R 1 、R 3a 、R 5 、R 10 and R 14 As described above for compounds of formula (I) or (Ia); wherein R 15 are independently selected from H, C1-C4-alkyl; wherein R 16 are independently selected from H, C1-C4-alkyl and cyclopropyl; or wherein R 15 and R 16 Together with the atoms to which they are attached, they form a 5- or 6-membered heterocycloalkyl ring, which is optionally substituted by 1 or 2 R 10 and y is independently selected from 0, 1, 2, 3, and 4.

[0163] In one embodiment, the compound of formula (I) is a compound of formula (XIII):

[0164]

[0165] where R 1 、R 3a 、R 4 、R 10 , Z 1 and Z 2 As described above for compounds of formula (I); and wherein z is independently selected from 0, 1, 2, 3 and 4. For clarity, throughout the specification, z R 10 The group may be attached to any ring of the pyrrolizidinyl group.

[0166] In one embodiment, the compound of formula (I) or (Ia) is a compound of formula (XIII):

[0167]

[0168] where R 1 、R 3a 、R 4 、R 5 and R 10 As described above for compounds of formula (I); and wherein z is independently selected from 0, 1, 2, 3 and 4. For clarity, throughout the specification, z R 10 The group may be attached to any ring of the pyrrolizidinyl group.

[0169] In one embodiment, the compound of formula (I) is a compound of formula (XIV):

[0170]

[0171] where R 1 、R 3a 、R 10 、R 14 , Z 1 and Z 2 As described above for compounds of formula (I); wherein x is independently selected from 0, 1, 2, 3 and 4; and wherein z is independently selected from 0, 1, 2, 3 and 4.

[0172] In one embodiment, the compound of formula (I) or (Ia) is a compound of formula (XIVa):

[0173]

[0174] where R 1 、R 3a 、R 5 、R 10 and R 14 As described above for compounds of formula (I); wherein x is independently selected from 0, 1, 2, 3 and 4; and wherein z is independently selected from 0, 1, 2, 3 and 4.

[0175] In one embodiment, the compound of formula (I) or (Ia) is a compound of formula (XV):

[0176]

[0177] where R 1 、R 2 、R 3b 、R 4 and R 5 As described above for compounds of formula (I) or (Ia).

[0178] In one embodiment, the compound of formula (I) or (Ia) is a compound of formula (XVI):

[0179]

[0180] where R 1 、R 2 、R 3b 、R 5 and R 14 As described above for compounds of formula (I) or (Ia); and wherein x is independently selected from 0, 1, 2, 3 and 4.

[0181] In one embodiment, the compound of formula (I) or (Ia) is a compound of formula (XVII):

[0182]

[0183] where R 1 、R 2 、R 3a 、R 4 、R 5 and R 18 As described above for compounds of formula (I) or (Ia).

[0184] In one embodiment, the compound of formula (I) or (Ia) is a compound of formula (XVIII):

[0185]

[0186] where R 1 、R 2 、R 3a 、R 5 、R 14 and R 18 As described above for compounds of formula (I) or (Ia); and x is independently selected from 0, 1, 2, 3 and 4.

[0187] The following embodiments are applicable to compounds of any formula (I)-(XVIII). These embodiments are independent and interchangeable. Where chemically permitted, any one embodiment can be combined with any other embodiment. In other words, any feature described in the following embodiments can (where chemically permitted) be combined with the feature described in one or more other embodiments. In particular, in the case of illustrating or illustrating a compound in this specification, any two or more of the embodiments listed below that are expressed with any general level comprising the compound can be combined to provide a further embodiment forming a part of this disclosure.

[0188] L 1 Can be a key. L 1 It can be -C(R 18 )2-.

[0189] R 18 Each occurrence may be independently selected from H, C1-C4-alkyl, NR 12 R 13 Substituted C1-C4-alkyl, 12 Substituted C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl; or two of R 18 The groups together with the carbon to which they are attached form a spirofused cyclopropyl group. 18Each occurrence can be independently selected from H, C1-C4-alkyl, cyclopropyl. 18 The groups together with the carbon to which they are attached form a spirofused cyclopropyl group. 18 It can be H at each occurrence, i.e., where L 1 It is -(CH2)-.

[0190] X 1 It can be -C(R 3a )2. X 1 Can be -NR 3b -.

[0191] It can be L 1 Yes key, X 1 Yes-C(R 3a )2. Therefore, including L 1 and X 1 The ring is a five-membered ring. It can be L 1 Yes key, X 1 Yes-NR 3b -. It can be L 1 Yes-C(R 18 )2-,X 1 Yes-C(R 3a )2. Therefore, including L 1 and X 1 The ring is a six-membered ring. It can be L 1 Yes-C(R 18 )2-,X 1 Yes-NR 3b -.

[0192] Z 1 It can be -O-. Z 1 Can be -NR 5 -.

[0193] Z 2 It can be -O-. Z 2 Can be -NR 6 -.

[0194] R 1 It can be C0-C3-alkylene-R 1a , where R 1a independently selected from a 4- to 7-membered heterocycloalkyl ring; a benzene ring; and optionally NR 7 R 8 wherein the heterocycloalkyl ring, the benzene ring or the cycloalkyl ring is optionally substituted with 1 to 4 R 9 Group substitution.

[0195] R 1 are independently C0-C3-alkylene-R1a , where R 1a are independently selected from 4 to 7 membered heterocycloalkyl rings; and 7 R 8 wherein the heterocycloalkyl ring or the cycloalkyl ring is optionally substituted with 1 to 4 R 9 Group substitution.

[0196] R 1 It can be C0-C3-alkylene-R 1a . R 1 It can be C0-C3-alkylene-R 1a , where R 1a is independently selected from an oxygen-containing 4- to 7-membered heterocycloalkyl ring, which is a 4- to 7-membered heterocycloalkyl ring; and 7 R 8 wherein the heterocycloalkyl ring or the cycloalkyl ring is optionally substituted with 1 to 4 R 9 Group substitution. 1 Can be CH2-R 1a , where R 1a are independently selected from 4 to 7 membered heterocycloalkyl rings; and 7 R 8 wherein the heterocycloalkyl ring or the cycloalkyl ring is optionally substituted with 1 to 4 R 9 Group substitution.

[0197] R 1 It can be C0-C3-alkylene-R 1a , where R 1a are independently selected from oxygen-containing 4 to 7 membered heterocycloalkyl rings, nitrogen-containing 4 to 7 membered heterocycloalkyl rings; and NR 7 R 8 wherein the heterocycloalkyl ring or the cycloalkyl ring is optionally substituted with 1 to 4 R 9 Group substitution. 1 Can be CH2-R 1a , where R 1a are independently selected from nitrogen-containing 4- to 7-membered heterocycloalkyl rings; and 7 R 8 wherein the heterocycloalkyl ring or the cycloalkyl ring is optionally substituted with 1 to 4 R 9 Group substitution.

[0198] R 1 It can be R 1a , where R 1a are independently selected from 4 to 7 membered heterocycloalkyl rings; and7 R 8 wherein the heterocycloalkyl ring or the cycloalkyl ring is optionally substituted with 1 to 4 R 9 Group substitution.

[0199] R 1 It can be R 1a , where R 1a are independently selected from nitrogen-containing 4- to 7-membered heterocycloalkyl rings; and 7 R 8 wherein the heterocycloalkyl ring or the cycloalkyl ring is optionally substituted with 1 to 4 R 9 Group substitution. 1 It can be R 1a , where R 1a is an oxygen-containing 4- to 7-membered heterocycloalkyl ring; wherein the heterocycloalkyl ring is optionally substituted by 1 to 4 R 9 Group substitution. 1 It can be R 1a , where R 1a is an oxygen-containing 4- to 7-membered heterocycloalkyl ring, such as a tetrahydropyran ring.

[0200] R 1 are independently C0-C3-alkylene-R 1a , where R 1a independently selected from 4 to 7 membered heterocycloalkyl rings; and optionally NR 7 R 8 wherein the heterocycloalkyl ring or the cycloalkyl ring is optionally substituted with 1 to 4 R 9 Group substitution.

[0201] R 1 It can be C0-C3-alkylene-R 1a . R 1 It can be C0-C3-alkylene-R 1a , where R 1a is independently selected from an oxygen-containing 4 to 7 membered heterocycloalkyl ring, which is a 4 to 7 membered heterocycloalkyl ring; and optionally NR 7 R 8 wherein the heterocycloalkyl ring or the cycloalkyl ring is optionally substituted with 1 to 4 R 9 Group substitution. 1 Can be CH2-R 1a , where R 1a are independently selected from 4 to 7 membered heterocycloalkyl rings; and 7 R 8wherein the heterocycloalkyl ring or the cycloalkyl ring is optionally substituted with 1 to 4 R 9 Group substitution.

[0202] R 1 It can be C0-C3-alkylene-R 1a , where R 1a are independently selected from an oxygen-containing 4 to 7-membered heterocycloalkyl ring, a nitrogen-containing 4 to 7-membered heterocycloalkyl ring; and optionally NR 7 R 8 wherein the heterocycloalkyl ring or the cycloalkyl ring is optionally substituted with 1 to 4 R 9 Group substitution. 1 Can be CH2-R 1a , where R 1a are independently selected from nitrogen-containing 4- to 7-membered heterocycloalkyl rings; and 7 R 8 wherein the heterocycloalkyl ring or the cycloalkyl ring is optionally substituted with 1 to 4 R 9 Group substitution.

[0203] R 1 It can be R 1a , where R 1a independently selected from 4 to 7 membered heterocycloalkyl rings; and optionally NR 7 R 8 wherein the heterocycloalkyl ring or the cycloalkyl ring is optionally substituted with 1 to 4 R 9 Group substitution.

[0204] R 1 It can be R 1a , where R 1a are independently selected from nitrogen-containing 4 to 7 membered heterocycloalkyl rings; and optionally NR 7 R 8 wherein the heterocycloalkyl ring or the cycloalkyl ring is optionally substituted with 1 to 4 R 9 Group substitution. 1 It can be R 1a , where R 1a is an oxygen-containing 4- to 7-membered heterocycloalkyl ring; wherein the heterocycloalkyl ring is optionally substituted by 1 to 4 R 9 Group substitution. 1 It can be R 1a , where R 1a is an oxygen-containing 4- to 7-membered heterocycloalkyl ring, such as a tetrahydropyran ring.

[0205] R 1It can be C0-C3-alkylene-R 1a , where R 1a is a 4- to 7-membered heterocycloalkyl ring; wherein the heterocycloalkyl ring is optionally substituted by 1 to 4 R 9 Group substitution. 1 It can be CH2-alkylene-R 1a , where R 1a is a 4- to 7-membered heterocycloalkyl ring; wherein the heterocycloalkyl ring is optionally substituted by 1 to 4 R 9 Group substitution.

[0206] R 1 It can be C0-C3-alkylene-R 1a , where R 1a is a nitrogen-containing 4- to 7-membered heterocycloalkyl ring; wherein the heterocycloalkyl ring is optionally substituted by 1 to 4 R 9 Group substitution. 1 It can be CH2-alkylene-R 1a , where R 1a is a nitrogen-containing 4- to 7-membered heterocycloalkyl ring; wherein the heterocycloalkyl ring is optionally substituted by 1 to 4 R 9 Group substitution.

[0207] R 1 It can be C0-C3-alkylene-R 1a , where R 1a is a 4- to 7-membered heterocycloalkyl ring, wherein the ring does not contain any nitrogen atoms; wherein the heterocycloalkyl ring is optionally substituted by 1 to 4 R 9 Group substitution. 1 It can be CH2-alkylene-R 1a , where R 1a is a 4- to 7-membered heterocycloalkyl ring, wherein the ring does not contain any nitrogen atoms; wherein the heterocycloalkyl ring is optionally substituted by 1 to 4 R 9 Group substitution.

[0208] R 1 It can be R 1a , where R 1a is a 4- to 7-membered heterocycloalkyl ring; wherein the heterocycloalkyl ring is optionally substituted by 1 to 4 R 9 Group substitution. 1 It can be R 1a , where R 1a is a nitrogen-containing 4- to 7-membered heterocycloalkyl ring; wherein the heterocycloalkyl ring is optionally substituted by 1 to 4 R 9 Group substitution. 1 It can be R 1a , where R 1a is a 4- to 7-membered heterocycloalkyl ring; wherein the heterocycloalkyl ring is optionally substituted by 1 to 4 R 9The ring is substituted with a group wherein the ring does not contain any nitrogen atoms.

[0209] R 1 It can be C0-C3-alkylene-R 1a , where R 1a Is NR 7 R 8 wherein the cycloalkyl ring is optionally substituted with 1 to 4 R 9 Group substitution. 1 It can be CH2-alkylene-R 1a , where R 1a Is NR 7 R 8 wherein the cycloalkyl ring is optionally substituted with 1 to 4 R 9 Group substitution.

[0210] R 1 It can be R 1a , where R 1a is optionally NR 7 R 8 wherein the cycloalkyl ring is optionally substituted with 1 to 4 R 9 Group substitution.

[0211] R 1 It can be R 1a , where R 1a Is NR 7 R 8 wherein the cycloalkyl ring is optionally substituted with 1 to 4 R 9 Group substitution.

[0212] R 1 It can be R 1a , where R 1a is optionally replaced by 1 to 4 R 9 Phenyl substituted with a group. 1 It can be R 1a , where R 1a It is an unsubstituted phenyl group.

[0213] R 1 It can be C2-C6-alkylene-R 1b . R 1 It can be C2-C3-alkylene-R 1b . R 1 It can be C3-alkylene-R 1b . R 1b Can be independently selected from: NR 7 R 8 , OR8 and SR 8 . R 1b It can be OR 8 . R 1b Can be SR 8 . R 1b It can be NR 7 R 8 . R 8 It may be C1-C4-alkyl, for example Me.

[0214] You can choose R 1 and R 5 , making NR 1 R 5 Contains no more than a monoamine, wherein the monoamine can be a primary amine, a secondary amine or a tertiary amine. 1 and R 5 , making NR 1 R 5 The invention relates to a novel compound comprising no more than a monoamine, wherein the monoamine may be a secondary or tertiary amine. Compounds having no more than a monoamine at this position surprisingly exhibit broad-spectrum inhibition across a range of mutant KRAS forms, as well as wild-type KRAS, at similar concentrations, rather than inhibition of specific KRAS G12C and G12D proteins. The compounds of the invention exhibit broad-spectrum inhibition across KRAS mutants, including KRAS G12D, KRAS G12C, KRAS G12V, KRAS G12A, KRAS G13D, and KRAS Q61H, as well as wild-type KRAS, at similar concentrations. Therefore, these compounds may have therapeutic benefits in treating cancers carrying KRAS mutations other than G12D and G12C, as well as cancers that are dependent on wild-type KRAS.

[0215] You can choose R 1 and R 5 , making NR 1 R 5 Contains more than one amine, wherein the amine can be a primary amine, a secondary amine or a tertiary amine. 1 and R 5 , making NR 1 R 5 Contains more than one amine, wherein the amine may be a secondary amine or a tertiary amine. 1 and R 5 , making NR 1 R 5a Contains two amines, wherein the amines can be primary, secondary or tertiary amines. 1 and R 5 , making NR 1 R 5Contains two amines, wherein the amines can be secondary amines or tertiary amines. 1 and R 5 Make NR 1 R 5 Compounds containing more than a single amine (eg, two amines) generally selectively inhibit KRAS G12D.

[0216] It can be R 1 and R 5 Together with the nitrogen to which they are attached, they form a ring system selected from the group consisting of: optionally substituted by 1 to 4 R 9 monocyclic 4 to 7 membered heterocycloalkyl substituted with a group; optionally substituted with 1 to 4 R 9 a fused or spirofused bicyclic 6- to 11-membered heterocyclic group substituted with a group; and optionally substituted with 1 to 4 R 9 a bridged bicyclic 6- to 11-membered heterocycloalkyl group substituted with a radical; wherein R 1 and R 5 The attached nitrogen is the only heteroatom in the ring system.

[0217] It can be R 1 and R 5 Together with the nitrogen to which they are attached, they form a ring system selected from the group consisting of: optionally substituted by 1 to 4 R 9 monocyclic 4 to 7 membered heterocycloalkyl substituted with a group; optionally substituted with 1 to 4 R 9 a fused or spirofused bicyclic 6- to 11-membered heterocyclic group substituted with a group; and optionally substituted with 1 to 4 R 9 a bridged bicyclic 6- to 11-membered heterocycloalkyl group substituted with a radical; wherein R 1 and R 5 The attached nitrogen is the only nitrogen in the ring system.

[0218] You can choose R 1 and R 5 , making NR 1 R 5 The nitrogen of the monoamine is the nitrogen of the monoamine. 1 and R 5 , making NR 1 R 5 is a monoamine. For the sake of clarity, 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 sake of clarity, the term "amine" as used herein does not include amides and lactams, such as piperazinyl.

[0219] It can be R 1 and R 5 Together with the nitrogen to which they are attached, they form a ring system having the following structure: where R 9cis selected from H and C1-C4-alkyl, p5 and q5 are each selected from 0, 1, 2 and 3; provided that the sum of p5 and q5 is 1 or greater.

[0220] It can be R 1 and R 5 Together with the nitrogen to which they are attached, they form a ring system having a structure selected from: wherein r6 is selected from 0, 1 and 2.

[0221] It can be R 1 and R 5 Together with the nitrogen to which they are attached, they form a ring system having a structure selected from: wherein r7 is selected from 0, 1 and 2.

[0222] It can be R 1 and R 5 Together with the nitrogen to which they are attached, they form a ring system selected from: optionally substituted by 1 to 4 R 9 monocyclic 4 to 7 membered heterocycloalkyl substituted with a group; optionally substituted with 1 to 4 R 9 A substituted fused, spirofused or bridged bicyclic 6- to 11-membered heterocyclyl.

[0223] It can be R 1 and R 5 Together with the nitrogen to which they are attached, they form a ring system selected from: optionally substituted by 1 to 4 R 9 monocyclic 4 to 7 membered heterocycloalkyl substituted with a group; optionally substituted with 1 to 4 R 9 a 6- to 11-membered bicyclic heterocyclic group substituted with a fused, spirofused or bridged group; wherein in addition to R 1 and R 5 The ring system contains no nitrogen other than the nitrogen to which it is attached.

[0224] It can be R 1 and R 5 Together with the nitrogen to which they are attached, they form a ring system selected from: optionally substituted by 1 to 4 R 9 monocyclic 4 to 7 membered heterocycloalkyl substituted with a group; optionally substituted with 1 to 4 R 9 a fused or spirofused bicyclic 6- to 11-membered heterocyclic group substituted with a group; and optionally substituted with 1 to 4 R 9 A bridged bicyclic 6- to 11-membered heterocycloalkyl group substituted with a group.

[0225] It can be R 1 and R 5 Together with the nitrogen to which they are attached, they form a ring system selected from: optionally substituted by 1 to 4 R 9 monocyclic 4 to 7 membered heterocycloalkyl substituted with a group; optionally substituted with 1 to 4 R 9A substituted fused or spirofused bicyclic 6- to 11-membered heterocyclyl.

[0226] It can be R 1 and R 5 Together with the nitrogen to which they are attached, they form a 6- or 7-membered heterocycloalkyl group, which is optionally substituted by 1 to 4 R 9 Group substitution. It can be R 1 and R 5 Together with the nitrogen to which they are attached, they form a 6- or 7-membered heterocycloalkyl group, which is optionally substituted by 1 to 4 R 9 wherein the total number of heteroatoms in the 6- or 7-membered heterocycloalkyl group is 1 or 2. The total number of heteroatoms may be 2. 1 and R 5 Together with the nitrogen to which they are attached, they form a 6- or 7-membered heterocycloalkyl group, which is optionally replaced by 1 R 9 Group substitution.

[0227] It can be R 1 and R 5 Together with the nitrogen to which they are attached, they form a monocyclic 4- to 7-membered heterocycloalkyl group, which is optionally substituted by 1 to 4 R 9 Group substitution. It can be R 1 and R 5 Together with the nitrogen to which they are attached, they form an unsubstituted monocyclic 4 to 7 membered heterocycloalkyl. 9 group, and the R 9 At least one of the groups is selected from NR 12 R 13 and NR 12 R 13 Substituted C1-C4-alkyl. It can be R 1 and R 5 Together with the nitrogen to which they are attached, they form a ring system having the following structure:

[0228] where R 9a Selected from NR 12 R 13 and NR 12 R 13 substituted C1-C4-alkyl; p1 is selected from 0, 1, 2 and 3, q1 is selected from 0, 1 and 2; and r1 is selected from 0, 1, 2 and 3. r1 may be 0. R 9 R may independently be methyl at each occurrence. 9a Can be selected from NHR 12 and NHR 12 Substituted C1-C4 alkyl.

[0229] It can be R 1 and R 5Together with the nitrogen to which they are attached, they form a monocyclic 4- to 7-membered heterocycloalkyl group containing two nitrogen atoms in the ring, which is optionally substituted by 1 to 4 R 9 Group substitution.

[0230] It can be R 1 and R 5 Together with the nitrogen to which they are attached, they form a ring system having the following structure: where Z 6 Independently selected from C(O)NR 9b NR 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 Can be selected from NR 9b , O, S, S(O)2, S(O) and S(O)(NH). Z 6 Can be selected from C(O)NR 9b ,O,S,S(O)2,S(O),S(O)(NR 9b ) and S(O)(NH). Z 6 It may be selected from O, S, S(O)2, S(O) and S(O)(NH).

[0231] Z 6 Can be selected from NR 9b , O and S. Z 6 Can be selected from O and S. Z 6 It can be O.

[0232] It can be R 1 and R 5 Together with the nitrogen to which they are attached, they form a ring system having the following structure: where 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 be methyl at each occurrence. 9b It can be H. R 9b It can be C1-C4-alkyl.

[0233] It can be R 1 and R 5 Together with the nitrogen to which they are attached, they form a fused or spirofused bicyclic 6- to 11-membered heterocyclyl, which is optionally substituted by 1 to 4 R 9 Group substitution. It can be R 1 and R 5Together with the nitrogen to which they are attached, they form a fused or spirofused bicyclic 6- to 11-membered heterocyclyl containing two nitrogen atoms in the ring system, which is optionally substituted by 1 to 4 R 9 Group substitution.

[0234] It can be R 1 and R 5 Together with the nitrogen to which they are attached, they form a spirofused bicyclic 6- to 11-membered heterocycloalkyl group, which is optionally substituted by 1 to 4 R 9 Group substitution. It can be R 1 and R 5 Together with the nitrogen to which they are attached, they form a spirofused bicyclic 6- to 11-membered heterocycloalkyl group comprising two nitrogen atoms in the ring system, which is optionally substituted by 1 to 4 R 9 Group substitution. It can be R 1 and R 5 Together with the nitrogen to which they are attached, they form a ring system having the following structure:

[0235] where 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; provided that the sum of p3, p4, q3 and q4 is 3 to 8, the sum of p3 and q3 is 2 or greater, and the sum of p4 and q4 is 2 or greater; and r3 is selected from 0, 1, 2 and 3. For clarity, throughout the specification, r3 R 9 The group may be attached to any ring of the spiro-fused bicyclic ring system. R3 may be 0. 9 R may independently be methyl at each occurrence. 9b It can be H.

[0236] It can be R 1 and R 5 Together with the nitrogen to which they are attached, they form a fused bicyclic 6- to 11-membered heterocyclic group, which is optionally substituted by 1 to 4 R 9 Group substitution. It can be R 1 and R 5 Together with the nitrogen to which they are attached, they form a fused bicyclic 6- to 11-membered heterocyclyl containing two nitrogen atoms in the ring system, which is optionally substituted by 1 to 4 R 9 Group substitution. It can be R 1 and R 5 Together with the nitrogen to which they are attached, they form a ring system having the following structure: where R 9bis selected from H and C1-C4-alkyl; p5, p6, q5 are each selected from 0, 1, 2 and 3; provided that the sum of p3, p4, q3 and q4 is 2 to 7, the sum of p5 and q5 is 1 or greater, the sum of p6 and q6 is 1 or greater; and r5 is selected from 0, 1, 2 and 3. For clarity, throughout the specification, r5 R 9 The group may be attached to any ring of the fused bicyclic ring system. R5 may be 0. 9 R may independently be methyl at each occurrence. 9b It can be H.

[0237] It can be R 1 and R 5 Together with the nitrogen to which they are attached, they form a bridged bicyclic 6- to 11-membered heterocycloalkyl group, which is optionally substituted by 1 to 4 R 9 Group substitution.

[0238] It can be R 1 and R 5 Together with the nitrogen to which they are attached, they form a fused bicyclic 6- to 11-membered heterocycloalkyl group, which is optionally substituted by 1 to 4 R 9 Group substitution.

[0239] It can be R 1 and R 5 Together with the nitrogen to which they are attached, they form a ring system selected from: optionally substituted by 1 to 4 R 9 monocyclic 4 to 7 membered heterocycloalkyl substituted with a group; optionally substituted with 1 to 4 R 9 a fused or spirofused bicyclic 6- to 11-membered heterocycloalkyl group substituted with a group; and optionally substituted with 1 to 4 R 9 A radical-substituted bridged bicyclic 6- to 11-membered heterocycloalkyl group, wherein the bridged bicyclic 6- to 11-membered heterocycloalkyl group is not:

[0240]

[0241] It can be R 1 and R 5 Together with the nitrogen to which they are attached, they form a bridged bicyclic 6- to 11-membered heterocycloalkyl group, which is optionally substituted by 1 to 4 R 9 The bridged bicyclic 6- to 11-membered heterocycloalkyl group is not:

[0242]

[0243] It can be R 1 and R 5 Together with the nitrogen to which they are attached, they form a ring system having the following structure: where Y 1 Independently selected from C(O)NR 9d , O and NR17 ; Z 3 Independently selected from the following: CH2, CH2CH2, CH2-O-CH2CH2, CH2-O-CH2, CH2-NR 17 -CH2CH2 and CH2-NR 17 -CH2; R 17 R is independently selected at each occurrence from H, C1-C4-haloalkyl and C1-C4-alkyl; 9d are independently selected from H and C1-C4-alkyl; and n1 is an integer selected from 0, 1, 2, 3 and 4. For clarity, throughout the specification, n1 R 9 The group may be attached to any ring of the bridged bicyclic system. 3 Can be independently selected from the following: CH2, CH2CH2, CH2-O-CH2CH2, CH2-O-CH2, Y 1 Can be independently selected from O and NR 17 .Y 1 It can be NR 17 .Y 1 Can be NH. n1 can be 0. R 9 Each occurrence may independently be methyl.

[0244] It can be R 1 and R 5 Together with the nitrogen to which they are attached, they form a ring system having the following structure: where Y 1 Independently selected from C(O)NR 9d , O and NR 17 ; Z 4 Independently selected from the following: CH2, CH2CH2, CH2-O-CH2CH2, CH2-O-CH2, CH2-NR 17 -CH2CH2 and CH2-NR 17 -CH2; R 17 R is independently selected at each occurrence from H, C1-C4-haloalkyl and C1-C4-alkyl; 9d are independently selected from H and C1-C4-alkyl; and n2 is an integer selected from 0, 1, 2, 3 and 4. For clarity, throughout the specification, n2 R 9 The group may be attached to any ring of the bridged bicyclic system. 4 Can be independently selected from the following: CH2, CH2CH2, CH2-O-CH2CH2, CH2-O-CH2, Y 1 Can be independently selected from O and NR 17 .Y 1 It can be NR 17 .Y 1Can be NH. n2 can be 0. R 9 Each occurrence may independently be methyl.

[0245] It can be R 1 and R 5 Together with the nitrogen to which they are attached, they form a ring system having the following structure: where Y 1 Independently selected from C(O)NR 9d , O and NR 17 ; R 17 R is independently selected at each occurrence from H, C1-C4-haloalkyl and C1-C4-alkyl; 9d are independently selected from H and C1-C4-alkyl; and n3 is an integer selected from 0, 1, 2, 3 and 4. For clarity, throughout the specification, n3 R 9 The group may be attached to any ring of the bridged bicyclic system. 1 Can be independently selected from O and NR 17 .Y 1 It can be NR 17 .Y 1 Can be NH. n3 can be 0. R 9 Each occurrence may independently be methyl.

[0246] It can be R 1 and R 5 Together with the nitrogen to which they are attached, they form a ring system having the following structure: where Y 1 Independently selected from C(O)NR 9d , O and NR 17 ; Z 5 Independently selected from the following: CH2, CH2CH2, CH2-O-CH2CH2, CH2-O-CH2, CH2-NR 17 -CH2CH2 and CH2-NR 17 -CH2; R 17 R is independently selected at each occurrence from H, C1-C4-haloalkyl and C1-C4-alkyl; 9d are independently selected from H and C1-C4-alkyl; and n5 is an integer selected from 0, 1, 2, 3 and 4. For clarity, throughout the specification, n5 R 9 The group may be attached to any ring of the bridged bicyclic system. 5 Y is independently selected from the following: CH2, CH2CH2, CH2-O-CH2CH2, CH2-O-CH2. 1 Can be independently selected from O and NR 17 .Y 1 It can be NR17 .Y 1 Can be NH. n5 can be 0. R 9 Each occurrence may independently be methyl.

[0247] It can be R 1 and R 5 Together with the nitrogen to which they are attached, they form a ring system having the following structure:

[0248] where Z 6 Independently selected from C(O)NR 9b ,O,S,S(O)2,S(O),S(O)(NR 9b ), S(O)(NH) and NR 9b ; 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. Z 6 Can be selected from NR 9b ,O,S,S(O)2,S(O),S(O)(NR 9b ) and S(O)(NH). Z 6 Can be selected from C(O)NR 9b , O, S, S(O)2, S(O) and S(O)(NH). Z 6 It may be selected from O, S, S(O)2, S(O) and S(O)(NH). 6 Can be selected from NR 9b , O and S. Z 6 Can be selected from O and S. Z 6 It can be O.

[0249] It can be R 1 and R 5 Together with the nitrogen to which they are attached, they form a ring system having the following structure:

[0250]

[0251] wherein n7 is an integer selected from 0, 1, 2 and 3.

[0252] It can be R 1 and R 5 Together with the nitrogen to which they are attached, they form a ring system having the following structure:

[0253]

[0254] wherein n7 is an integer selected from 0, 1, 2 and 3.

[0255] It can be R 1 and R 5Together with the nitrogen to which they are attached, they form a ring system having the following structure:

[0256]

[0257] wherein n8 is an integer selected from 0, 1, 2 and 3.

[0258] n7 can be 0.

[0259] It can be R 1 and R 5 Together with the nitrogen to which they are attached, they form a ring system having the following structure:

[0260]

[0261] where 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.

[0262] It can be R 1 and R 5 Together with the nitrogen to which they are attached, they form a ring system having a structure selected from the group consisting of:

[0263]

[0264] It can be R 1 and R 5 Together with the nitrogen to which they are attached, they form a ring system having the following structure:

[0265]

[0266] R 2 It can be C0-C4-alkylene-R 2a . R 2 Can be CH2-R 2a . R 2a can be selected from monocyclic 4 to 7 membered heterocycloalkyl, fused, spirofused or bridged bicyclic 6 to 11 membered heterocycloalkyl; wherein said R 2a The group is optionally substituted by 1 to 6 R 10 Group substitution. 2a At least one nitrogen may be contained in the ring system. 2a A single nitrogen may be contained in the ring system. 2a can be selected from monocyclic 4 to 7 membered heterocycloalkyl, fused, spirofused or bridged bicyclic 6 to 11 membered heterocycloalkyl; wherein said R 2a The group is optionally substituted by 1 to 6 R 10 group substituted, and wherein R 2a Contains at least one nitrogen in the ring system. 2aIt can be a monocyclic 4 to 7-membered heterocycloalkyl group; wherein said R 2a The group is optionally substituted by 1 to 6 R 10 group substituted, and wherein R 2a Contains at least one nitrogen in the ring system. 2a It may be a fused, spirofused or bridged bicyclic 6 to 11 membered heterocycloalkyl; wherein said R 2a The group is optionally substituted by 1 to 6 R 10 group substituted, and wherein R 2a Contains at least one nitrogen in the ring system.

[0267] R 2 Can have the following structure:

[0268] where R 15 are independently selected from H, C1-C4-alkyl; wherein R 16 are independently selected from H, C1-C4-alkyl and cyclopropyl; or wherein R 15 and R 16 Together with the atoms to which they are attached, they form a 5- or 6-membered heterocycloalkyl ring, which is optionally substituted by 1 or 2 R 10 and y is independently selected from 0, 1, 2, 3, and 4. y may be selected from 0 and 1. y may be 0. y may be 1. R 15 It can be H. R 16 It can be C1-C4-alkyl.

[0269] R 2 Can have the following structure:

[0270] 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.

[0271] R 2 Can have the following structure:

[0272]

[0273] R 2 Can have the following structure:

[0274]

[0275] R 3a Each occurrence may be independently selected from H, C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl; or wherein two R 3a The groups together with the carbon to which they are attached form a spirofused cyclopropyl group. 3a It can be H. R 3aIt may be C1-C4-alkyl, for example methyl.

[0276] R 3b R may be selected from H and C1-C4-alkyl. 3b It can be H. R 3b It may be C1-C4-alkyl, for example methyl.

[0277] R 4 It can be a phenyl group, which is optionally fused to a C5-C7-cycloalkyl ring, wherein R 4 Optionally 1 to 4 R 14 Group substitution. 4 It may be a phenyl group, which is optionally substituted by 1 to 4 R 14 Group substitution. 4 It may be a monocyclic 4 to 7-membered cycloalkyl group. 4 R may be a monocyclic 4 to 7 membered heterocycloalkyl group, which is optionally fused to a C5-C6-heteroaryl ring. 4 It may be a 5-membered heterocycloalkyl group, such as thienyl, which is fused to a monocyclic 5- to 6-membered cycloalkyl group, such as cyclohexyl. 4 Can be 1 to 4 R 14 For the sake of clarity, in R 4 In the case of a fused ring structure, for example a 5-membered heterocycloalkyl fused to a monocyclic 5- to 6-membered cycloalkyl, 1 to 4 R 14 The group may be attached to any ring. For example, a 5-membered heterocycloalkyl group may be substituted by, for example, cyano and -NH2, and the monocyclic 5- to 6-membered cycloalkyl group fused thereto may be further substituted by, for example, C1-C4-alkyl.

[0278] R 4 Can have the following structure:

[0279] where R 12a R is independently H or C1-C4-alkyl; x1 is independently selected from 0, 1, 2 and 3. 12a It can be H.

[0280] R 4 It may be naphthyl, which is optionally substituted by 1 to 4 R 14 Group substitution. 4 Can have the following structure:

[0281] wherein x is independently selected from 0, 1, 2, 3 and 4. For clarity, throughout the specification, xR 14 The group may be attached to any ring of the naphthyl group.

[0282] R 4 Can have the following structure:

[0283] where R 12a are independently H or C1-C4-alkyl; x2 is independently selected from 0, 1, 2 and 3. For clarity, throughout the specification, x2 R 14 The group may be attached to any ring of the naphthyl group. 12a It can be H.

[0284] R 4 Can have the following structure:

[0285] where R 14 are independently H, cyano, NR 12 R 13 and C1-C4-alkyl. X3 is independently selected from 0, 1, 2 and 3. For clarity, throughout the specification, x3 R 14 The group may be attached to any ring of the heterocyclic group.

[0286] R 4 Can have the following structure:

[0287]

[0288] R 4 It may be a 5-, 6-, 9- or 10-membered monocyclic or bicyclic heteroaryl group, which is optionally substituted by 1 to 4 R 14 Group substitution. 4 It may be a 9- or 10-membered bicyclic heteroaryl group, which is optionally substituted by 1 to 4 R 14 Group substitution.

[0289] R 5 It can be H. R 5 It may be C1-C4-alkyl, for example methyl.

[0290] R 6 It can be H. R 6 It may be C1-C4-alkyl, for example methyl.

[0291] R 7 R may be selected from H and C1-C4-alkyl. 7 It can be H. R 7 It may be C1-C4-alkyl, for example methyl.

[0292] R 8 R may be selected from H and C1-C4-alkyl. 8 It can be H. R 8 It may be C1-C4-alkyl, for example methyl.

[0293] R 9Each occurrence can be independently selected from the following: oxo, fluoro, cyano, NR 12 R 13 , OR 12 、COR 12 、C1-C4-alkyl、CONR 12 R 13 ; by NR 12 R 13 Substituted C1-C4-alkyl, 12 Substituted C1-C4-alkyl, C1-C4-alkyl substituted by cyano, C1-C4-alkyl substituted by phenyl. 9 Each occurrence may be independently selected from the following: oxo, fluoro, NR 12 R 13 , OR 12 、COR 12 、CONR 12 R 13 ; C1-C4-alkyl, NR 12 R 13 Substituted C1-C4-alkyl, C1-C4-alkyl substituted by phenyl and C1-C4-alkyl substituted by OR 12 Substituted C1-C4-alkyl.

[0294] R 9 Each occurrence may be independently selected from the following: oxo, fluoro, cyano, NR 12 R 13 , OR 12 、C1-C4-alkyl、NR 12 R 13 Substituted C1-C4-alkyl, 12 Substituted C1-C4-alkyl, C1-C4-alkyl substituted by cyano. 9 Each occurrence may be independently selected from the following: oxo, fluoro, NR 12 R 13 , OR 12 、C1-C4-alkyl、NR 12 R 13 Substituted C1-C4-alkyl and OR 12 Substituted C1-C4-alkyl.

[0295] R 9 Each occurrence may be independently selected from the following: oxo, halogen, cyano, NR 12 R 13 (The condition is R 12 Not H and R 13 Not H), OR 12 、COR 12 、CO2R12 、CONR 12 R 12 、C1-C4-alkyl、NR 12 R 13 Substituted C1-C4-alkyl (provided that R 12 Not H and R 13 Not H), OR 12 Substituted C1-C4-alkyl, C1-C4-alkyl substituted by cyano, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl.

[0296] R 9 Each occurrence may be independently selected from the following: oxo, halogen, cyano, NR 12 R 13 (The condition is R 12 Not H and R 13 Not H), OR 12 、CO2R 12 、CONR 12 R 12 、C1-C4-alkyl、NR 12 R 13 Substituted C1-C4-alkyl (provided that R 12 Not H and R 13 Not H), OR 12 Substituted C1-C4-alkyl, C1-C4-alkyl substituted by cyano, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl.

[0297] R 10 Each occurrence can be independently selected from the following: oxo, halogen, cyano, NR 12 R 13 , OR 12 、CO2R 12 、CONR 12 R 12 、C1-C4-alkyl、NR 12 R 13 Substituted C1-C4-alkyl, 12 Substituted C1-C4-alkyl, C1-C4-alkyl substituted by cyano, C1-C4-alkyl substituted by phenyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl.

[0298] R 10 Each occurrence may be independently selected from the following: oxo, halogen, cyano, NR 12 R 13 , OR 12、CO2R 12 、CONR 12 R 12 、C1-C4-alkyl、NR 12 R 13 Substituted C1-C4-alkyl, 12 Substituted C1-C4-alkyl, C1-C4-alkyl substituted by cyano, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl.

[0299] R 10 Each occurrence may be independently selected from the following: oxo, fluoro, NR 12 R 13 , OR 12 , C1-C4-alkyl, C1-C4-alkyl substituted by phenyl, NR 12 R 13 Substituted C1-C4-alkyl and OR 12 Substituted C1-C4-alkyl.

[0300] R 10 Each occurrence may be independently selected from the following: oxo, fluoro, NR 12 R 13 , OR 12 、C1-C4-alkyl、NR 12 R 13 Substituted C1-C4-alkyl and OR 12 Substituted C1-C4-alkyl.

[0301] R 11 Each occurrence can be independently selected from the following: halogen, cyano, nitro, NR 12 R 13 , OR 12 、C1-C4-alkyl、NR 12 R 13 Substituted C1-C4-alkyl, 12 Substituted C1-C4-alkyl, monocyclic 4- to 7-membered cycloalkyl or heterocycloalkyl, C1-C4-haloalkyl and cyclopropyl. 11 Each occurrence can be independently selected from OR 12 , monocyclic 4- to 7-membered cycloalkyl or heterocycloalkyl, C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl.

[0302] R 11 Each occurrence can be independently selected from the following: halogen, cyano, nitro, NR 12 R 13 , OR 12 、C1-C4-alkyl、NR12 R 13 Substituted C1-C4-alkyl, 12 Substituted C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl. 11 Each occurrence can be independently selected from OR 12 , C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl.

[0303] It can be R 12 is independently selected at each occurrence from H, C1-C4-haloalkyl, C1-C4-alkyl, and cyclopropyl; and R 13 is independently selected at each occurrence from H, C1-C4-alkyl, C1-C4-haloalkyl and C(O)-C1-C4-alkyl.

[0304] It can be R 12 is independently selected at each occurrence from H, C1-C4-haloalkyl and C1-C4-alkyl; and R 13 is independently selected at each occurrence from H, C1-C4-alkyl, C1-C4-haloalkyl and C(O)-C1-C4-alkyl.

[0305] R 12 R is independently selected at each occurrence from H, cyclopropyl and C1-C4-alkyl.

[0306] R 12 may be independently selected at each occurrence from H and C1-C4-alkyl.

[0307] R 12 Each occurrence may independently be cyclopropyl.

[0308] R 13 may be independently selected at each occurrence from H and C1-C4-alkyl.

[0309] It can be R 12 and R 13 Together with the nitrogen to which they are attached, they form a ring system selected from the group consisting of monocyclic 4 to 7 membered heterocycloalkyl, fused, spirofused or bridged bicyclic 6 to 11 membered heterocycloalkyl, optionally substituted by 1 to 6 R 10 Group substitution. It can be R 12 and R 13 Together with the nitrogen to which they are attached they form a monocyclic 4- to 7-membered heterocycloalkyl group, for example piperidinyl.

[0310] R 14 Each occurrence can be independently selected from the following: halogen, cyano, nitro, NR 12 R 13 , OR 12、C1-C4-alkyl、NR 12 R 13 Substituted C1-C4-alkyl, 12 Substituted C1-C4-alkyl, C1-C4-haloalkyl, phenyl and cyclopropyl. 14 Each occurrence can be independently selected from OR 12 , C1-C4-alkyl, C1-C4-haloalkyl, phenyl and cyclopropyl.

[0311] R 14 Each occurrence can be independently selected from the following: halogen, cyano, nitro, NR 12 R 13 , OR 12 、C1-C4-alkyl、NR 12 R 13 Substituted C1-C4-alkyl, 12 Substituted C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl. 14 Each occurrence can be independently selected from OR 12 , C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl.

[0312] The compound of formula (I) may be selected from the following:

[0313]

[0314]

[0315]

[0316]

[0317]

[0318]

[0319]

[0320]

[0321]

[0322]

[0323]

[0324]

[0325]

[0326] The compound of formula (I) may be selected from the following:

[0327]

[0328]

[0329]

[0330]

[0331]

[0332]

[0333]

[0334]

[0335]

[0336]

[0337] This application also includes the following numbered clauses:

[0338] 1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0339]

[0340] Z 1 Independently selected from -O- and -NR 5 -;

[0341] Z 2 Independently absent or selected from -O- and -NR 6 -;

[0342] L 1 Selected from bonds and -C(R 18 )2-

[0343] X 1 Selected from -C(R 3a )2 and -NR 3b -;

[0344] R 1 Independently selected from C0-C3-alkylene-R 1a and C2-C6-alkylene-R 1b ; where R 1a is independently selected from an oxygen-containing 4- to 7-membered heterocycloalkyl ring, which is a 4- to 7-membered heterocycloalkyl ring; and 7 R8 wherein the heterocycloalkyl ring or the cycloalkyl ring is optionally substituted with 1 to 4 R 9 Group substitution; R 1b Independently selected from the following: NR 7 R 8 , OR 8 SR 8 、SOR 8 、SO2R 8 and SO(NH)R 8 ; or R 1 and R 5 Together with the nitrogen to which they are attached, they form a ring system selected from: optionally substituted by 1 to 4 R 9 monocyclic 4 to 7 membered heterocycloalkyl substituted with a group; optionally substituted with 1 to 4 R 9 a substituted fused, spirofused or bridged bicyclic 6- to 11-membered heterocyclyl;

[0345] 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 ;

[0346] R 2a is independently selected from monocyclic 4 to 7 membered heterocycloalkyl, fused, spirofused or bridged bicyclic 6 to 11 membered heterocycloalkyl; 5, 6, 9 or 10 membered monocyclic or bicyclic heteroaryl; phenyl; C3-C7-cycloalkyl; wherein any heterocycloalkyl or cycloalkyl R 2a The group is optionally substituted by 1 to 6 R 10 group substituted, and any heteroaryl or phenyl R 2a The group is optionally substituted by 1 to 6 R 11 group substitution;

[0347] where R 2b Independently selected from CONR 12 R 12 and CO2R 12 ;

[0348] where R 2c Independently selected from NR 12 R 13 and OR 12 ;

[0349] or R 2 and R 6Together with the nitrogen to which they are attached, they form a ring system selected from the group consisting of monocyclic 4 to 7 membered heterocycloalkyl, fused, spirofused or bridged bicyclic 6 to 11 membered heterocycloalkyl, optionally substituted by 1 to 6 R 10 group substitution;

[0350] R 3a In each occurrence, independently selected from the group consisting of: H, C1-C4-alkyl, C1-C4-haloalkyl, 12 R 13 Substituted C1-C4-alkyl, 12 Substituted C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl; or two of R 3a The groups, together with the carbon to which they are attached, form a spiro-fused cyclopropyl group;

[0351] R 3b independently selected from H, C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl;

[0352] R 4 are independently selected from the group consisting of: 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 Optionally 1 to 4 R 14 group substitution;

[0353] R 5 、R 6 、R 8 and R 12 are independently selected at each occurrence from H, C1-C4-haloalkyl and C1-C4-alkyl;

[0354] R 7 and R 13 are independently selected at each occurrence from H, C1-C4-alkyl, C1-C4-haloalkyl and C(O)-C1-C4-alkyl;

[0355] R 9 and R 10 is independently selected at each occurrence from the group consisting of: oxo, halogen, cyano, NR 12 R 13 , OR 12 、CO2R 12 、CONR 12 R 12 、C1-C4-alkyl、NR 12 R 13 Substituted C1-C4-alkyl, 12Substituted C1-C4-alkyl, C1-C4-alkyl substituted by cyano, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl;

[0356] R 11 Independently selected from the following: halogen, cyano, nitro, NR 12 R 13 , OR 12 、CO2R 12 、CONR 12 R 12 、C1-C4-alkyl、NR 12 R 13 Substituted C1-C4-alkyl, 12 substituted C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl;

[0357] R 14 is independently selected at each occurrence from the group consisting of: H, halogen, cyano, nitro, NR 12 R 13 , OR 12 、CO2R 12 、CONR 12 R 12 、C1-C4-alkyl、NR 12 R 13 Substituted C1-C4-alkyl, 12 substituted C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl;

[0358] R 18 is independently selected at each occurrence from the group consisting of: H, halogen, cyano, nitro, NR 12 R 13 , OR 12 、CO2R 12 、CONR 12 R 12 、C1-C4 alkyl、NR 12 R 13 Substituted C1-C4-alkyl, 12 Substituted C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl; or two of R 18 The groups, together with the carbon to which they are attached, form a spiro-fused cyclopropyl group;

[0359] wherein any of the above alkyl, alkylene or cyclopropyl groups is optionally substituted, where chemically possible, by 1 to 5 substituents, each of which is independently selected at each occurrence from the group consisting of: C1-C4-alkyl, halogen, nitro, cyano, NR a R b , OR a SR 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; and 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.

[0360] 2. The compound according to claim 1, wherein R 1 and R 5 , making NR 1 R 5 Contains no more than a monoamine, wherein the monoamine can be a primary, secondary or tertiary amine.

[0361] 3. The compound according to claim 1 or 2, wherein R 1 and R 5 Together with the nitrogen to which they are attached, they form a ring system selected from the group consisting of: optionally substituted by 1 to 4 R 9 monocyclic 4 to 7 membered heterocycloalkyl substituted with a group; optionally substituted with 1 to 4 R 9 a fused or spirofused bicyclic 6- to 11-membered heterocyclic group substituted with a group; and optionally substituted with 1 to 4 R 9 a bridged bicyclic 6- to 11-membered heterocyclic group substituted by a group; wherein R 1 and R 5 The attached nitrogen is the only nitrogen in the ring system.

[0362] 4. The compound according to any one of claims 1 to 3, wherein R 1 and R 5 Together with the nitrogen to which they are attached, they form a ring system selected from the group consisting of: optionally substituted by 1 to 4 R 9 monocyclic 4 to 7 membered heterocycloalkyl substituted with a group; optionally substituted with 1 to 4 R 9 substituted fused or spirofused bicyclic 6- to 11-membered heterocycloalkyl.

[0363] 5. The compound according to claim 4, wherein R 1 and R 5Together with the nitrogen to which they are attached, they form a ring system having the following structure:

[0364] where Z 6 Independently selected from C(O)NR 9b NR 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.

[0365] 6. The compound according to claim 5, wherein R 1 and R 5 Together with the nitrogen to which they are attached, they form a ring system having the following structure:

[0366]

[0367] where Z 6 Independently selected from C(O)NR 9b ,O,S,S(O)2,S(O),S(O)(NR 9b ), S(O)(NH) and NR 9b ; 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.

[0368] 7. The compound according to claim 6, wherein Z 6 Can be O. The compound according to any one of claims 1 to 7, wherein R 2 Has the following structure:

[0369] where R 15 are independently selected from H, C1-C4-alkyl; wherein R 16 are independently selected from H, C1-C4-alkyl and cyclopropyl; or wherein R 15 and R 16 Together with the atoms to which they are attached, they form a 5- or 6-membered heterocycloalkyl ring, which is optionally substituted by 1 or 2 R 10 and y is independently selected from 0, 1, 2, 3 and 4.

[0370] 8. The compound according to claim 7, wherein R 2 Has the following structure:

[0371] wherein z is independently selected from 0, 1, 2, 3 and 4.

[0372] 9. The compound according to any one of claims 1 to 8, wherein L 1 Yes key.

[0373] 10. The compound according to any one of claims 1 to 8, wherein L 1 Yes-C(R 18 )2-.

[0374] 11. The compound according to claim 10, wherein R 18 It is H at every occurrence.

[0375] 12. A compound according to any one of claims 1 to 11, wherein X 1 Yes-C(R 3a )2-.

[0376] 13. The compound according to claim 12, wherein R 3a are independently selected at each occurrence from H, C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl; or wherein two R 3a The groups, together with the carbon to which they are attached, form a spiro-fused cyclopropyl.

[0377] 14. The compound according to claim 11 or 12, wherein R 3a It is H at every occurrence.

[0378] 15. A compound according to any one of claims 1 to 11, wherein X 1 Yes-NR 3b -.

[0379] 16. The compound according to claim 15, wherein R 3b is selected from H and C1-C4-alkyl.

[0380] 17. A compound according to any one of claims 1 to 16, wherein R 4 is a phenyl group, said phenyl group being optionally fused to a C5-C7-cycloalkyl ring, wherein R 4 Optionally 1 to 4 R 14 Group substitution.

[0381] 18. A compound according to any one of claims 1 to 16, wherein R 4 Has the following structure: wherein x is independently selected from 0, 1, 2, 3 and 4.

[0382] 19. The compound according to claim 18, wherein R 4 Has the following structure:

[0383] where R12a is independently H or C1-C4-alkyl; x2 is independently selected from 0, 1, 2 and 3.

[0384] 20. A compound according to any one of claims 1 to 16, wherein R 4 is a 5-, 6-, 9- or 10-membered monocyclic or bicyclic heteroaryl group, which is optionally substituted by 1 to 4 R 14 Group substitution.

[0385] 21. The compound according to claim 1, wherein the compound of formula (I) is selected from the group consisting of:

[0386]

[0387]

[0388]

[0389]

[0390] 22. A compound according to any one of claims 1 to 21 for use in medical treatment.

[0391] 23. A compound according to any one of claims 1 to 21 for use in the treatment of cancer.

[0392] 24. The compound of claim 23, wherein the cancer is selected from the group consisting of pancreatic cancer, colorectal cancer, rectal cancer, endometrial cancer, non-small cell lung cancer, gastric cancer, ovarian cancer, and small cell lung cancer.

[0393] 25. The compound of claim 23 or 24, wherein the subject being treated has a cancer with wild-type KRAS.

[0394] 26. The compound of claim 23 or 24, wherein the subject being treated has a cancer having a KRAS mutation selected from the group consisting of KRAS G12D, KRAS G12C, KRAS G12V, KRAS G12A, KRAS G12D, KRASG13D, and KRAS Q61H.

[0395] 27. A pharmaceutical composition comprising a compound according to any one of claims 1 to 21 and a pharmaceutically acceptable excipient.

[0396] This application also includes the following numbered clauses:

[0397] 1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0398]

[0399] Z 1 Independently selected from -O- and -NR 5 -;

[0400] Z 2 Independently absent or selected from -O- and -NR 6 -;

[0401] L 1 Selected from bonds and -C(R 18 )2-

[0402] X 1 Selected from -C(R 3a )2 and -NR 3b -;

[0403] R 1 Independently selected from C0-C3-alkylene-R 1a and C2-C6-alkylene-R 1b ; where R 1a is independently selected from an oxygen-containing 4- to 7-membered heterocycloalkyl ring, which is a 4- to 7-membered heterocycloalkyl ring; and 7 R 8 wherein the heterocycloalkyl ring or the cycloalkyl ring is optionally substituted with 1 to 4 R 9 Group substitution; R 1b Independently selected from the following: NR 7 R 8 , OR 8 SR 8 、SOR 8 、SO2R 8 and SO(NH)R 8 ; or R 1 and R 5 Together with the nitrogen to which they are attached, they form a ring system selected from the group consisting of: optionally substituted by 1 to 4 R 9 monocyclic 4 to 7 membered heterocycloalkyl substituted with a group; optionally substituted with 1 to 4 R 9 a substituted fused, spirofused or bridged bicyclic 6- to 11-membered heterocyclyl;

[0404] 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 ;

[0405] R 2ais independently selected from monocyclic 4 to 7 membered heterocycloalkyl, fused, spirofused or bridged bicyclic 6 to 11 membered heterocycloalkyl; 5, 6, 9 or 10 membered monocyclic or bicyclic heteroaryl; phenyl; C3-C7-cycloalkyl; wherein any heterocycloalkyl or cycloalkyl R 2a The group is optionally substituted by 1 to 6 R 10 group substituted, and any heteroaryl or phenyl R 2a The group is optionally substituted by 1 to 6 R 11 group substitution;

[0406] where R 2b Independently selected from CONR 12 R 12 and CO2R 12 ;

[0407] where R 2c Independently selected from NR 12 R 13 and OR 12 ;

[0408] or R 2 and R 6 Together with the nitrogen to which they are attached, they form a ring system selected from the group consisting of monocyclic 4 to 7 membered heterocycloalkyl, fused, spirofused or bridged bicyclic 6 to 11 membered heterocycloalkyl, optionally substituted by 1 to 6 R 10 group substitution;

[0409] R 3a In each occurrence, independently selected from the group consisting of: H, C1-C4-alkyl, C1-C4-haloalkyl, 12 R 13 Substituted C1-C4-alkyl, 12 Substituted C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl; or two of R 3a The groups, together with the carbon to which they are attached, form a spiro-fused cyclopropyl group;

[0410] R 3b independently selected from H, C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl;

[0411] R 4 are independently selected from the group consisting of: 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 Optionally 1 to 4 R 14 group substitution;

[0412] R 5 、R6 、R 8 and R 12 are independently selected at each occurrence from H, C1-C4-haloalkyl and C1-C4-alkyl;

[0413] R 7 and R 13 are independently selected at each occurrence from H, C1-C4-alkyl, C1-C4-haloalkyl and C(O)-C1-C4-alkyl;

[0414] or R 12 and R 13 Together with the nitrogen to which they are attached, they form a ring system selected from the group consisting of monocyclic 4 to 7 membered heterocycloalkyl, fused, spirofused or bridged bicyclic 6 to 11 membered heterocycloalkyl, optionally substituted by 1 to 6 R 10 group substitution;

[0415] R 9 and R 10 is independently selected at each occurrence from the group consisting of: oxo, halogen, cyano, NR 12 R 13 , OR 12 、CO2R 12 、CONR 12 R 12 、C1-C4-alkyl、NR 12 R 13 Substituted C1-C4-alkyl, 12 Substituted C1-C4-alkyl, C1-C4-alkyl substituted by cyano, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl;

[0416] R 11 Independently selected from the following: halogen, cyano, nitro, NR 12 R 13 , OR 12 、CO2R 12 、CONR 12 R 12 、C1-C4-alkyl、NR 12 R 13 Substituted C1-C4-alkyl, 12 Substituted C1-C4-alkyl, monocyclic 4- to 7-membered cycloalkyl or heterocycloalkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl; R 14 is independently selected at each occurrence from the group consisting of: H, halogen, cyano, nitro, NR 12 R 13 , OR 12 、CO2R12 、CONR 12 R 12 、C1-C4-alkyl、NR 12 R 13 Substituted C1-C4-alkyl, 12 substituted C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl;

[0417] R 18 is independently selected at each occurrence from the group consisting of: H, halogen, cyano, nitro, NR 12 R 13 , OR 12 、CO2R 12 、CONR 12 R 12 、C1-C4 alkyl、NR 12 R 13 Substituted C1-C4-alkyl, 12 Substituted C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl; or two of R 18 The groups, together with the carbon to which they are attached, form a spiro-fused cyclopropyl group;

[0418] wherein any of the above alkyl, alkylene or cyclopropyl groups is optionally substituted, where chemically possible, by 1 to 5 substituents, each of which is independently selected at each occurrence from the group consisting of: C1-C4-alkyl, halogen, nitro, cyano, NR a R b , OR a SR 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; and 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.

[0419] 2. The compound of clause 1, wherein R 1 and R 5 , making NR 1 R 5 Contains no more than a monoamine, wherein the monoamine can be a primary, secondary or tertiary amine.

[0420] 3. The compound of clause 1 or clause 2, wherein R1 and R 5 Together with the nitrogen to which they are attached, they form a ring system selected from: optionally substituted by 1 to 4 R 9 monocyclic 4 to 7 membered heterocycloalkyl substituted with a group; optionally substituted with 1 to 4 R 9 a fused or spirofused bicyclic 6- to 11-membered heterocyclic group substituted with a group; and optionally substituted with 1 to 4 R 9 a bridged bicyclic 6- to 11-membered heterocyclic group substituted by a group; wherein R 1 and R 5 The attached nitrogen is the only nitrogen in the ring system.

[0421] 4. The compound of any one of clauses 1 to 3, wherein R 1 and R 5 Together with the nitrogen to which they are attached, they form a ring system selected from: optionally substituted by 1 to 4 R 9 monocyclic 4 to 7 membered heterocycloalkyl substituted with a group; optionally substituted with 1 to 4 R 9 A substituted fused or spirofused bicyclic 6- to 11-membered heterocycloalkyl group.

[0422] 5. The compound of clause 4, wherein R 1 and R 5 Together with the nitrogen to which they are attached, they form a ring system having the following structure:

[0423] where Z 6 Independently selected from C(O)NR 9b NR 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.

[0424] 6. The compound of clause 5, wherein R 1 and R 5 Together with the nitrogen to which they are attached, they form a ring system having the following structure:

[0425]

[0426] where Z 6 Independently selected from C(O)NR 9b ,O,S,S(O)2,S(O),S(O)(NR 9b ), S(O)(NH) and NR 9b ; 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.

[0427] 7. The compound according to clause 6, wherein Z 6 It can be O.

[0428] 8. The compound of any one of clauses 1 to 7, wherein R 2 Has the following structure:

[0429] where R 15 are independently selected from H, C1-C4-alkyl; wherein R 16 are independently selected from H, C1-C4-alkyl and cyclopropyl; or wherein R 15 and R 16 Together with the atoms to which they are attached, they form a 5- or 6-membered heterocycloalkyl ring, which is optionally substituted by 1 or 2 R 10 and y is independently selected from 0, 1, 2, 3 and 4.

[0430] 9. The compound according to item 8, wherein R 2 Has the following structure:

[0431] wherein z is independently selected from 0, 1, 2, 3 and 4.

[0432] 10. The compound of any one of clauses 1 to 9, wherein L 1 Yes key.

[0433] 11. The compound of any one of clauses 1 to 9, wherein L 1 Yes-C(R 18 )2-.

[0434] 12. The compound according to item 11, wherein R 18 It is H at every occurrence.

[0435] 13. The compound of any one of clauses 1 to 12, wherein X 1 Yes-C(R 3a )2-.

[0436] 14. The compound of clause 13, wherein R 3a are independently selected at each occurrence from H, C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl; or wherein two R 3a The groups, together with the carbon to which they are attached, form a spiro-fused cyclopropyl.

[0437] 15. The compound of clause 12 or clause 13, wherein R 3a It is H at every occurrence.

[0438] 16. The compound of any one of clauses 1 to 12, wherein X 1 Yes-NR3b -.

[0439] 17. The compound according to item 16, wherein R 3b is selected from H and C1-C4-alkyl.

[0440] 18. The compound of any one of clauses 1 to 17, wherein R 4 is a phenyl group, said phenyl group being optionally fused to a C5-C7-cycloalkyl ring, wherein R 4 Optionally 1 to 4 R 14 Group substitution.

[0441] 19. The compound of any one of clauses 1 to 17, wherein R 4 Has the following structure:

[0442] wherein x is independently selected from 0, 1, 2, 3 and 4.

[0443] 20. The compound according to item 19, wherein R 4 Has the following structure:

[0444] where R 12a is independently H or C1-C4-alkyl; x2 is independently selected from 0, 1, 2 and 3.

[0445] 21. The compound of any one of clauses 1 to 17, wherein R 4 is a 5-, 6-, 9- or 10-membered monocyclic or bicyclic heteroaryl group, which is optionally substituted by 1 to 4 R 14 Group substitution.

[0446] 22. The compound of clause 1, wherein the compound of formula (I) is selected from the group consisting of:

[0447]

[0448]

[0449]

[0450]

[0451]

[0452]

[0453] 23. A compound according to any one of clauses 1 to 22 for use in medicine.

[0454] 24. A compound according to any one of clauses 1 to 22 for use in the treatment of cancer.

[0455] 25. The compound of clause 24, wherein the cancer is selected from the group consisting of pancreatic cancer, colorectal cancer, rectal cancer, endometrial cancer, non-small cell lung cancer, gastric cancer, ovarian cancer, and small cell lung cancer.

[0456] 26. The compound of clause 24 or 25, wherein the subject being treated has a cancer with wild-type KRAS.

[0457] 27. The compound of clause 24 or 25, wherein the subject being treated has a cancer having a KRAS mutation selected from the group consisting of KRAS G12D, KRAS G12C, KRAS G12V, KRAS G12A, KRAS G12D, KRAS G12S, KRAS G13D, and KRAS Q61H.

[0458] 28. A pharmaceutical composition comprising a compound according to any one of clauses 1 to 22 and a pharmaceutically acceptable excipient. DETAILED DESCRIPTION

[0459] In one aspect of the present invention there is provided a compound of the present invention for use as a medicament.

[0460] According to another aspect, the present invention provides a method of treating a condition modulatable by inhibition of a KRAS protein having a G12D mutation, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention.

[0461] According to another aspect, the present invention provides a pharmaceutical formulation comprising a compound of the present invention and a pharmaceutically acceptable excipient.

[0462] In one embodiment, the pharmaceutical composition can be a combination product comprising an additional pharmaceutically active agent. The additional pharmaceutically active agent can 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.

[0463] In one aspect of the present invention, there is provided a compound of the present invention for use in the treatment of cancer.

[0464] In one aspect of the present invention, a method of treating cancer is provided, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention.

[0465] In one aspect of the present invention, there is provided use of the compound of the present invention in the preparation of a medicament for treating cancer.

[0466] The cancer may be a solid tumor or a liquid tumor. The cancer may be a carcinoma.

[0467] The cancer can 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, chondosarcoma, Ewing's sarcoma, rabdomysarcoma, 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, cancer of unknown primary, ampullary cancer, 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.

[0468] 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.

[0469] The cancer may have wild-type KRAS. The cancer may have a KRAS mutation. The cancer may have a KRAS mutation selected from the group consisting of KRAS G12D, KRAS G12C, KRAS G12V, KRAS G12A, KRAS G12S, KRAS G13D, and KRASQ61H. The cancer may have a KRAS G12D mutation. The cancer may have a KRAS G12D mutation, and the cancer may be selected from the group consisting of pancreatic cancer, colorectal cancer, rectal cancer, endometrial cancer, non-small cell lung cancer, gastric cancer, ovarian cancer, and small cell lung cancer.

[0470] The cancer may have a confirmed KRAS G12D mutation. The cancer may have a confirmed KRAS G12D mutation, the cancer being selected from pancreatic cancer, colorectal cancer, rectal cancer, endometrial cancer, non-small cell lung cancer, gastric cancer, ovarian cancer, and small cell lung cancer.

[0471] The subject can be a human.

[0472] The subject may have a cancer having a KRAS G12D mutation. The subject may have a cancer having a KRAS G12D mutation selected from pancreatic cancer, colorectal cancer, rectal cancer, endometrial cancer, non-small cell lung cancer, gastric cancer, ovarian cancer, and small cell lung cancer.

[0473] The subject may have a cancer with a confirmed KRAS G12D mutation. The subject may have a cancer with a confirmed KRAS G12D mutation selected from pancreatic cancer, colorectal cancer, rectal cancer, endometrial cancer, non-small cell lung cancer, gastric cancer, ovarian cancer, and small cell lung cancer.

[0474] Subjects may have a confirmed G12D mutation in their tumor. To be confirmed, a test for the presence of G12D in the tumor must have an analytical specificity of >95% for detecting KRAS mutations. Such validation tests will include commercially available tests, namely Foundation One CDx and CARIS DNA sequencing.

[0475] As described above, the present invention includes a method for treating cancer. The method may include:

[0476] a) confirming that the subject has a cancer having a G12D mutation; and

[0477] b) administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention.

[0478] The term "halogen" refers to a halogen from Group 17 of the Periodic Table of the Elements. The term refers in particular to fluorine, chlorine, bromine and iodine. Preferably, the term refers to fluorine or chlorine.

[0479] The term "alkyl" refers to a straight or branched hydrocarbon chain. For example, the term "C 1-6 Alkyl" or "C 1-4 "Alkyl" means a straight or branched hydrocarbon chain containing 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. In the case of alkyl, C 0-4 In the case of an alkyl group, it should be understood that this means the possibility that the alkyl unit is absent or has a length of 1, 2, 3 or 4 carbon atoms. An alkylene group may likewise be straight-chain or branched and may have two positions at which it is attached to the rest of the molecule. Furthermore, an alkylene group may, for example, correspond to one of the alkyl groups listed in this paragraph. Alkyl and alkylene groups may be unsubstituted or substituted by one or more substituents. Possible substituents are described below. Substituents for alkyl groups may be halogens (e.g. fluorine, chlorine, bromine and iodine), OH, C 1-6 Alkoxy.

[0480] The term "alkoxy" refers to an alkyl group attached to the molecule through an oxygen. For example, the term "C 1-6 "Alkoxy" refers to an alkyl group attached to the molecule through an oxygen. This includes moieties in which the alkyl portion may be straight or branched and may 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 may be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy and n-hexyl. The alkyl portion of the alkoxy may be unsubstituted or substituted with one or more substituents. Possible substituents are described below. Alkyl substituents may be halogen (e.g., fluorine, chlorine, bromine and iodine), OH, C1-6 Alkoxy.

[0481] The term "haloalkyl" refers to a hydrocarbon chain substituted with at least one halogen atom, independently selected at each occurrence from, for example, fluorine, chlorine, bromine, and iodine. For example, the term "C 1-6 "Haloalkyl" refers to a straight or branched hydrocarbon chain containing 1, 2, 3, 4, 5 or 6 carbon atoms substituted by at least one halogen. The halogen atom may be present at any position on the hydrocarbon chain. For example, C 1-6 The haloalkyl group may refer to a chloromethyl group, a fluoromethyl group, a trifluoromethyl group, a chloroethyl group (e.g., 1-chloromethyl and 2-chloroethyl group), a trichloroethyl group (e.g., 1,2,2-trichloroethyl group, 2,2,2-trichloroethyl group), a fluoroethyl group (e.g., 1-fluoromethyl and 2-fluoroethyl group), a trifluoroethyl group (e.g., 1,2,2-trifluoroethyl group and 2,2,2-trifluoroethyl group), a chloropropyl group, a trichloropropyl group, a fluoropropyl group, a trifluoropropyl group.

[0482] 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. One or more double bonds may exist as E or Z isomers. The double bond may be in any possible position of the hydrocarbon chain. For example, "C 2-6 The term "alkenyl" may include ethenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl and hexadienyl.

[0483] The term "alkynyl" refers to a branched or straight 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 having 2, 3, 4, 5 or 6 carbon atoms. The triple bond can be in any possible position of the hydrocarbon chain. For example, "C 2-6 The term "alkynyl" may include ethynyl, propynyl, butynyl, pentynyl and hexynyl.

[0484] The term "heteroalkyl" refers to a branched or straight hydrocarbon chain containing at least one heteroatom selected from N, O and S between any carbon atoms in the chain or at the end of the chain. 1-6 "Heteroalkyl" refers to a branched or straight hydrocarbon chain containing 1, 2, 3, 4, 5 or 6 carbon atoms and at least one heteroatom selected from N, O and S and located between any carbon atoms in the chain or at the end of the chain. For example, the hydrocarbon chain may contain one or two heteroatoms. 1-6 A heteroalkyl group can be bonded to the rest of the molecule through a carbon or heteroatom. For example, a "C 1-6 "Heteroalkyl" can be C 1-6 N-alkyl, C 1-6 N,N-alkyl or C 1-6 O-alkyl.

[0485] The term "cycloalkyl" refers to a saturated hydrocarbon ring system. For example, "C 3-8 The "cycloalkyl" group may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

[0486] The term "cycloalkenyl" refers to a non-aromatic, unsaturated hydrocarbon ring system. The ring may contain more than one double bond, provided that the ring system is not aromatic. For example, "C 3-8 The "cycloalkyl" may be cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, cyclooctenyl and cycloatadienyl.

[0487] The term "heterocycloalkyl" refers to a saturated hydrocarbon ring system containing carbon atoms and at least one heteroatom selected from N, O and S in the ring. For example, there may be 1, 2 or 3 heteroatoms, optionally 1 or 2. "Heterocycloalkyl" can be bonded to the rest of the molecule through any carbon atom or heteroatom. For example, "heterocycloalkyl" can be "C 3-8 Heterocycloalkyl". The term "C 3-8 "Heterocycloalkyl" refers to a saturated hydrocarbon ring system containing 3, 4, 5, 6, 7 or 8 carbon atoms and at least one heteroatom selected from N, O and S in the ring. For example, there may be 1, 2 or 3 heteroatoms, optionally 1 or 2. "C 3-8 "Heterocycloalkyl" can be bonded to the rest of the molecule through any carbon atom or heteroatom. "Heterocycloalkyl" can be monocyclic. "Heterocycloalkyl" can be bicyclic, such as fused, spirofused or bridged heterocycloalkyl ring systems. For example, "C 3-8 The "heterocycloalkyl" group may be oxirane, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine and tetrahydropyran.

[0488] 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, optionally 1 or 2. A "heterocyclyl" may be bonded to the rest of the molecule through 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.

[0489] The term "heterocycloalkenyl" refers to a non-aromatic, unsaturated hydrocarbon ring system containing carbon atoms and at least one heteroatom selected from N, O and S in the ring. For example, there may be 1, 2 or 3 heteroatoms, optionally 1 or 2. "Heterocycloalkenyl" can be bonded to the rest of the molecule through any carbon atom or heteroatom. For example, "heterocycloalkenyl" can be "C 3-8 Heterocycloalkenyl". The term "C 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 selected from N, O and S within the ring. "Heterocycloalkenyl" can be tetrahydropyridine, dihydropyran, dihydrofuran, pyrroline.

[0490] The term "fused" refers to a bicyclic ring system in which the two rings are joined via two atoms in each ring that are adjacent to each other.

[0491] The term "spirofused" refers to a bicyclic ring system in which the two rings are joined by a single atom.

[0492] The term "bridged" refers to a bicyclic ring system in which the two rings are joined through two atoms in either ring that are not adjacent to each other.

[0493] The term "aromatic" as applied to a substituent as a whole refers to a monocyclic or polycyclic ring system having 4n+2 electrons in a conjugated π system within the ring or ring system, wherein all atoms contributing to the conjugated π system are in the same plane.

[0494] The term "aryl" refers to an aromatic hydrocarbon ring system. This ring system has 4n+2 electrons in a conjugated π system within the ring, where all atoms contributing to the conjugated π system are in the same plane. Examples of "aryl" include phenyl and naphthyl. Aryl systems themselves may be substituted with other groups.

[0495] The term "heteroaryl" refers to an aromatic hydrocarbon ring system having at least one heteroatom selected from O, N, and S in a monocyclic or fused ring system. The ring or ring system has 4n+2 electrons in a conjugated π system, wherein all atoms contributing to the conjugated π system are in the same plane. For example, "heteroaryl" can be imidazole, thiophene, furan, thianthrene, pyrrole, benzimidazole, pyrazole, pyrazine, pyridine, pyrimidine, and indole.

[0496] The term "halogen" herein includes reference to F, Cl, Br and I. Halogen may be Br. Halogen may be I.

[0497] by A bond ending in a cyclic structure indicates that the bond is attached to another atom not shown in the structure. A bond that ends inside a cyclic structure and does not terminate at an atom in the ring structure indicates that the bond may be attached to any atom in the ring structure, valence permitting.

[0498] Where a moiety is substituted, it may be substituted at any point on the moiety where chemically possible and consistent with valence requirements. The moiety may be substituted with one or more substituents, for example 1, 2, 3 or 4 substituents; optionally, there may be 1 or 2 substituents on a group. Where there are two or more substituents, these substituents may be the same or different.

[0499] Substituents are present only at positions where they are chemically possible, and one skilled in the art can readily determine (either experimentally or theoretically) which substitutions are chemically possible and which are not.

[0500] Ortho, meta, and para substitution are terms well known in the art. For clarity, "ortho" substitution is a substitution pattern in which adjacent carbons have substituents, whether simple groups, such as the fluorine group in the example below, or other parts of the molecule, such as The key at the end is shown.

[0501]

[0502] "Meta" substitution is a substitution pattern in which the two substituents are on carbons that are one carbon away from each other, meaning there is one carbon atom between the substituted carbons. In other words, there is a substituent on the second atom away from the atom bearing the other substituent. For example, the following group is meta-substituted.

[0503]

[0504] "Para" substitution is a substitution pattern in which the two substituents are on carbons two carbons away from each other, meaning there are two carbon atoms between the substituted carbons. In other words, there is a substituent on a third atom away from the atom bearing the other substituent. For example, the following groups are para-substituted:

[0505]

[0506] Throughout the specification, the disclosure of the compound also includes its pharmaceutically acceptable salts, solvates and stereoisomers. In the case of a compound having a stereocenter, the present invention contemplates (R) and (S) stereoisomers, and similarly, mixtures or racemic mixtures of stereoisomers are completed by the present application. In the case of a compound of the present invention having two or more stereocenters, any combination of (R) and (S) stereoisomers can be considered. The combination of (R) and (S) stereoisomers can produce a diastereomeric mixture or a single diastereoisomer. The compound of the present invention can exist in the form of a single stereoisomer, or can be a mixture of stereoisomers, such as a racemic mixture and other enantiomeric mixtures, and a diastereomeric mixture. In the case where the mixture is a mixture of enantiomers, the enantiomeric excess can be any of the above disclosed. In the case where the compound is a single stereoisomer, the compound may still contain other diastereomers or enantiomers as impurities. Thus, a single stereoisomer does not necessarily have an enantiomeric excess (ee) or diastereomeric excess (de) of 100%, but may have an ee or de of about at least 85%, at least 60%, or less. For example, the ee or de may be 90% or more, 90% or more, 80% or more, 70% or more, 60% or more, 50% or more, 40% or more, 30% or more, 20% or more, or 10% or more.

[0507] The present invention contemplates pharmaceutically acceptable salts of the compounds of the present invention. These salts may include acid addition salts and base salts of the compounds. These salts may be acid addition salts and base salts of the compounds. In addition, the present invention contemplates solvates of the compounds. These solvates may be hydrates or other solvated forms of the compounds.

[0508] Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include acetate, aspartate, benzoate, benzenesulfonate, bicarbonate / carbonate, bisulfate / sulfate, borate, camphorsulfonate, citrate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthylate, 1,5-naphthalenedisulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, sucrose, stearate, succinate, tartrate, toluenesulfonate, and trifluoroacetate.

[0509] Suitable alkali salts are formed from bases that form non-toxic salts. Examples include aluminum salts, arginine salts, benzathine salts, calcium salts, choline salts, diethylamine salts, diethanolamine salts, glycine salts, lysine salts, magnesium salts, meglumine salts, ethanolamine salts, potassium salts, sodium salts, tromethamine salts, and zinc salts. Hemisalts of acids and bases, such as hemisulphates and hemicalcium salts, can also be formed. For a review of suitable salts, see Stahl and Wermuth, "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, Weinheim, Germany, 2002).

[0510] Pharmaceutically acceptable salts of compounds of formula (I) can be prepared by one or more of the following three methods:

[0511] (i) by reacting a compound of the present invention with a desired acid or base;

[0512] (ii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of the invention, or by ring-opening a suitable cyclic precursor (e.g., a lactone or lactam), using the desired acid or base; or

[0513] (iii) converting one salt of a compound of the present invention into another salt by reaction with a suitable acid or base or by passing through a suitable ion exchange column.

[0514] All three reactions are typically performed in solution. The resulting salt can be precipitated and collected by filtration, or it can be recovered by evaporating the solvent. The degree of ionization of the resulting salt can range from completely ionized to almost non-ionized.

[0515] The compounds of the present invention may exist in unsolvated and solvated forms. The term "solvate" is used herein to describe a molecular complex comprising a compound of the present invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules (e.g., ethanol). When the solvent is water, the term "hydrate" is used.

[0516] Included within the scope of the present invention are complexes such as clathrates and drug-host inclusion complexes, in which, in contrast to the solvates described above, 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 Haleblian, J Pharm Sci, 64(8), 1269-1288 (August 1975).

[0517] Hereinafter, all references to compounds of any formula include reference to salts, solvates and complexes thereof, and to solvates and complexes of their salts.

[0518] The compounds of the present invention include compounds of the numerous formulae as defined herein, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical isomers, geometric isomers and tautomers) as defined below, and isotopically labeled compounds of the present invention.

[0519] The present invention also includes all pharmaceutically acceptable isotopically labeled compounds of the present invention, wherein one or more atoms are replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature.

[0520] Examples of suitable isotopes for inclusion in the compounds of the present invention include isotopes of hydrogen (e.g. 2 H and 3 H), carbon isotopes (such as 11 C. 13 C and 14 C), isotopes of chlorine (such as 36 Cl), fluorine isotopes (such as 18 F), iodine isotopes (such as 123 I and 125 I), nitrogen isotopes (such as 13 N and 15 N), oxygen isotopes (such as 15 O. 17 O and 18 O), phosphorus isotopes (such as 32 P) and sulfur isotopes (such as 35 S).

[0521] Certain isotopically labeled compounds, for example compounds incorporating radioactive isotopes, are useful in drug and / or substrate tissue distribution studies. 3 H) and carbon-14 (i.e. 14 C) are particularly suitable for this purpose because they are easy to incorporate and have readily available means of detection.

[0522] Using heavier isotopes such as deuterium (i.e. 2 H) substitutions may offer certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and therefore may be preferred in some circumstances.

[0523] Before purification, depending on the synthetic procedure used, the compounds of the present invention may exist as mixtures of enantiomers. Enantiomers may be separated by conventional techniques known in the art. Therefore, the present invention encompasses single enantiomers and mixtures thereof.

[0524] For some steps of the method for preparing the compounds of this invention, it may be necessary to protect the potential reactive functional groups that do not wish to react, and therefore the blocking group described in the cracking. In such a case, any compatible protected free radical can be used. Especially, the method for protection and deprotection can be used, as described in TWGREENE (Protective Groups in Organic Synthesis, A.Wiley-Interscience Publication, 1981) or PJKocienski (Protecting groups, Georg Thieme Verlag, 1994). The preparation of all the above-mentioned reactions and the new raw materials used in the aforementioned method is conventional, and reference precedents and examples related thereto and preparation are known to those skilled in the art for the suitable reagents and reaction conditions and the program for separating the required product to realize their performance or preparation.

[0525] Furthermore, the compounds of the present invention and the intermediates used in their preparation can be purified according to various well-known methods, such as crystallization or chromatography.

[0526] One or more compounds of the present invention can be combined with one or more pharmaceutical agents, such as anti-inflammatory agents, anti-fibrotic agents, chemotherapeutic agents, anti-cancer agents, immunosuppressive agents, anti-tumor vaccines, cytokine therapeutics, or tyrosine kinase inhibitors, for the treatment of conditions modulated by RAS protein inhibition, such as cancer, sarcoma, melanoma, skin cancer, hematological tumors, lymphomas, carcinomas, and leukemias.

[0527] The treatment methods or compounds defined above for the treatment of cancer, sarcoma, melanoma, skin cancer, hematological tumors, lymphomas, carcinomas and leukemias may be applied as a monotherapy or as a combination therapy in combination with another active agent.

[0528] In addition to the compounds of the present invention, the methods or compounds for treating cancer, sarcoma, melanoma, skin cancer, blood tumors, lymphomas, carcinomas and leukemias involve additional active agents. The additional active agents can be one or more active agents used to treat the condition treated by the compounds of the present invention and the additional active agent. The additional active agents can include one or more of the following active agents:

[0529] (i) Steroids, such as corticosteroids, including glucocorticoids and mineralocorticoids, for example, alclomethasone, alclomethasone dipropionate, aldosterone, amcinonide, beclomethasone, beclomethasone dipropionate, betamethasone, betamethasone dipropionate, betamethasone sodium phosphate, betamethasone valerate, budesonide, clobetasone, clobetasone butyrate, clobetasol propionate, cloprednisolone, cortisone, cortisone acetate, cortivazole, deoxycorticosterone, desonide, desoximetasone, dexamethasone, dexamethasone sodium phosphate, dexamethasone isonicotinate, diflucortolone, fluclorololone, flumethasone, flunisolide, fluocinolone acetonide, fluocinolone acetate, fluocinolone butyl, fluocinolone acetonide steroids, such as fluocinolone, fluocinolone, fluocinolone hexanoate, fluocinolone pivalate, fluorometholone, fluprednidene, fluprednisolone acetate, flurandrenolide, fluticasone, fluticasone propionate, halcinonide, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone acetate propionate, hydrocortisone propionate butyrate, hydrocortisone valerate, icomethasone, icomethasone acetate butyrate, methylprednisolone, methylprednisolone, mometasone, paramethasone, mometasone furoate monohydrate, prednicasone, prednisolone, prednisone, tixocortol, tixocortol pivalate, triamcinolone acetonide, triamcinolone acetonide acetate, triamcinolone acetonide alcohol, and their respective pharmaceutically acceptable derivatives. Combinations of steroids may be used, such as combinations of two or more of the steroids mentioned in this paragraph;

[0530] (ii) TNF inhibitors, such as etanercept; monoclonal antibodies (e.g., infliximab (Remicade), adalimumab (Humira), cetrimonium (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 dimethylazetidine);

[0531] (iii) anti-inflammatory drugs, such as nonsteroidal anti-inflammatory drugs;

[0532] (iv) dihydrofolate reductase inhibitors / antifolates, such as methotrexate, trimethoprim, bromoprim, tetraoxaprine, iclaprim, pemetrexed, ralitrexed, and pralatrexate; and

[0533] (v) Immunosuppressants, such as cyclosporine, tacrolimus, sirolimus, pimecrolimus, angiotensin II inhibitors (e.g., valsartan, telmisartan, losartan, irbesartan, 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), casokinin, lactokinin and lactotripeptide.

[0534] (vi) Anti-fibrotic agents, such as 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 etexilate), factor Xa inhibitors (e.g., apixaban, rivaroxaban), 15PGDH inhibitors, anti-αvβ6 monoclonal antibodies (e.g., BG00011), anti-CTGF monoclonal antibodies (FG-3019), PAR1 inhibitors, Nox4 inhibitors, and PAI-1 inhibitors

[0535] (vii) CNS therapies, e.g., 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 (Razad yne), rivastigmine (Exelon), memantine (Ebixa, Axura), aducanumab, ocrelizumab, interferon beta-1a (Avonex, Rebif), pegylated interferon beta-1a (Plegridy), teriflunomide (Aubagio), fingolimod (Gilenya), mitoxantrone (Novantrone), dimethyl fumarate (Tecfidera), and natalizumab (Tysabri).

[0536] In addition to the compounds of the present invention, the treatment methods or compounds used to treat cancer, sarcoma, melanoma, skin cancer, blood tumors, lymphomas, carcinomas, leukemias and central nervous system disorders may also include conventional surgery or radiotherapy or chemotherapy. Such chemotherapy may include one or more of the following classes of anti-tumor agents:

[0537] (i) antiproliferative / antineoplastic drugs and combinations thereof, such as alkylating agents (e.g., cisplatin, oxaliplatin, carboplatin, cyclophosphamide, mechlorethamine, uracil mechlorethamine, bendamustine, melphalan, chlorambucil, mechlorethamine, busulfan, temozolomide, nitrosoureas, ifosfamide, melphalan, pipobroman, triethylene-melamine, triethylenethiophoporamine, carmustine, lomustine, streptozocin, and dacarbazine); antimetabolites (e.g., gemcitabine and antifolates such as fluoropyrimidines (e.g., 5-fluorouracil and tegafur), raltitrexed, methotrexate, pemetrexed, cytosine arabinoside, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatin, gemcitabine, and hydroxyurea); antibiotics (e.g., anthracyclines such as doxorubicin, bleomycin, doxorubicin, daunorubicin, epirubicin, idarubicin, mitomycin-C, dactinomycin, and mithramycin); antimitotics (e.g., vinca alkaloids such as vincristine, vinblastine, vindesine, and vinorelbine, and taxanes such as paclitaxel and taxotere, and multikinase inhibitors); 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, cytarabine, paclitaxel (Taxol TM ), albumin-bound paclitaxel (nabpaclitaxel), docetaxel, mithramycin, deoxyco-formycin, mitomycin-C, L-asparaginase, interferon (especially IFN-a), etoposide, and teniposide;

[0538] (ii) cytostatic agents, such as antiestrogens (e.g., tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene, and iodoxyfene), antiandrogens (e.g., bicalutamide, flutamide, nilutamide, and cyproterone acetate), LHRH antagonists or LHRH agonists (e.g., goserelin, leuprorelin, and buserelin), progestins (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, raloxifene, cyclophosphamide, ifosfamide, and droloxafine;

[0539] (iii) anti-invasive agents, such as dasatinib and bosutinib (SKI-606), as well as metalloproteinase inhibitors, inhibitors of urokinase plasminogen activator receptor function, or heparanase antibodies;

[0540] (iv) Inhibitors of growth factor function: For example, such inhibitors include growth factor antibodies and growth factor receptor antibodies, such as the anti-erbB2 antibody trastuzumab [Herceptin TM ], anti-EGFR antibody panitumumab, anti-erbB1 antibody cetuximab, tyrosine kinase inhibitors, such as inhibitors of the epidermal growth factor family (e.g., EGFR family tyrosine kinase inhibitors, such as gefitinib, erlotinib, 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine (CI 1033), erbB2 tyrosine kinase inhibitors, such as lapatinib) and antibodies to costimulatory molecules (such as CTLA-4, 4-1BB and PD-1), or antibodies to cytokines (IL-10, TGF-β); inhibitors of the hepatocyte growth factor family; inhibitors of the insulin growth factor family; modulators of apoptosis protein regulators (e.g., Bcl-2 inhibitors); inhibitors of the platelet-derived growth factor family, such as imatinib and / or nilotinib (AMN107); inhibitors of serine / threonine kinases (e.g. Ras / Raf signaling inhibitors, such as farnesyl transferase inhibitors, for example, sorafenib, tipifarnib, and lonafarnib), inhibitors of cell signaling through MEK and / or AKT kinases, c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1R kinase inhibitors, IGF receptor, kinase inhibitors; Aurora kinase inhibitors and cyclin-dependent kinase inhibitors, for example, CDK2 and / or CDK4 inhibitors; and CCR2, CCR4, or CCR6 modulators;

[0541] (v) Anti-angiogenic agents, such as those that inhibit the action of vascular endothelial growth factor, such as the anti-vascular endothelial growth factor antibody bevacizumab (Avastin TM ); thalidomide; lenalidomide; and, for example, VEGF receptor tyrosine kinase inhibitors such as vandetanib, vatalanib, sunitinib, axitinib, and pazopanib;

[0542] (vi) gene therapy approaches, including, for example, approaches that replace abnormal genes such as abnormal p53 or abnormal BRCA1 or BRCA2;

[0543] (vii) Immunotherapy approaches, including, for example, antibody therapies such as alemtuzumab, rituximab, ibritumomab and ofatumumab; interferons, such as interferon alpha; interleukins, such as IL-2 (aldesleukin); interleukin inhibitors, such as IRAK4 inhibitors; cancer vaccines, including prophylactic and therapeutic vaccines, such as HPV vaccines, such as Gardasil, Cervarix, Oncophage, and Sipuleucel-T (Provenge); gp100; dendritic cell-based vaccines (such as Ad.p53 DC); and toll-like receptor modulators, such as TLR-7 or TLR-9 agonists; and

[0544] (viii) cytotoxic agents, such as fludarabine, cladribine, and pentostatin (Nipent™);

[0545] (ix) Steroids, such as corticosteroids, including glucocorticoids and mineralocorticoids, for example, alclomethasone, alclomethasone dipropionate, aldosterone, amcinonide, beclomethasone, beclomethasone dipropionate, betamethasone, betamethasone dipropionate, betamethasone sodium phosphate, betamethasone valerate, budesonide, clobetasone, clobetasone butyrate, clobetasol propionate, cloprednisolone, cortisone, cortisone acetate, cortivazole, deoxycorticosterone, desonide, desoximetasone, dexamethasone, dexamethasone sodium phosphate, dexamethasone isonicotinate, diflucortolone, fluclorololone, flumethasone, flunisolide, fluocinolone acetonide, fluocinolone acetate, fluocinolone butyl, fluocinolone butyl, fluocinolone acetonide Flucortolone, flucortolone hexanoate, flucortolone pivalate, fluorometholone, fluprednidine, fluprednisolone acetate, flurandrenolide, fluticasone, fluticasone propionate, halcinonide, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone acetate propionate, hydrocortisone propionate butyrate, hydrocortisone valerate, icomethasone, icomethasone acetate butyrate, methylprednisolone, methylprednisolone, mometasone, paramethasone, mometasone furoate monohydrate, prednicasone, prednisolone, prednisone, tixocortol, tixocortol pivalate, triamcinolone acetonide, triamcinolone acetonide acetate, triamcinolone acetonide alcohol, and pharmaceutically acceptable derivatives thereof. Combinations of steroids may be used, such as combinations of two or more of the steroids mentioned in this paragraph;

[0546] (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);

[0547] (xii) Chimeric antigen receptors, anticancer vaccines and arginase inhibitors.

[0548] Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate administration of the individual components of the treatment.Such combination products employ the compounds of this invention within the therapeutically effective dosage range described above and the other pharmaceutically active agent within its approved dosage range.

[0549] The compounds of the present invention may exist as a single crystal form or a mixture of crystal forms, or they may be amorphous. Therefore, the compounds of the present invention for pharmaceutical use may be administered as crystalline or amorphous products. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying. Microwave or radiofrequency drying may be used for this purpose.

[0550] For the above-mentioned compounds of the present invention, the dosage will certainly vary with the compound used, mode of administration, desired treatment and indicated disease. For example, if the compound of the present invention is administered orally, the daily dosage of the compound of the present invention can be in the range of 0.01 micrograms per kilogram of body weight (μg / kg) to 100 milligrams per kilogram of body weight (mg / kg).

[0551] The compounds of the present invention or their pharmaceutically acceptable salts can be used alone, but are generally administered in the form of pharmaceutical compositions in which the compounds of the present invention or their pharmaceutically acceptable salts are combined with a pharmaceutically acceptable adjuvant, diluent, or carrier. Conventional procedures for selecting and preparing suitable pharmaceutical formulations are described, for example, in "Pharmaceuticals - The Science of Dosage Form Designs", ME Aulton, Churchill Livingstone, 1988.

[0552] Depending on the mode of administration of the compound of the present invention, the pharmaceutical composition for administering the compound of the present invention will preferably contain 0.05 to 99% w (weight percentage) of the compound of the present invention, more preferably 0.05 to 80% w of the compound of the present invention, still more preferably 0.10 to 70% w of the compound of the present invention, and even more preferably 0.10 to 50% w of the compound of the present invention, all weight percentages being based on the total composition.

[0553] The pharmaceutical composition can be administered topically (e.g., to the skin) in the form of, for example, a cream, gel, lotion, solution, suspension, or systemically, for example, orally in the form of tablets, capsules, syrups, powders, or granules; or parenterally (including intravenously, subcutaneously, intramuscularly, intravascularly, or by infusion) in the form of a sterile solution, suspension, or emulsion for injection; rectally in the form of a suppository; or inhaled in the form of an aerosol.

[0554] For oral administration, the compounds of the present invention can be mixed with an adjuvant or carrier, such as lactose, sucrose, sorbitol, mannitol; starches such as potato starch, corn starch, or pullulan; cellulose derivatives; binders such as gelatin or polyvinyl pyrrolidone; and / or lubricants such as magnesium stearate, calcium stearate, polyethylene glycol, wax, paraffin, etc., and then compressed into tablets. If coated tablets are desired, the core tablets prepared as described above can be coated with a concentrated sugar solution, which can contain, for example, gum arabic, gelatin, talc, and titanium dioxide. Alternatively, the tablets can be coated with a suitable polymer dissolved in a volatile organic solvent.

[0555] In order to prepare soft gelatin capsules, the compound of the present invention can be mixed with, for example, vegetable oil or polyethylene glycol. Hard gelatin capsules can contain compound particles prepared using the above-mentioned excipients for tablets. In addition, the liquid or semisolid preparations of the compounds of this invention can be filled into hard gelatin capsules. Liquid preparations for oral use can be in the form of syrup or suspension, for example, a solution containing the compounds of this invention, with the remainder being a mixture of sugar and ethanol, water, glycerol and propylene glycol. Optionally, this liquid preparation can contain coloring agents, flavorings, sweeteners (such as saccharin), preservatives and / or carboxymethyl cellulose as thickeners or other excipients well known to those skilled in the art.

[0556] For intravenous (parenteral) administration, the compounds of the present invention may be administered as sterile aqueous or oily solutions.

[0557] According to well-known medical principles, the size of the dose of the compounds of the present invention for therapeutic purposes will naturally vary depending on the nature and severity of the condition, the age and sex of the animal or patient and the route of administration.

[0558] Dosage levels, dosing frequency, and duration of treatment with the compounds of the invention are expected to vary depending on the formulation and the clinical indication, age, and comorbid medical conditions of the patient.

[0559] Throughout the description and claims of this specification, the words "comprise" and "include" and their variations mean "including but not limited to", and they are not intended to (and do not) exclude other parts, additives, components, integers or steps. Throughout the description and claims of this specification, the singular encompasses the plural unless the context requires otherwise. In particular, where the indefinite article is used, the specification should be understood as contemplating plurality as well as singularity, unless the context requires otherwise.

[0560] Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All features disclosed in this specification (including any accompanying claims, abstract and drawings), and / or all steps of any method or process so disclosed, may be combined in any combination, except combinations in which at least some of such features and / or steps are mutually exclusive. The invention is not limited to the details of any foregoing embodiments. The invention extends to any novel one or any novel combination of features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one or any novel combination of steps of any method or process so disclosed.

[0561] The reader's attention is directed to all papers and documents filed concurrently with or prior to this specification in connection with this application, which papers and documents are open to the public with this specification, and the contents of all such papers and documents are incorporated herein by reference.

[0562] experiment

[0563] Unless otherwise stated, solvents, reagents, and raw materials were purchased from commercial suppliers and used as received. Unless otherwise stated, all reactions were performed at room temperature. Compounds were identified and their purity confirmed by LCMS UV using a Waters Acquity SQ detector 2 (ACQ-SQD2#LCA081). The wavelength of the diode array detector was 254 nM, and the MS was in positive and negative electrospray mode (m / z: 150-800). 2 μL aliquots were injected sequentially onto a guard column (0.2 μm × 2 mm filter) and a UPLC column (C18, 50 × 2.1 mm, <2 μm) maintained at 40°C. The sample was eluted using a mobile phase system at a flow rate of 0.6 mL / min according to the gradient listed in Table 1. The mobile phase system consisted of: A (0.1% (v / v) formic acid in water) and B (0.1% (v / v) formic acid in acetonitrile). Retention time RT is in minutes. The following methods were also used when described throughout the experimental sections, with gradients detailed in Table 1. Method 3 utilized a Shimadzu 2020 series spectrometer equipped with a binary pump and a diode array detector (collection wavelengths of 214 and 254 nm), with the MS in positive and negative electrospray modes (m / z: 100-900). A 2 μL aliquot was injected onto an Agilent Poroshell 120EC-C18 column (2.7 μm, 4.6 × 50 mm) maintained at 35°C and eluted at 1.0 ml / min using a mobile phase consisting of: A: 0.05% formic acid in water (v / v), B: 0.05% formic acid in MeCN (v / v). Method 4 utilized an Agilent Technologies 1290 series spectrometer equipped with a binary pump and a diode array detector (collection wavelengths of 214 and 254 nm), with the MS 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 using a mobile phase consisting of: A: 0.05% formic acid in water (v / v), B: 0.05% formic acid in MeCN (v / v).

[0564] Table 1

[0565]

[0566]

[0567] NMR was also used to characterize the final compounds. NMR spectra were obtained on a Bruker AVIII 400 Nanobay with a 5 mm BBFO probe. Optionally, the Rf values ​​of the compounds were measured on silica gel thin layer chromatography (TLC) plates.

[0568] Compounds were purified by silica gel flash column chromatography or preparative LCMS. LCMS purification was performed using a Waters 3100 mass spectrometer in positive and negative electrospray modes (m / z: 150-800) and a Waters 2489 UV / Vis detector. TM The sample was eluted on a preparative C18 5μM OBD 19×100mm column at a flow rate of 20 mL / min using a mobile phase system consisting of A (0.1% (v / v) formic acid in water) and B (0.1% (v / v) formic acid in acetonitrile).

[0569] Table 2

[0570] Time (min) ％A ％B 0 90 10 1.5 90 10 11.7 5 95 13.7 5 95 14 90 90 15 90 90

[0571] General reaction scheme

[0572] Certain compounds of the present invention can be prepared using the following general reaction schemes. Certain compounds of the present invention can be prepared according to or analogously to the following synthesis examples.

[0573]

[0574] Note: Step = step, same below

[0575] General plan 1

[0576] Compounds of formula (I) can be prepared by the synthetic routes outlined in General Scheme 1. In step A, the compound of formula GI-1 can 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 a pyrimidine of formula GI-2. In step B, the dihydroxypyrimidine can be chlorinated with phosphorus oxychloride to form a dichloropyrimidine. In step C, the dichloride GI-3 can be reacted with a nucleophile (HZ) in the presence of a base in an anhydrous solvent (such as DCM) at room temperature. 1 R 1 ) to undergo regioselective aromatic nucleophilic substitution. In step D, the remaining chloride of GI-4 can be reacted with HZ under conditions similar to those of step C. 2 R 2Perform a second nucleophilic substitution, or alternatively, Z 2 R 2 It can be introduced by Buchwald coupling with a suitable palladium catalyst. In step E, GI-5 is BOC-deprotected with an acid (such as TFA) to give the secondary amide GI-8. In step F, the amide GI-8 can be reacted with a halo-R by Buchwald coupling with a suitable palladium catalyst. 4 or the corresponding triflate reagent (X = Cl, Br, I or triflate). Step G may or may not be required and represents the reaction from R 4 , Z 1 R 1 and Z 2 R 2 A general deprotection step to remove acid labile protecting groups (if present) from reactive atoms on the group, such as R 4 The naphthol OH may contain a methoxymethyl (MOM) protecting group and / or Z 1 R 1 and / or Z 2 R 2 A tert-butyloxycarbamate (Boc) protecting group may be present on the primary or secondary amine, and all of these groups may be removed by treatment with an acid such as TFA.

[0577] Alternatively, steps C to F can be performed in a different order to obtain compounds of formula (I). Dichloropyrimidine GI-3 can be subjected to boc-deprotection (step E) to form GI-6, followed by a Buchwald reaction (step F) to form GI-9, followed by a sequential nucleophilic substitution of the chloride at the 4-position of the pyrimidine (step C) to form GI-10, and displacement of the chloride at the 2-position of the pyrimidine (step D), and finally (if desired) global deprotection (step G). Alternatively, chloropyrimidine GI-4 can be subjected to boc-deprotection (step E) to form GI-7, followed by a Buchwald reaction (step F) to give chloropyrimidine GI-10, followed by displacement of the chloride at the 2-position of the pyrimidine (step D), and finally (if desired) global deprotection (step G).

[0578]

[0579] General Scheme 2

[0580] Intermediates of formula GI-8 can also be formed by the route described in General Scheme 2 and then subsequently converted to compounds of formula (I) as shown in General Scheme 1 above. In step A, 2-thiomethyl-4,6-dichloropyrimidine of formula GI-11 is reacted in an anhydrous solvent (such as THF or 1,4-dioxane) with a suitable amine or alcohol nucleophile (HZ 1 R 1 ) is subjected to base-mediated regioselective nucleophilic displacement of the chloride at the 4-position to obtain a thiomethyl pyrimidine of formula GI-12. In step B, GI-12 can be subjected to chloride displacement at the 6-position of pyrimidine with a nitrile source (such as Zn(CN)2) in the presence of a Pd catalyst (such as Pd(PPh3)4) to obtain a 2-thiomethyl-6-cyanopyrimidine of formula GI-13. In step C, the thiomethyl of GI-13 can be oxidized to the corresponding methyl sulfone using an oxidant (such as m-CPBA) in a solvent (such as DCM). In the presence of a base (such as NaH), in a solvent (such as DMF or THF), a nucleophile (HZ 2 R 2 ) after nucleophilic displacement, the resulting sulfone is converted to an intermediate of formula GI-14. GI-14 can be treated with hydrogen and a heterogeneous catalyst (such as Pd on carbon) in the presence of an acid (such as 1N HCl) at elevated temperature (such as 50°C). Under these conditions, the amine product of the nitrile hydrogenation can spontaneously cyclize to the adjacent ester group to form an intermediate of formula GI-8. Alternatively, steps C, D, and E can be reordered such that GI-13 undergoes reduction / cyclization (step E) to form GI-15, which is then subjected to thiomethyl oxidation and displacement (steps C and D) to provide the intermediate of formula GI-8.

[0581]

[0582] General Scheme 3

[0583] The compounds of formula (VII) of the present invention can be prepared by general scheme 3. In step A, compound GI-16 is oxidized with a catalytic oxidant reagent (such as ruthenium trichloride) in the presence of a stoichiometric amount of sodium periodate using EtOAc and water as co-solvents. In step B, dichloride GI-17 can be reacted with a nucleophile (HZ) in the presence of a base in an anhydrous solvent (such as DCM) at room temperature. 1 R 1 ) to undergo regioselective aromatic nucleophilic substitution. In step C, the remaining chloride of GI-18 can be reacted with HZ under conditions similar to step B. 2 R 2 Perform a second nucleophilic substitution, or alternatively, Z 2 R 2It can be introduced by Buchwald coupling with a suitable palladium catalyst. In step D, GI-19 is Boc-deprotected with an acid (such as TFA) to give the secondary amide GI-20. In step E, the amide GI-20 can be coupled with a halo-R4 or a corresponding triflate reagent (X = Cl, Br, I or triflate) by Buchwald coupling with a suitable palladium catalyst. Step F may or may not be required and represents the reaction from R 4 , Z 1 R 1 and Z 2 R 2 A general deprotection step to remove acid labile protecting groups (if present) from reactive atoms on the group, such as R 4 The naphthol OH may contain a methoxymethyl (MOM) protecting group and / or Z 1 R 1 and / or Z 2 R 2 A tert-butyloxycarbamate (Boc) protecting group may be present on the primary or secondary amine, and all of these groups may be removed by treatment with an acid such as TFA.

[0584] Alternatively, steps B to E can be performed in a different order to obtain compounds of formula (VII). Dichloropyrimidine GI-17 can be subjected to boc-deprotection (step D) to form GI-23, followed by a Buchwald reaction (step E) to form GI-24, followed by a sequential nucleophilic substitution of the chloride at the 4-position of the pyrimidine (step B) to form GI-22, and a displacement of the chloride at the 2-position of the pyrimidine (step C), and finally (if desired) a global deprotection (step F). Alternatively, chloropyrimidine GI-18 can be subjected to boc-deprotection (step D) to form GI-21, followed by a Buchwald reaction (step E) to give chloropyrimidine GI-22, followed by a displacement of the chloride at the 2-position of the pyrimidine (step C), and finally (if desired) a global deprotection (step F).

[0585] intermediates

[0586] Intermediates I-1, 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-ol and I-1a, [8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl] trifluoromethanesulfonate.

[0587]

[0588] Intermediates I-1 and I-1a were prepared according to the route described in Scheme 1.

[0589]

[0590] Solution 1

[0591] Step A, 2-bromoethynyl (triisopropyl) silane. Under N2, silver nitrate (302mg, 1.78mmol) was added to a solution of N-bromosuccinimide (3.49g, 19.6mmol) and triisopropylsilyl acetylene (4.0mL, 17.8mmol) in acetone (89mL). The reaction mixture was stirred at room temperature for 1h. All volatiles were removed under reduced pressure. The residue was distributed between a gasoline layer (30mL) and an aqueous layer (30mL). The organic layer was separated. The aqueous layer was extracted with gasoline (30mL), the organic extracts were combined, washed with a saturated saline solution (20mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain 2-bromoethynyl (triisopropyl) silane (4.96g, 19.0mmol, 100% yield), which was a transparent oil.

[0592] 1 H NMR (400MHz, CDCl3) δ / ppm: 1.11-1.02 (m, 21H).

[0593] 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 nitrogen-degassed 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). The mixture was then stirred at 110°C for 1 hour, then cooled back to room temperature, and all volatiles were removed under reduced pressure. Purification by flash column chromatography on silica gel eluting with 0-25% ethyl acetate in petrol gave 7-fluoro-8-(2-triisopropylsilylethynyl)naphthalene-1,3-diol (4.59 g, 12.8 mmol, 76% yield) as a black oil.

[0594] UPLC-MS(ES - , Method 2): 2.47 min, m / z 357.4 [MH] - .

[0595] Step C, 7-fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)naphthalene-1-ol. At 0 ° C, 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) were added bromomethyl methyl ether (0.99 mL, 12.2 mmol). The mixture was stirred at this temperature for 30 min, then concentrated under reduced pressure and distributed between ethyl acetate layer (40 mL) and water layer (40 mL). The organic layer was separated, the water layer was extracted with ethyl acetate (40 mL), the organic layers were combined, washed with saturated brine solution (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 in petrol gave 7-fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)naphthalen-1-ol (3.04 g, 7.55 mmol, 59% yield) as a brown oil.

[0596] 1 H NMR (400MHz, CDCl3) δ / ppm: 10.30 (s, 1H), 7.88 (dd, J = 9.1, 5.7Hz, 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).

[0597] Step D, [7-fluoro-3-(methoxymethyl)-8-(2-triisopropylsilylethynyl)-1-naphthyl] 2,2-dimethylpropanoate. At 0 ° C, to a solution of 7-fluoro-3-(methoxymethoxy)-8-{2-[tri(propyl-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). The reaction mixture was stirred at 0 ° C for 30 min, and then an additional portion of trimethylacetyl chloride (2.2 mL, 18.1 mmol) and N, N-diisopropylethylamine (1.6 mL, 9.07 mmol) was added. The reaction mixture was stirred at 0 ° C for 16 h. The reaction mixture is concentrated under reduced pressure, and distributed between ethyl acetate (40mL) and water (40mL).Separate each layer, aqueous layer is extracted with ethyl acetate (40mL).The organic layer merged is washed with saturated brine solution (20mL), Na is used SO Drying, filter and concentrate under reduced pressure, to obtain [7-fluoro-3-(methoxymethyl)-8-(2-triisopropylsilylethynyl)-1-naphthyl] 2,2-dimethyl propanoate (4.88g, 10.0mmol, 100% yield), is brown oil.

[0598] 1 H NMR (400MHz, CDCl3) δ / ppm: 7.68 (dd, J=9.1, 5.5Hz, 1H), 7.28 (d, J=2.4Hz, 1H), 7.27-7.20 (m,1H),6.83(d,J=2.1Hz,1H),5.25(s,2H),3.50(s,3H),1.47(s,9H),1.22-1.09(m,21H).

[0599] Step E, [8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl] 2,2-dimethylpropanoate. Cesium fluoride (5.73 g, 37.8 mmol) was added to a suspension of [7-fluoro-3-(methoxymethoxy)-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 h and then distributed between an ethyl acetate layer (100 mL) and an aqueous layer (100 mL). The organic layer was separated, the aqueous layer was extracted with ethyl acetate (2 x 50 mL), the organic layers were combined, washed with water (2 x 50 mL), a saturated saline solution (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 in petrol gave [8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl] 2,2-dimethylpropanoate (2.48 g, 7.51 mmol, 99% yield) as a brown oil.

[0600] UPLC-MS(ES + , Method 2): 2.01 min, m / z 331.5 [M+H] + .

[0601] Step F, [8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl] 2,2-dimethylpropanoate. A solution of [8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl] 2,2-dimethylpropanoate (2.48g, 7.51mmol) in methanol (15.0mL) was evacuated and backfilled with nitrogen (3x). Dry palladium (10wt.% on carbon powder) (240mg, 2.25mmol) was then added, the mixture was evacuated and backfilled with nitrogen (3x). The mixture was then evacuated and backfilled with hydrogen (2x). The reactants were stirred at room temperature overnight. The mixture was then passed through a celite pad and washed with MeOH. The filtrate was concentrated under reduced pressure to give [8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl] 2,2-dimethylpropanoate (928 mg, 2.78 mmol, 37% yield) as a yellow oil.

[0602] UPLC-MS(ES + , Method 2): 2.29 min, m / z 335.2 [M+H] + .

[0603] Step G, 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalene-1-ol (I-1). Potassium hydroxide (467mg, 8.33mmol) is added to a solution of [8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl] 2,2-dimethylpropanoate (928mg, 2.78mmol) in methanol (13.9mL). Then, it is stirred at room temperature for 30min. All volatiles are removed under reduced pressure, and the pH is adjusted to pH 7 with saturated ammonium chloride solution. The reaction mixture is distributed between ethyl acetate layer (40mL) and water layer (40mL). The organic layer is separated. The aqueous layer is extracted with ethyl acetate (40mL), the organic layers are combined, washed with saturated saline solution (20mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica gel eluting with 0-30% ethyl acetate in petrol gave 8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-ol (411 mg, 1.64 mmol, 59% yield) as a brown oil.

[0604] UPLC-MS(ES + , Method 2): 1.90 min, m / z 251.1 [M+H] + .

[0605] Step H, [8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl] trifluoromethanesulfonate (I-1a). At -40 ° C, 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-(methoxymethoxy)naphthalene-1-ol (411 mg, 1.64 mmol) in DCM (8.2 mL). Afterwards, the mixture was stirred at this temperature for 30 min. The reaction mixture was diluted with ice water (20 mL), warmed to room temperature, and extracted with ethyl acetate (3 × 20 mL). The organic layers were combined, washed with saturated brine solution (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 in petrol afforded intermediate I-1a, [8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]trifluoromethanesulfonate (515 mg, 1.35 mmol, 82% yield) as a yellow oil.

[0606] UPLC-MS(ES + , Method 2): 2.25 min, m / z 383.3 [M+H] + .

[0607] 1H NMR(400MHz, CDCl3)δ / ppm:7.62(dd,J=9.0,5.6Hz,1H),7.42(d,J=2.4Hz,1H),7.36(d,J=2.4Hz,1H ),7.32-7.25(m,1H),5.28(s,2H),3.52(s,3H),3.24(dq,J=7.5,2.9Hz,2H),1.24(t,J=7.6Hz,3H).

[0608] Intermediate I-2,1-bromo-3-(methoxymethoxy)naphthalene

[0609]

[0610] Intermediate 1-2 was prepared according to the route described in Scheme 2.

[0611]

[0612] Option 2

[0613] 1-bromo-3-(methoxymethoxy) naphthalene (I-2). At 0 ℃, to 4-bromonaphthalene-2-ol (2.00g, 8.97mmol) and N, N-diisopropylethylamine (4.7mL, 26.9mmol) in DCM (20mL) solution, add chloromethyl methyl ether (1.0mL, 13.5mmol). The reaction mixture is stirred for 90min, then diluted with distilled water and extracted with DCM x2. Merge organic matter, wash with salt water (x2), use Na2SO4 dry and filter. The filtrate is evaporated in vacuo, and by flash silica gel column chromatography, eluted with 0-60% EtOAc (40g, dry load) in petroleum ether. Required fractions are merged and evaporated in vacuo to obtain 1-bromo-3-(methoxymethoxy) naphthalene (1.98g, 7.41mmol, 83% yield), which is a colorless oil.

[0614] UPLC-MS(ES + , Method 2): 2.09 min, m / z 268.9 [M+H] + .

[0615] 1 H NMR(400MHz, CDCl3)δ / ppm:8.09-8.05(m,1H),7.68-7.64(m,1H),7.50(d,J=2 .0Hz,1H),7.43-7.36(m,2H),7.31(d,J=2.0Hz,1H),5.21(s,2H),3.45(s,3H).

[0616] Intermediate I-3, N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepane-2-carboxamide.

[0617]

[0618] As shown in Scheme 3, intermediate I-3 was prepared according to the procedure described in WO2022 / 133038.

[0619]

[0620] Option 3

[0621] Step A, 2-nitro-N-prop-2-ynyl-benzenesulfonamide.A solution of propargylamine (29.1mL, 454mmol) and diisopropylethylamine (158mL, 908mmol) in DCM (1250mL) is cooled to 0 ℃.2-nitrobenzene methanesulfonyl chloride (101g, 454mmol) is added in batches, and the reaction mixture is stirred at room temperature for 16h.The reaction mixture is concentrated in vacuo, and the gained residue is directly purified on silica gel, eluted with 20-50% EtOAc / petroleum ether, to obtain 2-nitro-N-prop-2-ynyl-benzenesulfonamide (100g, 375mmol, 83% yield), as a yellow solid.

[0622] LC-MS(ES + , Method 3): 1.30 min, m / z 258.00 [M+NH4] +

[0623] 1 H NMR (400MHz, 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 = 2.3Hz, 2H), 3.05 (t, J = 2.3Hz, 1H).

[0624] Step B, N-(3-chloropropyl)-2-nitro-N-prop-2-ynyl-benzenesulfonamide.To 2-nitro-N-prop-2-ynyl-benzenesulfonamide (50.0g, 208mmol) and CsCO(170g, 520mmol) in the mixture of acetone (2000mL), 1-bromo-3-chloropropane (154mL, 1560mmol) is added dropwise.Reaction mixture is at room temperature stirred to 5h.The reaction mixture is concentrated in vacuo, and residue is distributed between EtOAc (3000mL) and water (2000mL).Separate each layer, water layer is extracted with EtOAc (1500mL x 2).Use anhydrous NaSODry the organic layer merged, and concentrate in vacuo. The crude material was purified by silica gel 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.

[0625] LC-MS(ES + , Method 3): 1.93 min, m / z 317.0 [M+H] +

[0626] 1 H NMR(400MHz,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=2.2Hz,2H),3.63(t,J=6.4Hz,2H),3.46(t,J=7.0Hz,2H),3.25(t,J=2.5Hz,1H).

[0627] Step C, 5-(2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepane-2-carboxylic acid ethyl ester. 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 in a microwave reactor at 140 ° C for 1 h. After cooling to room temperature, Cs2CO3 (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 in vacuo, and the resulting residue was distributed between water (300 mL) and EtOAc (200 mL). In 40 DEG C of 40 DEG C, 2-nitro-4-nitro-2-pyrazoles (3.70g, 7.51mmol) of 4-nitro-2-pyrazoles (1.5-a, 1.4-diazepane) was added to the 4-nitro-2-pyrazoles (2.00g, 7.51mmol) solution of 4-nitro-2-pyrazoles (1.5-a, 1.4-diazepane) (1.5-a, 1.4-diazepane) to obtain ethyl 2-nitro-2-pyrazoles (3.70g, 7.51mmol, assuming quantitative yield), as a brown solid.

[0628] LC-MS(ES + , Method 3): 1.63 min, m / z 395.1 [M+H] +

[0629] 1 H NMR(400MHz,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=7.1Hz,2H),3.71-3.62(m,2H),1.96-1.87(m,2H),1.27(t,J=7.1Hz,3H).

[0630] Step D, 5- (2- nitrophenyl) sulfonyl -4,6,7,8- tetrahydropyrazolo [1,5-a] [1,4] diazepane -2- carboxylic acid. To a solution of 5- (2- nitrophenyl) sulfonyl -4,6,7,8- tetrahydropyrazolo [1,5-a] [1,4] diazepane -2- carboxylic acid ethyl ester (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 h. 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]diazepane-2-carboxylic acid (4.00 g, 9.83 mmol, 82% yield) as a white solid.

[0631] LC-MS(ES + , Method 4): 1.20 min, m / z 367.1 [M+H] +

[0632] 1 H NMR(400MHz,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,1 H),4.66(s,2H),4.51-4.43(m,2H),3.71-3.62(m,2H),1.97-1.87(m,2H).

[0633] Step E, N, N- dimethyl -5- (2- nitrophenyl) sulfonyl -4,6,7,8- tetrahydropyrazolo [1,5-a] [1,4] diazepane -2- carboxamide. At room temperature and N2, to 5- (2- nitrophenyl) sulfonyl -4,6,7,8- tetrahydropyrazolo [1,5-a] [1,4] diazepane -2- carboxylic acid (6.50g, 17.7mmol) and TBTU (6.27g, 19.5mmol) in DMF (70mL) solution, diisopropylethylamine (12.4mL, 71.0mmol) was added. The reaction mixture was stirred at room temperature for 15min. Dimethylamine hydrochloride (1.74g, 21.3mmol) was added and the reaction mixture was stirred at room temperature for 4h. The reaction mixture was diluted with water (1000mL) and extracted with EtOAc (200mL x 3). The combined organic phases were washed with brine (200 mL x 2), dried over Na2SO4, filtered and concentrated in vacuo to give N,N-dimethyl-5-(2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepane-2-carboxamide (7.30 g, 15.8 mmol, 88% yield) as a yellow oil which was used in the next reaction without any further purification.

[0634] LC-MS(ES + , Method 3): 1.27 min, m / z 394.1 [M+H] +

[0635] 1 H NMR(400MHz,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.

[0636] Step F, N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepane-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]diazepane-2-carboxamide (7.30 g, 18.6 mmol) and Cs2CO3 (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 h. 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]diazepane-2-carboxamide (2.80 g, 12.1 mmol, 65% yield) as a yellow solid.

[0637] UPLC-MS(ES + , Method 2): 0.34 min, m / z 209.0 [M+H] + .

[0638] 1 H NMR (400MHz, 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).

[0639] Intermediate I-4,6-chloro-N,N-bis[(4-methoxyphenyl)methyl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine.

[0640]

[0641] Intermediate 1-4 was prepared according to the route described in Scheme 4.

[0642]

[0643] Option 4

[0644] Step A, 6-chloro-5-iodo-4-methyl-pyridin-2-amine.To the solution of 6-chloro-4-methyl-2-pyridinamine (1.00g, 7.01mmol) in MeCN (16mL), N-iodosuccinimide (1.89g, 8.42mmol) is added.The reaction mixture is stirred at room temperature for 2h.The reaction mixture is concentrated to dryness, and distributed between DCM and salt solution.The organic matter is extracted, by phase separation filter paper, and is concentrated in vacuo.By column chromatography purification of crude material, eluted with 10-100% EtOAc in petroleum ether.Desired fraction is merged and concentrated to dryness, to obtain 6-chloro-5-iodo-4-methyl-pyridin-2-amine (1.52g, 5.66mmol, 81% yield), it is orange solid.

[0645] UPLC-MS(ES + , Method 2): 1.76 min, m / z 268.8 / 270.8 [M+H] +

[0646] Step B, 6-chloro-5-iodo-N, N-bis[(4-methoxyphenyl) methyl]-4-methyl-pyridine-2-amine.To a solution of 6-chloro-5-iodo-4-methyl-pyridine-2-amine (1.50g, 5.59mmol) in DMF (20mL), 4-methoxybenzyl chloride (2.3mL, 16.8mmol) and sodium hydride (60% is disperseed in mineral oil) (536mg, 22.4mmol) are added, and the reactant is stirred at room temperature for 16h. The reaction mixture is distributed between EtOAc and water. Organic matter is separated, and the water layer is washed three times with EtOAc. The organic wash solution merged is washed with salt water, and by phase separation filter paper, it is concentrated to dryness afterwards. Then by column chromatography purification of crude material, eluted with 10% EtOAc to 100% EtOAc in petroleum ether. The desired fractions were combined and concentrated in vacuo 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.

[0647] UPLC-MS(ES + , Method 2): 2.59 min, m / z 509.0 [M+H] +

[0648] 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 (1.00g, 1.97mmol) in DMF (10mL) was added copper (I) iodide (749mg, 3.93mmol) and 2,2-difluoro-2-(fluorosulfonyl)acetic acid methyl ester (0.5mL, 3.93mmol), and the reactants were heated to 90°C for 16h. The reactants were diluted with EtOAc and water, the organic matter was extracted, the phase was separated by filter paper and concentrated to dryness. The crude material was then purified by flash column chromatography, eluting with 0-60% EtOAc in petroleum ether. The desired fractions were combined and concentrated in vacuo 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 which solidified to a white solid upon standing.

[0649] UPLC-MS(ES + , Method 2): 2.51 min, m / z 451.1 [M+H] +

[0650] Intermediate I-5, [8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate.

[0651]

[0652] Intermediate 1-5 was prepared according to the route described in Scheme 5, and the preparation of 1-1 is described in Scheme 1.

[0653]

[0654] Option 5

[0655] [8-Ethyl-7-fluoro-3-(methoxymethoxy)-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-(methoxymethoxy)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 phase was separated, and the aqueous phase was extracted with DCM (2 x 75 mL). In 40 DEG C of 10mL 40mL 40mL 40mL 40mL in 40mL 40mL 40mL 40mL 80mL in 40mL 40mL 80mL 30mL 40mL 80mL 2 ...40mL 20mL 40mL 40mL 40mL 40mL 40mL 40mL 40mL 40mL 40mL 40mL 40mL 40mL 40mL 40mL 40mL

[0656] UPLC-MS(ES-, Method 1):5.97min m / z 531.3[MH] _

[0657] 1 H NMR(400MHz, DMSO-d6)δ / ppm:7.95(dd,J=8.9,5.6Hz,1H),7.73(d,J=2.2Hz,1H),7.58-7.52(m, 1H),7.36(d,J=2.2Hz,1H),5.36(s,2H),3.44(s,3H),3.21-3.13(m,2H),1.16(t,J=7.5Hz,3H).

[0658] Intermediate I-6, [1-(1-piperidinylmethyl)cyclopropyl]methanol.

[0659]

[0660] Intermediate 1-6 was prepared according to the route described in Scheme 6.

[0661]

[0662] Option 6

[0663] Step A, 1-(piperidine-1-carbonyl)cyclopropanecarboxylic acid methyl ester. At 0 ° C, 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). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated in vacuo to obtain a yellow oily residue, which was dissolved in THF (1.7 mL), cooled to 0 ° C, and then 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 matter was washed twice with brine. The combined organics were dried over Na2SO4, filtered, and concentrated in vacuo 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] +

[0664] 1 H NMR(400MHz,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).

[0665] Step B, [1- (1-piperidinylmethyl) cyclopropyl] methanol (I-6). At 0 ° C, to a solution of 1- (piperidinyl-1-carbonyl) cyclopropanecarboxylic acid methyl ester (496 mg, 2.35 mmol) in anhydrous THF (1.9 mL) was slowly added lithium aluminum hydride (5.2 mL, 5.17 mmol, 1 M in THF). 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 precipitate was filtered and the filtrate was loaded onto an SCX column (5 g, pre-washed with MeOH). The crude material was washed with MeOH and then washed with 1 M NH3 in MeOH. The ammonia fraction was evaporated in vacuo to obtain [1- (1-piperidinylmethyl) cyclopropyl] methanol (134 mg, 0.792 mmol, 34%) as a light yellow oil.

[0666] 1H NMR(400MHz,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).

[0667] Intermediate I-7, [1-(diethylaminomethyl)cyclopropyl]methanol.

[0668]

[0669] Intermediate 1-7 was prepared according to the route described in Scheme 7.

[0670]

[0671] Option 7

[0672] Step A, 1-(diethylaminoformyl)cyclopropanecarboxylate. At 0 ° C, oxalyl chloride (0.3 mL, 3.55 mmol) was added 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). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was evaporated in vacuo to obtain a yellow oily residue, which was dissolved in THF (1.7 mL) and cooled to 0 ° C. Diethylamine (0.9 mL, 1.79 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 washed twice with brine. The organics were combined, dried over Na2SO4, filtered, and concentrated in vacuo to give 1-(diethylcarbamoyl)cyclopropanecarboxylate (235 mg, 1.18 mmol, 57% yield) as a yellow oil.

[0673] 1 H NMR (400MHz, 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 = 7.1Hz, 3H), 1.01 (t, J = 7.1Hz, 3H).

[0674] Step B, [1- (diethylaminomethyl) cyclopropyl] methanol (I-7). At 0 ° C, to a solution of 1- (diethylaminomethyl) cyclopropanecarboxylic acid methyl ester (235mg, 1.18mmol) in anhydrous THF (1.9mL), lithium aluminum hydride (2.6mL, 2.59mmol, 1M in THF) was added. The reaction mixture was stirred at room temperature for 2h. The reaction mixture was quenched with 2M HCl at 0 ° C. The solid was filtered and washed with MeOH. The filtrate was loaded onto an SCX column (2g) balanced with MeOH, washed with MeOH, and then washed with 1MNH3 / MeOH. The ammonia fraction was evaporated in vacuo to obtain [1- (diethylaminomethyl) cyclopropyl] methanol (93.0mg, 0.591mmol, 50% yield) as a colorless oil.

[0675] 1 H NMR(400MHz,DMSO-d6)δ / ppm:5.40-4.65(m,1H),3.17(d,J=4.9Hz,2H),2.57-2.51 (m,4H),2.42(s,2H),0.95(t,J=7.1Hz,6H),0.41-0.36(m,2H),0.27-0.22(m,2H).

[0676] Intermediate I-8, [1-(morpholinomethyl)cyclopropyl]methanol.

[0677]

[0678] Intermediate 1-8 was prepared according to the route described in Scheme 8.

[0679]

[0680] Option 8

[0681] Step A, 1-(morpholine-4-carbonyl)cyclopropanecarboxylic acid methyl ester. At 0 ° C, 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). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated in vacuo to obtain a yellow semi-solid residue, which was dissolved 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 matter was washed twice with brine. The combined organics were dried over Na2SO4, filtered, and concentrated in vacuo to give methyl 1-(morpholine-4-carbonyl)cyclopropanecarboxylate (496 mg, 2.33 mmol, 84% yield) as a yellow oil.

[0682] UPLC-MS(ES + , Method 2): 1.03 min, m / z 214.0 [M+H] +

[0683] 1 H NMR(400MHz, 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).

[0684] Step B, [1- (morpholinemethyl) cyclopropyl] methanol (I-8). At 0 ° C, to a solution of 1- (morpholine-4-carbonyl) cyclopropanecarboxylic acid methyl ester (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). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was cooled to 0 ° C and quenched with 2M HCl. The solid was filtered and the filtrate was loaded onto an SCX post (5 g, pre-washed with MeOH), washed with MeOH, and then washed with 1M NH / MeOH. The ammonia fraction was evaporated in vacuo to obtain [1- (morpholinemethyl) cyclopropyl] methanol (221 mg, 1.29 mmol, 57% yield) as a colorless oil.

[0685] 1 H NMR(400MHz, 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).

[0686] Intermediate I-9, N,N-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxamide trifluoroacetic acid.

[0687]

[0688] Intermediate 1-9 was prepared according to the route described in Scheme 9.

[0689]

[0690] Option 9

[0691] 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 NaHCO3 aqueous solution. The organic phase was extracted, passed through a phase separation filter paper, and concentrated to dryness. The crude material 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.

[0692] UPLC-MS(ES + , Method 2): 1.42 min, m / z 295.1 [M+H] +

[0693] 1 H NMR (400MHz, DMSO-d6) δ / ppm: 7.77 (s, 1H), 4.70 (s, 2H), 4.11 (t, J = 5.6Hz, 2H), 3.81 (t, J = 5.3Hz, 2H), 3.27-2.83 (m, 6H), 1.43 (s, 9H).

[0694] 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 min. 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.

[0695] UPLC-MS(ES + , method 1): 0.25min, m / z 195.1[M+H] +

[0696] 1 H NMR(400MHz,DMSO-d6)δ / ppm:9.40(s,2H),7.89(s,1H),4.53(s,2H),4.38-4 .29(t,J=5.8Hz,1H),3.69(t,J=5.9Hz,2H),3.57(s,1H),3.26-2.87(m,6H).

[0697] Intermediate I-10, 1-bromo-N,N-bis[(4-methoxyphenyl)methyl]isoquinolin-3-amine.

[0698]

[0699] Intermediate 1-10 was prepared according to the route described in Scheme 10.

[0700]

[0701] Plan 10

[0702] 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) was 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 organics were separated and the aqueous layer was washed three times with EtOAc. The combined organics were washed with brine and passed through a phase separation filter paper before being concentrated to dryness. The crude material was purified by column chromatography, eluting with 10% EtOAc to 100% EtOAc in petroleum ether. The major fractions were combined and concentrated in vacuo 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 analysis.

[0703] Intermediate I-11, tert-butyl 2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-4-hydroxy-5-oxo-7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate.

[0704]

[0705] Intermediate 1-11 was prepared according to the route described in Scheme 11.

[0706]

[0707] Plan 11

[0708] Step A, 4-benzyloxy-2-chloro-5,7-dihydropyrrolo[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester. At 25 ° C, 2,4-dichloro-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylic acid tert-butyl ester (500 mg, 1.72 mmol) and benzyl alcohol (0.20 mL, 1.90 mmol) in DCM (10 mL) were added potassium tert-butoxide (212 mg, 1.90 mmol), 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 matter was passed through a phase separation filter paper and concentrated to dryness. The crude material was purified by column chromatography and eluted with 20% EtOAc to 100% EtOAc in petroleum ether. The desired fractions were combined and concentrated in vacuo 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 light yellow solid.

[0709] UPLC-MS(ES + , Method 2): 2.22 min, m / z 362.1 [M+H] +

[0710] 1 H NMR(400MHz, 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).

[0711] Step B, 4-benzyloxy-2-chloro-5-oxo-7H-pyrrolo[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester. To a solution of 4-benzyloxy-2-chloro-5,7-dihydropyrrolo[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester (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 h. The reaction mixture was diluted with EtOAc and water, and passed through a diatomaceous earth pad. Organic matter was separated, filtered and concentrated to dryness by phase separation. The crude material was then purified by column chromatography, eluted with 10% EtOAc in petroleum ether to 50% EtOAc in petroleum ether. The desired fractions were combined and concentrated to dryness in vacuo 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 light yellow oil.

[0712] UPLC-MS(ES + , Method 2): 2.03 min, m / z 398.0 [M+Na] +

[0713] Step C, tert-butyl 4-benzyloxy-5-oxo-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-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 was diluted with EtOAc, passed through a phase separation filter paper and concentrated to dryness. The crude material was then purified by column chromatography eluting with 100% DCM to 20% MeOH in DCM. The desired fractions were combined and concentrated to dryness in vacuo to afford tert-butyl 4-benzyloxy-5-oxo-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolazin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (2.38 g, 4.78 mmol, 45% yield) as a yellow solid.

[0714] UPLC-MS(ES + , Method 2): 1.56 min, m / z 499.4 [M+H] +

[0715] Step D, 2-[[(2R, 8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolazin-8-yl]methoxy]-4-hydroxy-5-oxo-7H-pyrrolo[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester (I-11). Under nitrogen, to a solution of 4-benzyloxy-5-oxo-2-[[(2R, 8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolazin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester (2.38 g, 4.38 mmol) in ethyl acetate (30 mL) was added anhydrous palladium (233 mg, 0.220 mmol, based on carbon powder 10 wt%). The reactant was purged with hydrogen (x 3) and stirred at 25 ° C for 16 h. The reaction mixture was passed through a pad of celite and washed with EtOAc. The organics were concentrated under reduced pressure to give tert-butyl 2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-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.

[0716] UPLC-MS(ES +, Method 2): 1.25 min, m / z 409.2 [M+H] +

[0717] Intermediate I-12, tert-butyl 2-chloro-4-(1,4-oxazepan-4-yl)-5-oxo-7h-pyrrolo[3,4-d]pyrimidine-6-carboxylate.

[0718]

[0719] Intermediate 1-12 was prepared according to the route described in Scheme 12.

[0720]

[0721] Plan 12

[0722] Step A, 2,4-dichloro-5-oxo-7H-pyrrolo-[3,4-d] pyrimidine-6-carboxylic acid tert-butyl ester. To 2,4-dichloro-5H-pyrrolo-[3,4-d] pyrimidine-6 ​​(7H)-carboxylic acid tert-butyl ester (2.00g, 6.89mmol) and ruthenium chloride (214mg, 1.03mmol) in ethyl acetate (20mL) and water (20mL), sodium periodate (4.42g, 20.7mmol) was added, and the reactant was stirred at room temperature overnight. The reactant was diluted and separated between EtOAc (50mL) and water (50mL), filtered with a diatomaceous earth plug, and the diatomaceous earth plug was washed with ethyl acetate (2x 50mL). The filtrate was collected, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (50mL), the organic layers were combined, washed with a saturated saline solution (50mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica gel eluting with 0-60% ethyl acetate in petroleum afforded tert-butyl 2,4-dichloro-5-oxo-7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate as part of a mixture containing an alternative product where the oxidation occurred at the other benzyl methylene group of the pyrrole ring (1.75 g, 5.76 mmol, 84% yield) as a clear oil which was used in Step B without further purification.

[0723] UPLC-MS(ES + , Method 2): 1.72 min, m / z 326.0 [M+Na] + .

[0724] 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 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 in petrol gave 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 clear oil.

[0725] UPLC-MS(ES + , Method 2): 1.77 min, m / z 369.1 [M+H] + .

[0726] 1 H NMR(400MHz, 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).

[0727] Intermediates 1-13 to 1-16 were prepared according to Scheme 13.

[0728]

[0729] Plan 13

[0730] Step A, 4,6-dichloro-2-methylthio-pyrimidine-5-carboxylic acid ethyl ester. At -78 ° C, n-butyl lithium (37.43 mL, 397 mmol) was added dropwise to a solution of diisopropylamine (55.7 mL, 397 mmol) in THF (1000 L). After addition, the solution was stirred at room temperature for 1 h 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 h. Ethyl chloroformate (73.5 mL, 769 mmol) was added, and the resulting solution was warmed to room temperature and stirred for 2 h. The mixture was quenched with saturated aqueous ammonium chloride solution and diluted with EtOAc. The phases were separated and the organics were washed with water and brine, dried over sodium sulfate and concentrated in vacuo to give crude 4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (56 g) as a black solid which was used without purification.

[0731] UPLC-MS(ES + , Method 4): 1.09 min, m / z 267.0 [M+H] + .

[0732] Step B, 4-chloro-2-methylthio-6-(1,4-oxazacycloheptane-4-yl)pyrimidine-5-carboxylic acid ethyl ester. Under N2 atmosphere, a solution of 4,6-dichloro-2-methylthio-pyrimidine-5-carboxylate (60g, 225mmol) and Et3N (68.2g, 674mmol) in DMF (250mL) was stirred at 0°C for 5min. 1,4-oxazacycloheptane hydrochloride (30.91g, 225mmol) was added and the mixture was stirred at 0°C for 30min, then warmed to room temperature and stirred for 3h. The mixture was poured into water (3000mL) and extracted with EtOAc (400mL x4). The combined organic layers were washed with brine (1500mL x 3), dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel (1%-20% EtOAc in petroleum ether) to give ethyl 4-chloro-2-methylsulfanyl-6-(1,4-oxazepan-4-yl)pyrimidine-5-carboxylate (50 g, 67%) as a yellow solid.

[0733] UPLC-MS(ES + , Method 4): 0.48 min, m / z 332.1 [M+H] + .

[0734] Step C, ethyl 4-cyano-2-methylthio-6-(1,4-oxazepan-4-yl)pyrimidine-5-carboxylate. Under N2 atmosphere, a mixture of ethyl 4-chloro-2-methylthio-6-(1,4-oxazepan-4-yl)pyrimidine-5-carboxylate (33 g, 99 mmol), Pd(PPh3)4 (11.49 g, 9.95 mmol), and Zn(CN)2 (17.52 g, 149 mmol) in DMF (120 mL) was heated at 120°C for 4 h. After cooling to ambient temperature, the mixture was filtered through celite, and the filtrate was concentrated under vacuum. 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.

[0735] UPLC-MS(ES + , Method 3): 1.77 min, m / z 323.1 [M+H] + .

[0736] Step D, 2-methylthio-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-methylthio-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 minutes. This was then added dropwise to a stirred NaBH4 solution (2.93 g, 78 mmol) and stirred at -78°C for 1 hour, then heated to 50°C and stirred for an additional 3 hours. The reaction mixture was quenched with saturated NH4Cl aqueous solution, filtered through celite, and the filtrate was concentrated under reduced pressure, then diluted with water (700mL), and extracted with EtOAc (150mL x 3). The combined organic layers were washed with brine (500mL x 3), dried over Na2SO4 and concentrated, then purified by silica gel column chromatography (2% DCM in MeOH) to obtain 2-methylthio-4-(1,4-oxazacycloheptane-4-yl)-6,7-dihydropyrrolo[3,4-d]pyrimidin-5-one (I-13) (1.8 g, 41%) as a yellow solid.

[0737] UPLC-MS(ES + , Method 3): 1.41 min, m / z 281.2 [M+H] + .

[0738] 1H NMR(400MHz,DMSO-d6)δ / ppm:8.29(s,1H),4.47(s,2H),4.17(d,J=1.2Hz,2H ),3.91(s,2H),3.70(s,2H),3.61(t,J=5.6Hz,2H),2.47(s,3H),1.89(s,2H).

[0739] Step E, 6-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-2-methylthio-4-(1,4-oxazepan-4-yl)-7H-pyrrolo[3,4-d]pyrimidin-5-one (I-14). A mixture of 2-methylthio-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), Pd2(dba)3 (490 mg, 0.54 mmol), Xantphos (310 mg, 0.54 mmol) and Cs2CO3 (2.61 g, 8.03 mmol) in 1,4-dioxane (20 mL) was stirred at 100°C under N2 for 3 h. The reaction mixture was concentrated and purified by silica gel column (eluting with 20% EtOAc in 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.

[0740] UPLC-MS(ES + , Method 4): 1.30 min, m / z 513.2 [M+H] + .

[0741] Step F, 6-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-2-methanesulfonyl-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-methylthio-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 at 25 ° C for 2 h. The reaction was quenched with saturated aqueous sodium sulfite solution (40 mL) and washed with saturated sodium carbonate solution (10 mL×2). The organic phases 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-methanesulfonyl-4-(1,4-oxazepan-4-yl)-7H-pyrrolo[3,4-d]pyrimidin-5-one (I-15) (420 mg, 94%).

[0742] UPLC-MS(ES + , Method 3): 2.09 min, m / z 545.2 [M+H] + .

[0743] Step G, 6-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-4-(1,4-oxazepan-4-yl)-2-prop-2-ynyloxy-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 slowly added NaH (35.26 mg, 0.88 mmol) at 0°C under N2 over 30 min. 6-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-2-methanesulfonyl-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 in vacuo and purified by silica gel column chromatography (eluting with 33% EtOAc in petroleum ether) to give 6-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-4-(1,4-oxazepan-4-yl)-2-prop-2-ynyloxy-7H-pyrrolo[3,4-d]pyrimidin-5-one (I-16) as a yellow solid (73 mg, 23.8%).

[0744] UPLC-MS(ES +, Method 4): 0.99 min, m / z 521.2 [M+H] + .

[0745] 1 H NMR(400MHz, DMSO-d6)δ / ppm:7.86(dd,J=9.1,5.9Hz,1H),7.60(d,J=2.7Hz,1H),7.46–7.38(m,2H),5.35–5.31(m,2H),5.03(s,2H),4.80–4.6 7(m,2H),4.63–3.82(m,5H),3.65(s,3H),3.56(t,J=2.4Hz,1H),3.43(s ,3H),2.96–2.75(m,2H),1.90(d,J=84.4Hz,2H),1.04(t,J=7.4Hz,3H).

[0746] Intermediate 1-17 was prepared according to the route described in Scheme 14.

[0747]

[0748] Plan 14

[0749] Step A, 2-chloro-4-(1,4-oxazacycloheptane-4-yl)-6,7-dihydropyrrolo[3,4-d]pyrimidin-5-one. To 2-chloro-4-(1,4-oxazacycloheptane-4-yl)-5-oxo-7H-pyrrolo[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester (3.28 g, 8.9 mmol) in DCM (15 mL) was added trifluoroacetic acid (6.82 mL, 89.01 mmol), and the reactants were stirred at room temperature for 1 h. The reactants were concentrated under reduced pressure. It was basified with saturated sodium bicarbonate solution, filtered with filter paper, and the filter paper was washed with ethyl acetate (x2). The resulting solid was collected and the residual solvent was removed in vacuo to give 2-chloro-4-(1,4-oxazepan-4-yl)-6,7-dihydropyrrolo[3,4-d]pyrimidin-5-one (2.705 g, 100% yield) as a yellow solid.

[0750] UPLC-MS(ES + , Method 4): 1.44 min, m / z 269.0 [M+H] + .

[0751] 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 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 N2 degassed toluene (15 mL) was added XantPhos Pd G3 (211.76 mg, 0.22 mmol). Reactant is evacuated, re-filled with N2(x3) and heated to 110 DEG C and kept 3.5h.Reaction mixture is cooled back to room temperature, diluted with ethyl acetate, filtered with diatomaceous earth plug, washed with ethyl acetate diatomaceous earth plug, collected filtrate and concentrated under reduced pressure.Purified by flash column chromatography on 40g silica gel column (wet loading in 10:1DCM: ethyl acetate), eluted with 20-60% ethyl acetate in petroleum, obtain 2- chloro- 6- [8- ethyl -7- fluoro- 3- (methoxymethoxy) -1- naphthyl] -4- (1,4- oxazacycloheptane -4- bases) -7H- pyrrolo- [3,4-d] pyrimidine -5- one (I-17) (296mg, 26.5% yield), it is yellow jelly.

[0752] UPLC-MS(ES + , Method 4): 2.34 min, m / z 501.1 [M+H] + .

[0753] Table 3 describes the intermediates synthesized by following the same procedure as I-3 (Scheme 13) by replacing dimethylamine hydrochloride in step C with the appropriate building blocks.

[0754] Table 3

[0755]

[0756]

[0757] Table 4 describes the intermediates synthesized by following the same procedure as I-2 (Scheme 2) by substituting the appropriate building blocks for 4-bromonaphthalen-2-ol.

[0758] Table 4

[0759]

[0760]

[0761] I-23, [7,8-difluoro-3-(methoxymethoxy)-1-naphthyl] trifluoromethanesulfonate.

[0762]

[0763] Step A, 7,8-difluoro-3-(methoxymethoxy)naphthalene-1-ol. At -40 ° C, 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). The mixture was stirred at this temperature for 30 min and then distributed between ethyl acetate layer (20 mL) and water layer (20 mL). The organic layer was separated and the water layer was extracted with ethyl acetate (20 mL). The organic layers were combined, washed with saturated brine solution (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica gel eluting with 0-50% ethyl acetate in petrol gave 7,8-difluoro-3-(methoxymethoxy)naphthalen-1-ol (26.8 mg, 0.11 mmol, 11% yield) as a brown oil.

[0764] UPLC-MS(ES + , Method 2): 1.63 min, m / z 240.9 [M+H] + .

[0765] Step B, [7,8-difluoro-3-(methoxymethoxy)-1-naphthyl] trifluoromethanesulfonate. At -40 ° C, 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)naphthalene-1-ol (26.8 mg, 0.11 mmol) in DCM (0.75 mL). Then stirred at this temperature for 15 min, distributed between ethyl acetate layer (20 mL) and water layer (20 mL). The organic layer was separated and the water layer was extracted with ethyl acetate (20 mL). The organic layers were combined, washed with saturated brine solution (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica gel eluting with 0-50% ethyl acetate in petrol gave [7,8-difluoro-3-(methoxymethoxy)-1-naphthyl] trifluoromethanesulfonate (15.4 mg, 0.041 mmol, 37% yield) as a clear oil.

[0766] UPLC-MS(ES + , Method 2): 2.07 min, m / z 372.9 [M+H] + .

[0767] 1 H NMR (400MHz, CDCl3) δ / ppm: 7.54 (ddd, J=9.2, 4.6, 1.9Hz, 1H), 7.45-7.42 (m, 1H), 7.41-7.35 (m, 1H), 7.28 (d, J=2.1Hz, 1H), 5.29 (s, 2H), 3.52 (s, 3H).

[0768] I-30, 3,8-diazabicyclo[3.2.1]octan-8-yl-(2,2-difluorocyclopropyl)methanone; 2,2,2-trifluoroacetic acid.

[0769]

[0770] Steps A, 8- (2,2- difluorocyclopropane carbonyl) -3,8- diazabicyclo [3.2.1] octane -3- carboxylic acid tert-butyl esters. Under room temperature and nitrogen atmosphere, HATU (1.07g, 2.83mmol) is added to the stirred solution of 3-boc-3,8- diazabicyclo [3.2.1] octane (500mg, 2.36mmol), triethylamine (0.66mL, 4.71mmol), 2,2- difluorocyclopropane carboxylic acid (431mg, 3.53mmol) and DCM (10mL). Reactant is stirred to 1h at such a temperature. Reaction mixture is poured in water (100mL), and extracted with DCM (3x 100mL). The organic layer merged is filtered by phase separation filter paper, and is concentrated in vacuo. The residue was subjected to silica gel column chromatography using 0-100% EtOAc in petroleum ether as eluent 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 clear film.

[0771] Step B, 3,8-diazabicyclo [3.2.1] octane -8- base -(2,2- difluorocyclopropyl) ketone; 2,2,2- trifluoroacetic acid. To 8- (2,2- difluorocyclopropanecarbonyl) -3,8-diazabicyclo [3.2.1] octane -3- carboxylic acid tert-butyl ester (861mg, 2.72mmol) in DCM (14mL) was added trifluoroacetic acid (2.08mL, 27.22mmol), and the reactants were stirred at room temperature for 90min. The reactants were concentrated under reduced pressure and subjected to flash column chromatography, eluted with 0-20% MeOH in DCM to give crude material 3,8-diazabicyclo [3.2.1] octane -8- base -(2,2- difluorocyclopropyl) ketone; 2,2,2- trifluoroacetic acid (735mg, 2.25mmol, 81.77% yield) as a foamy white solid.

[0772] I-31, N,N-dimethyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamide; 2,2,2-trifluoroacetic acid.

[0773]

[0774] I-31 is prepared analogously to I-9 (Scheme 9) by replacing 5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylic acid with 5-(tert-butoxycarbonyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-3-carboxylic acid in step A.

[0775] UPLC-MS(ES + , Method 2): 0.29 min, m / z 195.1 [M+H] + .

[0776] I-32, 1-[(4-methoxyphenyl)methyl]-4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine.

[0777]

[0778] Step A, 1- [(4- methoxyphenyl) methyl] -6,7- dihydro -4H- pyrazolo [4,5-c] pyridine -5- carboxylic acid tert-butyl ester. At room temperature, to a solution of 6,7- dihydro -1H- pyrazolo [4,3-c] pyridine -5 (4H) -carboxylic acid tert-butyl ester (500mg, 2.24mmol) in DMF (10mL) was added 4- methoxybenzyl chloride (0.33mL, 2.46mmol) and potassium carbonate (371.39mg, 2.69mmol). The mixture was heated to 70 ° C and stirred at this temperature overnight. The mixture was cooled to room temperature and distributed between EtOAc and water. The organic matter was washed with brine, passed through a phase separator and concentrated. The crude material was purified by flash chromatography, eluted with 0%-100% EtAc in petroleum ether. The desired fractions were combined and concentrated to give tert-butyl 2-[(4-methoxyphenyl)methyl]-6,7-dihydro-4H-pyrazolo[4,5-c]pyridine-5-carboxylate (563 mg, 1.64 mmol, 73% yield) as a colorless oil.

[0779] UPLC-MS(ES + , Method 2): 1.98 min, m / z 344.2 [M+H] + .

[0780] Step B, 1- [(4- methoxyphenyl) methyl] -4,5,6,7- tetrahydropyrazolo [4,3-c] pyridine. To 2- [(4- methoxyphenyl) methyl] -6,7- dihydro -4H- pyrazolo [4,3-c] pyridine -5- carboxylic acid tert-butyl ester (563mg, 1.64mmol) in DCM (7mL) is added trifluoroacetic acid (0.19mL, 2.46mmol), and the reactant is stirred at room temperature for 90min. More trifluoroacetic acid (0.19mL, 2.46mmol) is added to the reactant, and stirring is continued for 1h. The reactant is concentrated under reduced pressure and purified by flash column chromatography on KP amino-D posts by 0-20% MeOH in 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 clear oil.

[0781] UPLC-MS(ES + , Method 2): 1.21 min, m / z 244.1 [M+H] + (33%)

[0782] I-33, 2-[[3-bromo-4-(trifluoromethoxy)phenyl]methoxy]tetrahydropyran.

[0783]

[0784] 3,4-dihydro-2H-pyran (0.16mL, 1.77mmol) and p-toluenesulfonic acid monohydrate (28.07mg, 0.15mmol) are added to a stirred solution of (3-bromo-4-(trifluoromethoxy)phenyl)methanol (400mg, 1.48mmol) in DCM (15mL). The reaction mixture is stirred at room temperature overnight. Water and DCM are added to the reactant and the layers are separated. The aqueous layer is extracted with more DCM. The organic fraction is collected, washed with saturated NaHCO3 and brine, then passed through a phase separator, and the solvent is reduced in vacuo. The crude material is purified by flash column chromatography (eluted in 0-40% EtOAc in petroleum ether) to obtain 2-[[3-bromo-4-(trifluoromethoxy)phenyl]methoxy]tetrahydropyran (420mg, 1.18mmol, 80% yield) as a colorless aqueous oil.

[0785] I-34, tert-butyl N-(4-bromo-1,3-benzothiazol-2-yl)carbamate.

[0786]

[0787] By 4- bromobenzo [d] thiazole -2- amine (500mg, 2.18mmol), 4- dimethylaminopyridine, DMAP (26.66mg, 0.22mmol) and di-tert-butyl dicarbonate (571.58mg, 2.62mmol) in DCM (18mL) solution at 25 DEG C stir 16h.After the completion of the reaction, mixture H o (15mL), salt solution (15mL) washing, organic layer is filtered and concentrated in vacuo by phase separation column.By flash chromatography (0-40% EA in petroleum ether) purification of residue, to obtain N- (4- bromo -1,3- benzothiazol-2-yl) tert-butyl carbamate (628mg, 1.91mmol, 87% yield), it is crystalline white solid.

[0788] UPLC-MS (ES+, method 2): 1.95 min, m / z 329.0 & 330.9 [M+H] + .

[0789] I-35, tert-butyl N-[1-(hydroxymethyl)cycloheptyl]carbamate.

[0790]

[0791] Step A, 1-(tert-butoxycarbonylamino) heptylcarboxylic acid methyl esters.To 1-(boc-amino) heptylcarboxylic acid (300mg, 1.17mmol) in the solution of anhydrous THF (3mL), add (trimethylsilyl) diazomethane solution (2.0M in hexane) (1.17mL, 2.33mmol), and at room temperature stir 16h.The solvent is evaporated in vacuo, with resistates at EtOAc and saturated Na CO Distribute between the aqueous solution.Water and salt water washing organism, merge and use Na SO Drying, filter, evaporation, to obtain 1-(tert-butoxycarbonylamino) heptylcarboxylic acid methyl esters (316mg, 1.16mmol, 100% productive rate), is yellow solid.

[0792] Step B, N-[1-(hydroxymethyl) cycloheptyl] t-butyl carbamate.At 0 ℃, to 1-(tert-butoxycarbonyl amino) cycloheptyl carboxylic acid methyl esters (316mg, 1.16mmol) in anhydrous THF (7mL), add lithium borohydride (0.11mL, 5.82mmol), and reactant is stirred and spent the night.Use saturated NH at 0 ℃ the quenching reaction of Cl solution, with EtOAc aqueous layer extracted.Merge organic matter, use Na sO dry, filter, vacuum evaporation filtrate, thick material by flash column chromatography purification, with the 0-60% EA wash-out in petroleum ether, to obtain N-[1-(hydroxymethyl) cycloheptyl] t-butyl carbamate (176mg, 0.72mmol, 62% productive rate), is white solid.

[0793] 1 H NMR (400MHz, CDCl3) δ / ppm: 4.60 (s, 1H), 4.30 (s, 1H), 3.60 (d, J = 6.2Hz, 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).

[0794] 1-36, 3-(2-Bromo-4-methoxy-phenyl)benzonitrile.

[0795]

[0796] To 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 N2 degassed 1,4-dioxane (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 in petroleum to give 3-(2-bromo-4-methoxy-phenyl)benzonitrile (178 mg, 0.62 mmol, 39% yield) as a brown solid.

[0797] UPLC-MS(ES + , Method 2): 2.05 min, m / z 289.9 [M+H] + .

[0798] 1 H NMR(400MHz,DMSO-d6)δ / ppm:7.87-7.84(m,2H),7.74-7.71(m,1H),7.65(dt, J=0.56,8.0Hz,1H),7.39-7.33(m,2H),7.07(dd,J=2.5,8.6Hz,1H)3.83(s,3H)

[0799] 1-37, 4-Bromo-2-(methoxymethoxy)-1-methyl-naphthalene.

[0800]

[0801] Step A, 4-bromo-1-iodo-naphthalene-2-ol. To 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 at 25 ° C for 18 h. The reaction was concentrated to dryness and purified by column chromatography, eluting with 0-50% ethyl acetate in petroleum ether to obtain 4-bromo-1-iodo-naphthalene-2-ol (843 mg, 2.42 mmol, 54% yield) as a brown solid.

[0802] UPLC-MS(ES + , Method 2): 1.96 min, m / z 349.9 [M+H] + .

[0803] 1 H NMR (400MHz, DMSO-d6) δ / ppm: 11.04 (s, 1H), 8.04 (q, J = 6.7, 8.2Hz, 2H), 7.66-7.62 (m, 1H), 7.60 (s, 1H), 7.54-7.49 (m, 1H).

[0804] Step B, 4-bromo-1-iodo-2-(methoxymethoxy)naphthalene. At 0 ° C, 4-bromo-1-iodo-naphthalene-2-ol (583 mg, 1.67 mmol) and N, N-diisopropylethylamine (0.87 mL, 5.01 mmol) in DCM (14.32 mL) were added chloromethyl methyl ether (175 mg, 2.17 mmol) and stirred for 2 h. The reactant was distributed between ethyl acetate (20 mL) and water (10 mL). The aqueous phase was extracted with ethyl acetate (3 × 20 mL). The organic matter was dried over Na2SO4 and concentrated to give 4-bromo-1-iodo-2-(methoxymethoxy)naphthalene (719 mg, 1.82 mmol, 100% yield) as a yellow solid.

[0805] UPLC-MS(ES + , Method 2): 2.26 min, m / z 393.8 [M+H] + .

[0806] 1 H NMR(400MHz,DMSO-d6)δ / ppm:8.17(d,J=7.9Hz,1H),8.09(d,J=7.6Hz,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).

[0807] Step C, 4-bromo-2-(methoxymethoxy)-1-methyl-naphthalene. To 4-bromo-1-iodo-2-(methoxymethoxy)naphthalene (200 mg, 0.51 mmol) and cesium carbonate (497.41 mg, 1.53 mmol) in N2 degassed 1,4-dioxane (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-trimethylboroxane (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 in petroleum ether to give 4-bromo-2-(methoxymethoxy)-1-methyl-naphthalene (102 mg, 0.36 mmol, 71% yield) as a yellow oil.

[0808] UPLC-MS(ES + , Method 2): 2.22 min, m / z 282.7 [M+H] + .

[0809] 1 H NMR (400MHz, CDCl3) δ / ppm: 8.20-8.14 (m, 1H), 7.94 (d, J = 8.4Hz, 1H), 7.53-7.43 (m, 3H), 5.24 (s, 2H), 3.53 (s, 3H), 2.53 (s, 3H).

[0810] I-38, 1-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclopropylamine.

[0811]

[0812] Step A, N-[1-[[tert-butyl (diphenyl) silyl] oxygen methyl] cyclopropyl] tert-butyl carbamate.At 0 ℃ and N2, to the boc-1-aminocyclopropylmethanol (200mg, 1.07mmol) in DCM (3mL) and tert-butyl (chloro) diphenylsilane (0.31mL, 1.17mmol) add imidazoles (160mg, 2.35mmol), and the reaction mixture is stirred overnight.By mixture in DCM (10mL) and H2O (10mL) between distribution.Water layer is further washed with DCM.The organic matter merged is further used saturated NaHCO3 and salt water washing, by phase separator and concentrated. The residue was purified by column chromatography eluting with 0-80% EtOAc in petroleum ether to give tert-butyl N-[1-[[tert-butyl(diphenyl)silyl]oxymethyl]cyclopropyl]carbamate (412 mg, 0.97 mmol, 91% yield) as a colorless oil.

[0813] UPLC-MS(ES + , Method 2): 2.62 min, m / z 448.2 [M+Na] + .

[0814] Step B, 1-[[tert-butyl (diphenyl) silyl] oxygen methyl] cyclopropylamine.To the N-[1-[[tert-butyl (diphenyl) silyl] oxygen methyl] cyclopropyl] t-butyl carbamate (220mg in DCM (3mL), add trifluoroacetic acid (0.2mL, 2.58mmol), and reactant is at room temperature stirred to 90min.Reactant is concentrated under reduced pressure, and by flash column chromatography on KP amino-D post by the 0-20%MeOH purifying in DCM, to obtain 1-[[tert-butyl (diphenyl) silyl] oxygen methyl] cyclopropylamine (126mg, 0.39mmol, 75% productive rate), is colorless oil.

[0815] UPLC-MS(ES + , Method 2): 1.87 min, m / z 326.1 [M+H] + .

[0816] I-39, 4-bromo-1-fluoro-2-(methoxymethoxy)naphthalene.

[0817]

[0818] Steps A, 4-bromo-1-fluoro-naphthalene-2-alcohol.At 0 ℃, add Selectfluor (794mg, 2.24mmol) in the 1-bromo-3-hydroxynaphthalene (500mg, 2.24mmol) in MeCN (20mL), and reactant is stirred overnight.Reaction is quenched with sodium bicarbonate solution, extracted three times with DCM.The organic layer merged is filtered and concentrated into dryness by phase separation column, to obtain 4-bromo-1-fluoro-naphthalene-2-alcohol (540mg, 2.24mmol, 100% productive rate), is yellow oil.

[0819] UPLC-MS (ES-, method 2): 2.02min, m / z 238.9&240.9[MH] - .

[0820] Step B, 4-bromo-1-fluoro-2-(methoxymethoxy) naphthalene.At 0 ℃, to the 4-bromo-1-fluoro-naphthalene-2-ol (101mg, 0.26mmol) and N, N-diisopropylethylamine (0.09mL, 0.52mmol) in DCM (2.5mL), add bromomethyl methyl ether (0.02mL, 0.29mmol), and reactant is stirred to 1h at 0 ℃.Water quenching reaction mixture, extract three times with DCM.The organic extract merged is filtered by phase separation column, and is concentrated into dryness.By column chromatography (0-20%EtOAc in petroleum ether) purification of residue, to obtain 4-bromo-1-fluoro-2-(methoxymethoxy) naphthalene (41mg, 0.14mmol, 55% productive rate), be orange oil.

[0821] UPLC-MS (ES+, method 2): 2.23 min, mass ion 1-40, 3-[2-bromo-4-(methoxymethoxy)phenyl]benzonitrile was not detected.

[0822]

[0823] Step A, 3-(2-bromo-4-hydroxy-phenyl)benzonitrile. To N2 degassed 1,4-dioxane (9.3mL) and water (1.3mL) was added tetrakis(triphenylphosphine)palladium(0) (169mg, 0.15mmol) (3-bromo-4-iodophenol (400mg, 1.34mmol), 3-cyanophenylboronic acid (180mg, 1.22mmol) and potassium carbonate (564.34mg, 4.08mmol). The reaction was heated to 90°C for 3h. The reaction was concentrated and purified by column chromatography, eluted with 0-100% ethyl acetate in petroleum ether to obtain 3-(2-bromo-4-hydroxy-phenyl)benzonitrile (209mg, 0.76mmol, 57% yield) as a brown solid.

[0824] UPLC-MS(ES + , Method 2): 1.75 min, m / z 275.9 [M+H] + .

[0825] 1 H NMR(400MHz,DMSO-d6)δ / ppm:10.11(s,1H),7.85-7.81(m,2H),7.70(dt,J=1.7,8.1Hz,1H),7 .63(t,J=7.9Hz,1H)7.26(d,J=8.4Hz,1H),7.13(d,J=2.4Hz,1H),6.88(dd,J=2.4,8.4Hz,1H).

[0826] Step B, 3-[2-Bromo-4-(methoxymethoxy)phenyl]benzonitrile. 3-[2-Bromo-4-(methoxymethoxy)phenyl]benzonitrile (I-40) was synthesized following the same procedure as I-2 (Scheme 2) using 3-(2-bromo-4-hydroxy-phenyl)benzonitrile instead of 4-bromonaphthalen-2-ol.

[0827] UPLC-MS(ES + , Method 2): 2.15 min, m / z 320.0 [M+H] + .

[0828] 1 H NMR(400MHz, DMSO-d6)δ / ppm:7.88-7.85(m,2H),7.73(dt,J=1.36,7.90Hz,1H),7.66(dt,J=0.84,7.60Hz,1 H),7.42(d,J=2.48Hz,1H),7.39(d,J=8.52Hz,1H),7.15(dd,J=2.52,8.52Hz,1H),5.28(s,2H),3.41(s,3H).

[0829] I-41, azetidin-3-yl 2,2-dimethylpropanoate; 2,2,2-trifluoroacetic acid

[0830]

[0831] Step A, 3- (2,2- dimethylpropionyloxy) azetidine -1- carboxylic acid tert-butyl esters. To 1-N-boc-3- hydroxyazetidine (500mg, 2.89mmol) in pyridine (11mL) was added trimethylacetyl chloride (0.71mL, 5.77mmol), and the mixture was stirred at 25 ° C overnight. The reactant was concentrated to dryness, and the crude material was purified by column chromatography (0-100% EtOAc in petroleum ether) to obtain 3- (2,2- dimethylpropionyloxy) azetidine -1- carboxylic acid tert-butyl esters (254mg, 0.99mmol, 34% yield) as a colorless oil.

[0832] Step B, azetidin-3-yl 2,2-dimethylpropanoate; 2,2,2-trifluoroacetic acid. To tert-butyl 3-(2,2-dimethylpropionyloxy)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 h. The reaction was concentrated to dryness to give azetidin-3-yl 2,2-dimethylpropanoate; 2,2,2-trifluoroacetic acid (218 mg, 0.80 mmol, 83% yield) as a colorless oil.

[0833] 1 H NMR (400MHz, CDCl3) δ / ppm: 9.76 (s br, 2H), 5.28 (m, 1H), 4.42 (m, 2H), 4.11 (m, 2H), 1.22 (s, 9H).

[0834] I-42, azetidin-3-ylmethyl 2,2-dimethylpropanoate; 2,2,2-trifluoroacetic acid

[0835]

[0836] Intermediate 42 (I-42) was prepared analogously to Intermediate 41 (I-41) by replacing 1-N-boc-3-hydroxyazetidine with tert-butyl 3-(2,2-dimethylpropionyloxymethyl)azetidine-1-carboxylate in step A.

[0837] 1 H NMR (400MHz, CDCl3) δ / ppm: 9.87 (s br, 1H), 9.40 (s br, 1H), 4.20 (d, J = 5.4Hz, 2H), 4.11 (m, 2H), 4.00 (m, 2H), 3.32 (m, 1H), 1.23 (s, 9H).

[0838] I-43, morpholin-2-ylmethyl 2,2-dimethylpropanoate; 2,2,2-trifluoroacetic acid

[0839]

[0840] Intermediate 43 (I-43) was prepared analogously to Intermediate 41 (I-41) by replacing 1-N-boc-3-hydroxyazetidine with tert-butyl 2-(2,2-dimethylpropionyloxymethyl)morpholine-4-carboxylate in step A.

[0841] 1 H NMR (400MHz, CDCl3) δ / ppm: 4.10 (dd, J=5.6, 11.5Hz, 1H), 4.03 (dd, J=5.0, 11.6Hz, 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).

[0842] Example

[0843] 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-hexahydropyrrolizine-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one.

[0844] Example 1 was prepared according to the route described in Scheme 15.

[0845]

[0846] Note: Example = Example, the same below

[0847] Plan 15

[0848] 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. 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) were heated to 100° C. overnight. The reaction mixture was cooled back to room temperature, diluted with ethyl acetate (10 mL), filtered on a hydrophobic glass frit, washed with ethyl acetate (2 x 20 mL), the filtrate was collected and concentrated under reduced pressure. Purified by flash column chromatography on silica gel, eluted with 0-16% MeOH in DCM, to give 4- (1,4- oxazepane -4- bases) -5- oxo -2- [[(2R, 8S) -2- fluoro -1,2,3,5,6,7- hexahydropyrrolizine -8- bases] methoxy] -7H- pyrrolo [3,4-d] pyrimidine -6- carboxylic acid tert-butyl ester (723 mg, 1.47 mmol, 100% yield) as a brown oil.

[0849] UPLC-MS(ES + , Method 2): 1.24 min, m / z 492.4 [M+H] +

[0850] Step B, 4-(1,4-oxazepan-4-yl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-6,7-dihydropyrrolo[3,4-d]pyrimidin-5-one. To tert-butyl 4-(1,4-oxazepan-4-yl)-5-oxo-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-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 min. The reaction was concentrated under reduced pressure and purified by flash column chromatography on a KP amino-D silica gel column with 0-15% MeOH in DCM to give 4-(1,4-oxazepan-4-yl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolazin-8-yl]methoxy]-6,7-dihydropyrrolo[3,4-d]pyrimidin-5-one (527 mg, 1.04 mmol, 76% yield) as a brown oil as a TFA salt.

[0851] UPLC-MS(ES + , short acidic): 1.01 min, m / z 392.3 [M-TFA+H] + .

[0852] Step C, 6-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-4-(1,4-oxazepan-4-yl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-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-hexahydropyrrolazin-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 cooled back to room temperature. The reaction was then diluted with EtOAc (10 mL), passed through a phase separator frit, washed with ethyl acetate (2 x 10 mL), and the filtrate collected and concentrated to dryness. The crude material was then purified by flash column chromatography on a KP-amino D silica gel column, eluting with 0-80% ethyl acetate in petrol to afford 6-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-4-(1,4-oxazepan-4-yl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one (35.9 mg, 0.0600 mmol, 45% yield) as a clear oil.

[0853] UPLC-MS(ES + , Method 2): 1.52 min, m / z 624.4 [M+H] + .

[0854] 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-hexahydropyrrolizin-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-(methoxymethoxy)-1-naphthyl]-4-(1,4-oxazepan-4-yl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolazin-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 h. It was concentrated under reduced pressure. Purification by reverse phase chromatography eluting with 5-40% MeCN (0.1% formic acid) in water (0.1% formic acid) with fractions containing product isolated by SCX (methanol wash (x2) followed by 1 M NH3 in MeOH (x2)) gave 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-hexahydropyrrolizin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one, Example 1 (16.9 mg, 0.0300 mmol, 51% yield) as an off-white solid.

[0855] UPLC-MS(ES + , method 1): 3.03 min, m / z 580.4 [M+H] + .

[0856] 1 H NMR(400MHz,DMSO-d6)δ / ppm:9.93(s,1H),7.73(dd,J=9.1,6.0Hz,1H),7.36–7.31 (m,1H),7.26(d,J=2.6Hz,1H),7.15(d,J=2.5Hz,1H),5.39-5.17(m,1H),4.73-4.4 6(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,3 H),2.95-2.78(m,2H),2.77-2.66(m,1H),2.19-1.69(m,8H),1.02(t,J=7.4Hz,3H).

[0857] Table 5 describes examples synthesized according to the same procedure as Example 1 (Scheme 15), wherein appropriate building blocks are substituted for ((2R,7aS)-2-fluorohexahydro-1H-pyrrolidin-7a-yl)methanol in Step A and / or I-1a in Step C. In the case where the building blocks in Step A or Step C lack a protecting group, Step D is not required.

[0858] Table 5

[0859]

[0860]

[0861]

[0862]

[0863]

[0864]

[0865]

[0866]

[0867]

[0868]

[0869]

[0870]

[0871]

[0872]

[0873] 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-hexahydropyrrolazin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one.

[0874] Example 2 was prepared according to the route described in Scheme 16.

[0875]

[0876] Plan 16

[0877] 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 is described in Scheme 15 for the preparation of Example 1.

[0878] 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-hexahydropyrrolazin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one. To a solution of 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-hexahydropyrrolizine-8-yl]-1H-indazole in nitrogen degassed toluene (2.3 mL) was added 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-hexahydropyrrolizine-8-yl]-1H-indazole. To the TFA salt of tris(dibenzylideneindeneacetone)dipalladium(0) (21.5 mg, 0.0200 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (27.1 mg, 0.0500 mmol) was added 6,7-dihydropyrrolo[3,4-d]pyrimidin-5-one (119 mg, 0.230 mmol) and the reaction was heated to 110°C for 3 hours. The reaction mixture was cooled back to room temperature. The reaction was then diluted with ethyl acetate, passed through a phase separator frit, and the filtrate was collected and concentrated to dryness. The crude material was then purified by flash column chromatography on a KP-amino D silica gel column eluting with 0-70% ethyl acetate in petrol to afford 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-hexahydropyrrolazin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one (40.5 mg, 0.0700 mmol, 28% yield) as a clear oil.

[0879] UPLC-MS(ES + , Method 2): 1.41 min, m / z 620.5 [M+H] + .

[0880] 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-hexahydropyrrolazin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one (Example 2).

[0881] Hydrogen chloride (0.33 mL, 1.31 mmol) (4N in 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-hexahydropyrrolazin-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. The mixture was concentrated under reduced pressure. The product was purified twice by reverse phase chromatography eluting with 5-40% MeCN (0.1% formic acid) in water (0.1% formic acid) and fractions containing the product were separated by SCX (methanol wash (x2) followed by 1 M NH3 in MeOH wash (x2)) to give 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-hexahydropyrrolizin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one (12.2 mg, 0.0200 mmol, 35% yield) as a white solid.

[0882] UPLC-MS(ES + , method 1): 2.58 min, m / z 536.4 [M+H] + .

[0883] 1 H NMR(400MHz, 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=18.4,2.5Hz,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).

[0884] Example 4, 4-(3,8-diazabicyclo[3.2.1]oct-3-yl)-2-(1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethoxy)-6-(3-hydroxy-1-naphthyl)-7H-pyrrolo[3,4-d]pyrimidin-5-one.

[0885] Example 4 was prepared according to the route described in Scheme 17.

[0886]

[0887] Plan 17

[0888] Step A, 4-(8-tert-butoxycarbonyl-3,8-diazabicyclo[3.2.1]octan-3-yl)-2-chloro-5-oxo-7H-pyrrolo[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester. To 2,4-dichloro-5-oxo-7H-pyrrolo[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester (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 in vacuo to dryness and the crude material was purified by column chromatography, eluting with 10-100% EtOAc in petroleum ether. The desired fractions were concentrated in vacuo to dryness 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 light yellow oil.

[0889] UPLC-MS(ES + , Method 2): 2.20 min, m / z 480.2 [M+H] + .

[0890] 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. 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) were heated to 100° C. overnight. The reactant is diluted with EtOAc, passed through phase separation filter paper and concentrated to dryness.Then the crude material is purified by silica gel column chromatography, eluted with 20% MeOH from 100% DCM to DCM.The required fraction is concentrated in vacuo to dryness, to obtain 4- (8- tert-butoxycarbonyl -3,8- diazabicyclo [3.2.1] octyl -3- bases) -2- (1,2,3,5,6,7- hexahydro pyrrolizine -8- ylmethoxy) -5- oxo -7H- pyrrolo [3,4-d] pyrimidine -6- carboxylic acid tert-butyl ester (229 mg, 0.390 mmol, 82% yield), as an orange oil.

[0891] UPLC-MS(ES + , Method 2): 1.68 min, m / z 585.4 [M+H] + .

[0892] 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 tert-butyl 4-(8-tert-butoxycarbonyl-3,8-diazabicyclo[3.2.1]octane-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 at 60°C overnight. The reaction was concentrated to dryness and the crude material was purified by silica gel column chromatography eluting with 100% DCM to 20% MeOH in DCM. The desired fractions were collected and concentrated in vacuo to give tert-butyl 3-[2-(1,2,3,5,6,7-hexahydropyrrolazin-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.

[0893] Step D, tert-butyl 3-[2-(1,2,3,5,6,7-hexahydropyrrolazin-8-ylmethoxy)-6-[3-(methoxymethoxy)-1-naphthyl]-5-oxo-7H-pyrrolo[3,4-d]pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. To 1-bromo-3-(methoxymethoxy)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]octane-8-carboxylate (196 mg, 0.400 mmol) in degassed 1,4-dioxane (2 mL) was added 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (23.4 mg, 0.0400 mmol) and tris(dibenzylideneacetone)dipalladium(0) (18.5 mg, 0.0200 mmol) and the reaction was heated to 100 °C for 4 h. The reactant is then diluted with EtOAc, passed through phase separation filter paper and concentrated to dryness.Then crude material is purified by column chromatography on a KP-NH modified silica column, eluted with 20% MeOH from 100% DCM to DCM. The required fraction is concentrated in vacuo to dryness, to obtain 3- [2- (1,2,3,5,6,7- hexahydropyrrolizine -8- ylmethoxy) -6- [3- (methoxymethoxy) -1- naphthyl] -5- oxo -7H- pyrrolo [3,4-d] pyrimidine -4- bases] -3,8- diazabicyclo [3.2.1] octane -8- carboxylic acid tert-butyl esters (77.0 mg, 0.110 mmol, 28% yield), as a yellow oil.

[0894] UPLC-MS(ES + , Method 2): 1.94 min, m / z 671.4 [M+H] + .

[0895] Step E, 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(1,2,3,5,6,7-hexahydropyrrolazin-8-ylmethoxy)-6-(3-hydroxy-1-naphthyl)-7H-pyrrolo[3,4-d]pyrimidin-5-one (Example 4). To tert-butyl 3-[2-(1,2,3,5,6,7-hexahydropyrrolazin-8-ylmethoxy)-6-[3-(methoxymethoxy)-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 at 25 ° C. overnight. The reaction was loaded onto an SCX column (washing the column with MeOH and then eluting the product with 1 M NH3 in MeOH). The ammonia wash was concentrated to dryness and the crude product was purified by column chromatography on a KP-NH modified silica column, eluting with 100% DCM to 20% MeOH in DCM. The desired fractions were concentrated to dryness in vacuo to give 4-(3,8-diazabicyclo[3.2.1]octan-3-yl)-2-(1,2,3,5,6,7-hexahydropyrrolazin-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 light yellow solid.

[0896] UPLC-MS(ES + , method 1): 2.20 min, m / z 527.3 [M+H] + .

[0897] 1 H NMR(400MHz,DMSO-d6)δ / ppm:9.95(br s,1H),7.77(d,J=8.2Hz,1H),7.54(d,J=8.6Hz,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).

[0898] The following examples (Table 6) were prepared analogously to Example 4 (Scheme 17), replacing the building blocks in steps A, B and D as described in the table where necessary.

[0899] Table 6

[0900]

[0901]

[0902]

[0903]

[0904]

[0905]

[0906]

[0907]

[0908]

[0909]

[0910]

[0911]

[0912]

[0913]

[0914]

[0915]

[0916]

[0917]

[0918]

[0919]

[0920] 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.

[0921] Example 49 was prepared according to the route described in Scheme 18.

[0922]

[0923] Plan 18

[0924] 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 solution of tert-butyl 2-chloro-4-(1,4-oxazepan-4-yl)-5-oxo-7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (200 mg, 0.540 mmol), tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate (218 mg, 1.08 mmol) and cesium carbonate (530 mg, 1.63 mmol) in toluene (2 mL) was added (+ / -)-BINAP (67.5 mg, 0.110 mmol) and palladium(II) acetate (12.2 mg, 0.0500 mmol). The reaction mixture is stirred at 110 DEG C for 1h.The reaction mixture is diluted with EtOAc and passed through phase separation filter paper.The filtrate is concentrated in vacuo, and the residue is purified by flash column chromatography, eluted with 0-100% EtOAc in petroleum ether, then eluted with 0-100% MeOH (20% solution in DCM), to obtain 2- [(1- tert-butoxycarbonyl pyrrolidin-3-yl) methoxy] -4- (1,4- oxazepane -4- bases) -5- oxo -7H- pyrrolo [3,4-d] pyrimidine -6- carboxylic acid tert-butyl ester (45.0mg, 0.0843mmol, 16% yield), as a yellow solid.

[0925] UPLC-MS(ES + , Method 2): 2.02 min, m / z 534.3 [M+H] +

[0926] 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). The reaction mixture was stirred at 60 ° C for 2 h. The reaction mixture was concentrated in vacuo and the residue was purified by flash column chromatography eluting with 0-100% MeOH (20% solution in DCM) to give 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.

[0927] UPLC-MS(ES + , Method 2): 1.64 min, m / z 434.2 [M+H] +

[0928] 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(dibenzylideneinacetone)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 phase separation filter paper. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography eluting with 0-100% EtOAc in 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.

[0929] UPLC-MS(ES + , Method 2): 2.33 min, m / z 666.3 [M+H] +

[0930] Step D, 6- (8-ethyl -7- fluoro-3-hydroxy -1- naphthyl) -4- (1,4- oxazepan -4- base) -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- base) -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 h. The reaction mixture was concentrated in vacuo and the residue was purified by flash column chromatography eluting with 0-100% MeOH (20% solution in DCM) to give 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.

[0931] UPLC-MS(ES + , method 1): 2.97 min, m / z 522.5 [M+H] + .

[0932] 1 H NMR(400MHz, DMSO-d6)δ / ppm:7.73(dd,J=9.0,5.9Hz,1H),7.37–7.29(m,1H),7.27(d,J=2.4Hz,1H),7.16(d,J=2.1Hz,1H),4.72–4.48(m,3H),4.3 1-4.21(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=7.5Hz,3H).

[0933] The following examples in Table 7 were prepared analogously to Example 49 (Scheme 18) by substituting the appropriate building blocks described in the table for tert-butyl 3-(hydroxymethyl)pyrrolidine-1-carboxylate in Step A.

[0934] Table 7

[0935]

[0936]

[0937]

[0938]

[0939]

[0940]

[0941]

[0942]

[0943]

[0944] 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.

[0945] Example 63 was prepared according to the route described in Scheme 19.

[0946]

[0947] Plan 19

[0948] 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 min. Sodium triacetoxyborohydride (44.8 mg, 0.210 mmol) was added and stirring continued for 1 h. The mixture was diluted with methanol (10 mL) and allowed to stand at room temperature overnight. The solvent was removed in vacuo, and the resulting solid was suspended in DCM (2 mL). The suspension was purified by flash chromatography using 5.9 g irregular NH silica gel column, eluting with 0-15% MeOH in DCM. The fractions containing the product were concentrated in vacuo, and the resulting solid was transferred to methanol (1 mL) in a tare weight vial. The solvent was removed in a Smart Evaporator, and the vial was dried in a vacuum oven at 50 ° C for 3 h to obtain 6- (8- ethyl -7- fluoro-3- hydroxy -1- naphthyl) -2- [[ (2S, 4R) -4- fluoro-1-methyl -pyrrolidin-2-yl] methoxy] -4- (1,4- oxazacycloheptane -4-yl) -7H- pyrrolo [3,4-d] pyrimidine -5- one (15.3 mg, 0.0280 mmol, 39% yield) as a light yellow solid.

[0949] UPLC-MS(ES + , method 1): 3.02 min, m / z 554.4 [M+H] + .

[0950] 1H NMR(400MHz,DMSO-d6)δ / ppm:9.96(br s,1H),7.73(dd,J=8.7,5.9Hz,1H),7.39-7.29(m,1H),7.26(d,J=2.5Hz,1H),7.16(d,J= 2.5Hz,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=1.1Hz,3H),2.19-2.08(m,1H),2.02-1.72(m,3H),1.02(t,J=7.3Hz,3H).

[0951] The examples in Table 8 below were prepared analogously to Example 63 (Scheme 19), using the examples described in the table instead of Example 60 as precursors.

[0952] Table 8

[0953]

[0954]

[0955]

[0956]

[0957]

[0958] Example 64, 6-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-4-(1,4-oxazepan-4-yl)-2-[[1-(4-piperidinyl)triazol-4-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one

[0959] Example 64 was prepared according to the route described in Scheme 20.

[0960]

[0961] Plan 20

[0962] Step A, 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. Water (0.25 mL) was added 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-(methoxymethoxy)-1-naphthyl]-4-(1,4-oxazepan-4-yl)-2-prop-2-ynyloxy-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), 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 in vacuo 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.

[0963] UPLC-MS(ES + , Method 2): 2.20 min, m / z 747.4 [M+H] +

[0964] Step B, 6-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-4-(1,4-oxazepan-4-yl)-2-[[1-(4-piperidinyl)triazol-4-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one (Example 64). Trifluoroacetic acid (0.12mL, 1.54mmol) is added to triethylsilane (0.02mL, 0.150mmol) and 4-[4-[[6-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-4-(1,4-oxaazepan-4-yl)-5-oxo-7H-pyrrolo[3,4-d]pyrimidin-2-yl]oxymethyl]triazol-1-yl]piperidine-1-carboxylic acid tert-butyl ester (46.0mg, 0.0300mmol) in DCM (1mL).The reaction mixture is stirred at room temperature for 4.5h, and the mixture is concentrated in vacuo.The mixture is dissolved in DMSO:MeCN:H2O (1mL, 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-piperidinyl)triazol-4-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one (2.9 mg, 0.00480 mmol, 16% yield) as a light yellow solid.

[0965] UPLC-MS(ES + , Method 1): 2.91 min, m / z 603.4 [M+H] +

[0966] 1H NMR(400MHz,MeOH-d4)δ / ppm:8.52(br s,1H),8.20(s,1H),7.67(dd,J=9.0,5.8Hz,1H),7.12(d,J=2.6Hz,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),3.6 5-3.43(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=7.4Hz,3H).

[0967] 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-hexahydropyrrolazin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one.

[0968] Example 65 was prepared according to the route described in Scheme 21.

[0969]

[0970] Plan 21

[0971] 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-hexahydropyrrolazin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate. To tert-butyl 4-hydroxy-5-oxo-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-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 in vacuo to dryness and purified by column chromatography eluting with 100% DCM to 20% MeOH in 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-hexahydropyrrolazin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (123 mg, 0.244 mmol, 100% yield) as a yellow oil.

[0972] UPLC-MS(ES + , Method 2): 1.42 min, m / z 504.2 [M+H] +

[0973] 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-hexahydropyrrolazin-8-yl]methoxy]-6,7-dihydropyrrolo[3,4-d]pyrimidin-5-one. To 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-hexahydropyrrolazin-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 in 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-hexahydropyrrolazin-8-yl]methoxy]-6,7-dihydropyrrolo[3,4-d]pyrimidin-5-one (20.0 mg, 0.0496 mmol, 20% yield) as an orange oil.

[0974] UPLC-MS(ES + , Method 2): 1.26 min, m / z 404.2 [M+H] +

[0975] Step C, 4-(1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5-yl)-6-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolazin-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-hexahydropyrrolazin-8-yl]methoxy]-6,7-dihydropyrrolo[3,4-d]pyrimidin-5-one (20.0 mg, 0.0500 mmol), cesium carbonate (40.4 To a mixture of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (5.7 mg, 0.0100 mmol) and [8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl] trifluoromethanesulfonate (28.4 mg, 0.0700 mmol) was added 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (5.7 mg, 0.0100 mmol) and tris(dibenzylideneindeneacetone)dipalladium(0) (4.54 mg, 0.00500 mmol). The reaction flask was evacuated, refilled with N2 and heated to 110°C for 2 h. The reaction was diluted with EtOAc, passed through a phase separation filter paper and concentrated to dryness. The crude product was then purified by column chromatography on a KP-NH column eluting with 100% DCM to 20% MeOH in DCM to give 4-(1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5-yl)-6-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolazin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one (13.0 mg, 0.0204 mmol, 41% yield) as a yellow oil.

[0976] UPLC-MS(ES + , Method 2): 1.80 min, m / z 636.3 [M+H] +

[0977] 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-hexahydropyrrolazin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one (Example 65). To 4-(1,3,3a,4,6,6a-hexahydrofuro[3,4-c]pyrrol-5-yl)-6-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolazin-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 (washing the column with MeOH and then eluting the product with 1 M NH in MeOH). The ammonia washes were concentrated to dryness and the crude product was purified by column chromatography on a KP-NH modified column eluting with DCM to 10% MeOH in DCM. The desired fractions were combined and concentrated to dryness in vacuo to afford 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-hexahydropyrrolazin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one (3.0 mg, 0.00510 mmol, 25% yield) as an orange solid.

[0978] UPLC-MS (method 1): 2.95, 2.97 min, m / z 592.5 [M+H] + (5,6%)and 2.99,3.01min,m / z 592.6[M+H] + (33,53%).

[0979] 1H NMR(400MHz,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),3.1 4-2.79(m,7H),2.75-2.69(m,1H),2.14-1.75(m,6H),1.06-1.00(m,3H).

[0980] The following examples (Table 9) were prepared analogously to Example 65 (Scheme 21), substituting the described building blocks for hexahydro-1H-furo[3,4-c]pyrrole hydrochloride in Step A.

[0981] Table 9

[0982]

[0983]

[0984]

[0985]

[0986]

[0987]

[0988]

[0989]

[0990]

[0991]

[0992]

[0993]

[0994]

[0995]

[0996]

[0997] Example 69, 6-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-4-[methyl(4-piperidinyl)amino]-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one

[0998] Example 69 was prepared according to the route described in Scheme 22.

[0999]

[1000] Plan 22

[1001] Step A, 4,6-dichloro-2-methylthio-pyrimidine-5-carboxylic acid ethyl ester. At -78 ° C, to a solution of diisopropylamine (55.7 mL, 397 mmol) in THF (100 mL), n-butyl lithium (159 mL, 397 mmol) and 4,6-dichloro-2-methylthiopyrimidine (50.0 g, 256 mmol) in THF (200 mL) were added dropwise. The reaction mixture was stirred at -78 ° C for 1 h. Ethyl chloroformate (73.5 mL, 769 mmol) was added dropwise, and the reaction mixture was stirred at 0 ° C for 30 min. The reaction mixture was quenched with saturated NH4Cl aqueous solution and the layers were separated. The aqueous layer was extracted with EtOAc (500 ml x 3). The combined organic layer was washed with brine (2000 mL), dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (PE / EtOAc = 1 / 0 to PE / EtOAc = 100 / 1, v / v) to give 4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (40.0 g, 44.9 mmol, 18% yield) as a light yellow solid.

[1002] LC-MS(ES + , Method 4) 1.09 min, m / z 267.0 / 269.0 [M+H] +

[1003] Step B, 4-[(1-tert-butoxycarbonyl-4-piperidinyl)-methyl-amino]-6-chloro-2-methylthio-pyrimidine-5-carboxylic acid ethyl ester. A solution of 4,6-dichloro-2-(methylthio)pyrimidine-5-carboxylic acid ethyl ester (30.0g, 67.4mmol), N-boc-4-(methylamino) piperidine (14.4g, 67.4mmol) and triethylamine (28.2mL, 202mmol) in DMF (300mL) was stirred for 3h at room temperature under nitrogen. The reaction mixture was diluted with water (3000mL), and each layer was separated. The aqueous layer was extracted with EtOAc (800mL x 3). The organic phase merged was washed with salt water, used Na2SO4, and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with 20% EtOAc in petroleum ether to give 4-[(1-tert-butoxycarbonyl-4-piperidinyl)-methyl-amino]-6-chloro-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (25.0 g, 56.2 mmol, 83% yield) as a yellow solid.

[1004] LC-MS(ES + , Method 4): 2.32 min, m / z 445.1 [M+H] +

[1005] Step C, 4-[(1-tert-butoxycarbonyl-4-piperidyl)-methyl-amino]-6-cyano-2-methylthio-pyrimidine-5-carboxylic acid ethyl ester. By 4-[(1-tert-butoxycarbonyl-4-piperidyl)-methyl-amino]-6-chloro-2-methylthio-pyrimidine-5-carboxylic acid ethyl ester (13.0g, 29.2mmol), Zn(CN) 2 (51.5g, 43.8mmol) and tetrakis(triphenylphosphine)palladium (33.8g, 2.92mmol) in DMF (20mL) stir 16h at 120 ℃. Dilute the reaction mixture with water (500mL), and separate each layer. Extract the aqueous layer with EtOAc (200mL x 3). Wash the organic phase merged with salt water, use Na 2 SO 4 dry and vacuum concentrate. The crude material was purified by silica gel chromatography (eluting with 1 / 3 EtOAc / petroleum ether) to give 4-[(1-tert-butoxycarbonyl-4-piperidinyl)-methyl-amino]-6-cyano-2-methylsulfanyl-pyrimidine-5-carboxylic acid ethyl ester (12.0 g, 27.6 mmol, 94% yield) as a yellow solid.

[1006] LC-MS(ES + , Method 4): 2.17 min, m / z 436.2 [M+H] +

[1007] Step D, tert-butyl 4-[methyl-(2-methylthio-5-oxo-6,7-dihydropyrrolo[3,4-d]pyrimidin-4-yl)amino]piperidine-1-carboxylate. A solution of 4-[(1-tert-butoxycarbonyl-4-piperidinyl)-methyl-amino]-6-cyano-2-methylthio-pyrimidine-5-carboxylate (6.00g, 13.8mmol), CoCl2-6H2O (11.5g, 41.3mmol) and sodium borohydride (2.61g, 68.9mmol) in methanol (300mL) was stirred at -78°C and nitrogen for 45min. The reaction mixture was heated to 50°C and maintained for 4h. The reaction mixture was diluted with water (3000mL) and extracted with EtOAc (1000mL x 3). The combined organic phases were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (eluting with 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.

[1008] LC-MS(ES + , Method 4): 1.97 min, m / z 392.2 [M+H] +

[1009] Step E, tert-butyl 4-[methyl-(2-methanesulfonyl-5-oxo-6,7-dihydropyrrolo[3,4-d]pyrimidin-4-yl)amino]piperidine-1-carboxylate. A solution of ethyl 4-[(1-tert-butoxycarbonyl-4-piperidinyl)-methyl-amino]-6-cyano-2-methanesulfonyl-pyrimidine-5-carboxylate (100 mg, 0.214 mmol) and Ni (500 mg, 0.214 mmol) in IPA (2 mL) was stirred at 70° C. for 3 h. The reaction mixture was concentrated in vacuo and used in the next step without further purification.

[1010] LC-MS(ES + , Method 4): 1.55 min, m / z 426.2 [M+H] +

[1011] Step F, tert-butyl 4-[[6-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-2-methanesulfonyl-5-oxo-7H-pyrrolo[3,4-d]pyrimidin-4-yl]-methyl-amino]piperidine-1-carboxylate.

[1012] At 0 ° C and N2, to a solution of tert-butyl 4-[[6-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-2-methylthio-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). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with water (100 mL) and the layers were separated. The aqueous layer was extracted with DCM (30 mL x 3). The combined organics 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-methanesulfonyl-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.

[1013] LC-MS(ES + , Method 3): 2.35 min, m / z 658.2 [M+H] + .

[1014] Step G, 4-[[6-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-5-oxo-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolazin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-4-yl]-methyl-amino]piperidine-1-carboxylic acid tert-butyl ester. A solution of tert-butyl 4-[[6-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-2-methanesulfonyl-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 h. The reaction mixture was concentrated in vacuo and used in the next step without any further purification.

[1015] LC-MS(ES + , Method 3): 1.80 min, m / z 769.30 [M+Na] +

[1016] Step H, 6-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-4-[methyl(4-piperidinyl)amino]-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one (Example 69). By 4-[[6-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-5-oxo-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolazine-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-4-yl]-methyl-amino]piperidine-1-carboxylic acid tert-butyl ester (65.0mg, 0.0900mmol) and HCl in dioxane (3mL) in DCM (3mL) solution stirred at room temperature for 30min.With saturated NaCOThe reaction mixture is adjusted to pH 8 with aqueous solution.Separate each layer, the aqueous layer is extracted with EtOAc (20mL x3), over anhydrous NaSODry and vacuum concentration. The crude material was purified by preparative HPLC to give 6-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-4-[methyl(4-piperidinyl)amino]-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolazin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one (5.2 mg, 0.00880 mmol, 10% yield) as a white solid.

[1017] LC-MS(ES + , Method 4): 1.30 min, m / z 593.3 [M+H] +

[1018] 1H NMR(400MHz,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=8.9,6.0Hz,1H),7.38-7.31(m,1H),7.30-7.28(m,1H),7.21-7.15(m,1H),5.59(br d,J=52.6Hz,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=7.3Hz,3H).

[1019] Table 10 describes examples synthesized following the same procedure as Example 69 (Scheme 22) by substituting appropriate building blocks for N-Boc-4-(methylamino)piperidine in Step B.

[1020] Table 10

[1021]

[1022]

[1023]

[1024]

[1025]

[1026]

[1027]

[1028]

[1029]

[1030]

[1031]

[1032]

[1033]

[1034] 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.

[1035] Example 74 was prepared according to the route described in Scheme 23.

[1036]

[1037] Plan 23

[1038] Step A, (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-carboxylic acid tert-butyl ester. To a degassed (N2) 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), (2S,4R)-2-(hydroxymethyl)-4-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester (20.78 mg, 0.09 mmol) and cesium carbonate (58.54 mg, 0.18 mmol) in toluene (1 mL) was added (+ / -)-BINAP (7.46 mg, 0.01 mmol) and palladium(II) acetate (1.34 mg, 0.01 mmol). The mixture was stirred at 110° C. for 1 h. The mixture was diluted with ethyl acetate, passed through a phase separation filter paper, and the filtrate was evaporated in vacuo to give a brown residue. The material was purified by flash column chromatography (4 g Biotage KP-NH column, wet loaded with minimal DCM) eluting with 0-100% ethyl acetate in petroleum ether and the desired fractions combined and evaporated in vacuo to give (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-carboxylic acid tert-butyl ester (25 mg, 60.0% yield) as a waxy yellow solid.

[1039] UPLC-MS(ES + , Method 4): 2.32 min, m / z 696.3 [M+H] + .

[1040] 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 (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-carboxylic acid tert-butyl ester (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 h. The mixture was evaporated in vacuo 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 in DCM (as a 10% solution in DCM), and the desired fractions were combined and passed through an SCX column (1 g, pre-equilibrated with MeOH), washing first with MeOH and then with 1 M NH3 / MeOH. The ammonia fraction was evaporated in vacuo to give a white solid. The material was transferred to a tared vial with MeOH, evaporated using a smart evaporator, and dried in a vacuum oven overnight 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 (4 mg, 20.2% yield) as a white solid.

[1041] UPLC-MS(ES + , Method 1): 2.92 min, m / z 552.5 [M+H] + .

[1042] 1H NMR(400MHz, DMSO-d6)δ / ppm:9.93(s,1H),7.73(dd,J=6.3,9.1Hz,1H),7.32(t,J=10.0Hz,1H ),7.26(d,J=2.4Hz,1H),7.16(d,J=2.4Hz,1H),4.66(d,J=2.8Hz,2H),4.21-4.17(m,3H),3.90 -3.87(m,2H),3.67-3.62(m,3H),3.54(t,J=6.9Hz,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=7.7Hz,3H).

[1043] The following examples in Table 11 below were prepared analogously to Example 74 (Scheme 23), substituting the appropriate building block for (2S,4R)-2-(hydroxymethyl)-4-methoxy-pyrrolidine-1-carboxylic acid tert-butyl ester in Step A.

[1044] Table 11

[1045]

[1046]

[1047]

[1048]

[1049]

[1050]

[1051]

[1052]

[1053]

[1054]

[1055]

[1056]

[1057] 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.

[1058] Example 84 was prepared according to the route described in Scheme 24.

[1059]

[1060] Plan 24

[1061] 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 h. 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 glass frit. The solvent was removed in vacuo. The crude residue was purified by flash chromatography (4 g KP-amino column, wet loaded with 30-100% EA in PE then 0-20% MeOH in 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 (19.5 mg, 28.5% yield) as a yellow solid.

[1062] UPLC-MS(ES + , Method 4): 1.46 min, m / z 591.4 [M+H] + .

[1063] 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 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). Stir 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 column, wet loaded with DCM, 0-20% MeOH in DCM). The relevant fractions were combined, concentrated in vacuo and further dried to afford 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 (11.7 mg, 64.8% yield) as a pink / off-white solid.

[1064] UPLC-MS(ES + , Method 1): 2.88 min, m / z 547.7 [M+H] + .

[1065] 1 H NMR(400MHz,DMSO-d6)δ / ppm:9.99(s,1H),7.75-7.71(m,1H),7.34-7.30(m,1H),7.27-7.2 6(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=7.1 Hz,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).

[1066] The following examples were prepared analogously to Example 84 (Scheme 23) by replacing 2-(1-methyl-1H-imidazol-2-yl)ethanol in Step A with the appropriate building blocks.

[1067] 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.

[1068]

[1069] Example 100 was prepared analogously to Example 84 (Scheme 24) substituting 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-3-yl)ethanol for 2-(1-methyl-1H-imidazol-2-yl)ethanol in Step A.

[1070] UPLC-MS(ES + , method 1): 3.00 min, m / z 573.5 [M+H] + .

[1071] 1 H NMR(400MHz,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).

[1072] 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.

[1073]

[1074] Example 188 was prepared analogously to Example 84 (Scheme 24) substituting 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-3-yl)ethanol for 2-(1-methyl-1H-imidazol-2-yl)ethanol in Step A using benzyl alcohol.

[1075] UPLC-MS(ES +, method 1): 4.64 min, m / z 529.4 [M+H] + .

[1076] 1 H NMR(400MHz, DMSO-d6)δ / ppm:9.94(s,1H),7.73(dd,J=6.7,9.2Hz,1H),7.48-7.39(m,4H),7.37-7.30(m,2H),7.26(d,J=3.7Hz,1H),7 .17(d,J=2.0Hz,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=7.3Hz,3H).

[1077] Example 133, 6-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-2-[(6-methylene-2,3,5,7-tetrahydro-1H-pyrrolazin-8-yl)methoxy]-4-(1,4-oxazepan-4-yl)-7H-pyrrolo[3,4-d]pyrimidin-5-one.

[1078]

[1079] Example 133 was prepared analogously to Example 84 (Scheme 24) substituting (6-methylene-2,3,5,7-tetrahydro-1H-pyrrolizin-8-yl)methanol for 2-(1-methyl-1H-imidazol-2-yl)ethanol in Step A.

[1080] UPLC-MS(ES + , Method 1): 2.91 min, m / z 574.7 [M+H] + .

[1081] 1H NMR(400MHz, DMSO-d6)δ / ppm:9.93(s,1H),7.73(dd,J=6.2,9.2Hz,1H),7.33(t,J=9.2Hz,1H),7.26(d, J=3.0Hz,1H),7.16(d,J=2.0Hz,1H),4.91(s,2H),4.66(d,J=1.6Hz,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=15.1Hz,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=14.0Hz,1H),1.98-1.65(m,6H),1.02(t,J=7.5Hz,3H).

[1082] Example 99, 1-[4-(1,4-oxazepan-4-yl)-5-oxo-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolazin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-6-yl]-2H-isoquinolin-3-one.

[1083]

[1084] To 6-(3-chloro-1-isoquinolyl)-4-(1,4-oxazepan-4-yl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolazin-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 N2-degassed 1,4-dioxane (2 mL) and water (0.3 mL) were 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 in vacuo and purified by column chromatography to give a light yellow oil. The material was purified by reverse phase column chromatography, eluting with 0-45% acetonitrile in water (0.1% formic acid), passing the appropriate fractions through SCX, washing with 1M ammonia in methanol, and concentrating the ammoniacal fractions to give 1-[4-(1,4-oxazepan-4-yl)-5-oxo-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-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.

[1085] UPLC-MS(ES + , method 1): 2.62 min, m / z 535.3 [M+H] + .

[1086] 1 H NMR(400MHz, 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=5 3.7Hz,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).

[1087] Example 108, 6-[2-(hydroxymethyl)-1-naphthyl]-4-(1,4-oxazepan-4-yl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one.

[1088]

[1089] PI-1 was synthesized according to the same procedure as in Example 1 (Scheme 15), substituting 1-bromonaphthalene-2-carboxylic acid methyl ester for I-1a in Step C. Step D was omitted.

[1090] UPLC-MS(ES + , Method 2): 1.56 min, m / z 576.2 [M+H] + .

[1091] Step A 6-[2-(Hydroxymethyl)-1-naphthyl]-4-(1,4-oxazepan-4-yl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one. A stirred solution of 1-[4-(1,4-oxazepan-4-yl)-5-oxo-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolazine-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-6-yl]naphthalene-2-carboxylic acid methyl ester (65.mg, 0.11mmol) in THF (1mL) was cooled to 0°C and lithium aluminum hydride (0.11mL, 0.1mmol) in THF was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 4h. The reaction was quenched with 2M HCl aqueous solution. The reactant was basified and extracted with EtOAc. The organic fractions were collected, passed through a phase separation filter paper, and the solvent was concentrated in vacuo. The crude material was purified by reverse phase chromatography (eluting with 0-50% acetonitrile (0.1% formic acid) in water (0.1% formic acid)). The product-containing fractions were loaded onto a pre-equilibrated SCX-2 column (2 g, washed with MeOH and eluted with 1N NH / MeOH) to give 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-hexahydropyrrolizin-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.

[1092] UPLC-MS(ES + , method 1): 2.61 min, m / z 548.6 [M+H] + ,2.64min,m / z 548.6[M+H] + .

[1093] 1H NMR(400MHz, DMSO-d6)δ / ppm:8.05-7.97(m,2H),7.35(d,J=8.6Hz,1H),7.65-7.59(m,1H),7.57-7.49(m,2H),5.29(t,J=5.26Hz,1H) ,5.29(d,J=54.5Hz,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).

[1094] 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-hexahydropyrrolizin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one.

[1095]

[1096] PI-2 was synthesized according to the same procedure as in Example 1 (Scheme 15), substituting 2-[[3-bromo-4-(trifluoromethoxy)phenyl]methoxy]tetrahydropyran I-33 for I-1a in Step C. Step D was omitted.

[1097] Hydrogen chloride (4N in 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-hexahydropyrrolazin-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 in vacuo, and the crude material was purified by reverse phase chromatography (eluting with 0-40% acetonitrile (0.1% formic acid) in water (0.1% formic acid)). Product containing fractions were loaded onto a pre-equilibrated SCX-2 column (2 g, washed with MeOH and eluted with 1N NH3 / MeOH) to afford 6-[5-(hydroxymethyl)-2-(trifluoromethoxy)phenyl]-4-(1,4-oxazepan-4-yl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolazin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one (19 mg, 0.03 mmol, 12% yield) as an off-white solid.

[1098] UPLC-MS(ES + , method 1): 2.67 min, m / z 582.8 [M+H] + .

[1099] 1 H NMR(400MHz, DMSO-d6)δ / ppm:7.57(d,J=1.5Hz,1H),7.48-7.39(m,2H),5.39(t,J=5.7Hz,1H),5.28(d,J=53.7Hz,1H),4.64( s,2H),4.55(d,J=5.6Hz,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).

[1100] 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-hexahydropyrrolizin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one.

[1101]

[1102] 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.

[1103] 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-hexahydropyrrolazin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-6-yl]-1,3-benzothiazol-2-yl]carbamate. To 4-(1,4-oxazepan-4-yl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolazin-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 N2-degassed 1,4-dioxane (0.7 mL) was added BrettPhos Pd G1 MTBE Adduct (12.24 mg, 0.02 mmol). The reaction was evacuated, refilled with N2 and heated to 130°C by MW for 1 h. 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 in water, 0.1% HCO2H) and the product was collected on SCX (methanol wash (x2) followed by 1M NH3 in MeOH wash (x2)) 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-hexahydropyrrolazin-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.

[1104] UPLC-MS (ES+, method 2): 1.71 min, m / z 640.3 [M+H] + .

[1105] 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-hexahydropyrrolizin-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-hexahydropyrrolazin-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 in water, 0.1% HCO2H) and the product was collected on SCX (methanol wash (x2) followed by 1M NH3 in MeOH wash (x2)) 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-hexahydropyrrolizin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one (17 mg, 0.032 mmol, 65% yield) as an off-white solid.

[1106] UPLC-MS(ES + , method 1): 2.41 min, m / z 540.3 [M+H] + .

[1107] 1 H NMR (400MHz, DMSO-d6) δ / ppm: 7.67 (s, 2H), 7.63 (dd, J=7.8, 1.2Hz, 1H), 7.31 (dd, J=7.8, 1.2Hz, 1H), 7.06 (t, J=7.8Hz, 1H), 5.27 (d, J=53. 7Hz,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).

[1108] 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-hexahydropyrrolazin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one.

[1109]

[1110] Step A, 4-chloro-2-methylthio-6-(1,4-oxazepan-4-yl)pyrimidine-5-carboxylic acid ethyl ester. While cooling in an ice bath, a solution of 4,6-dichloro-2-(methylthio)pyrimidine-5-carboxylic acid ethyl ester (4.8 g, 17.9 mmol) and Et3N (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). After complete addition, the reaction mixture was stirred at room temperature overnight. The mixture was quenched with water (300 mL), extracted with EtOAc (100 mL×3), and the combined organic layers were washed with brine, dried over Na 2 SO 4 , concentrated in vacuo, and purified by silica gel chromatography (eluted with 20 / 1 petroleum ether / EtOAc) to give ethyl 4-chloro-2-methylsulfanyl-6-(1,4-oxazepan-4-yl)pyrimidine-5-carboxylate (5.5 g, 92% yield) as a yellow solid.

[1111] UPLC-MS(ES + , Method 4): 0.55 min, m / z 332.1 [M+H] + .

[1112] 1 H NMR(400MHz, 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).

[1113] Step B, ethyl 4-(1-ethoxyvinyl)-2-methylthio-6-(1,4-oxazepan-4-yl)pyrimidine-5-carboxylate. A mixture of ethyl 4-chloro-2-methylthio-6-(1,4-oxazepan-4-yl)pyrimidine-5-carboxylate (20 g, 60.27 mmol), Pd(PPh3)2Cl2 (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 N2 for 4 h. The mixture was quenched with water (1000 mL) and extracted with EtOAc (300 mL×3). The combined organic layers were washed with brine, dried over Na 2 SO 4 , concentrated in vacuo, and purified by silica gel chromatography (eluted with 4 / 1 petroleum ether / EtOAc) to give ethyl 4-(1-ethoxyvinyl)-2-methylthio-6-(1,4-oxazepan-4-yl)pyrimidine-5-carboxylate (42 g, 91% yield) as a yellow oil.

[1114] UPLC-MS(ES + , Method 4): 1.83 min, m / z 368.10 [M+H] + .

[1115] Step C, 4-acetyl-2-methylthio-6-(1,4-oxazepane-4-yl)pyrimidine-5-carboxylic acid ethyl ester.A mixture of 4-(1-ethoxyvinyl)-2-methylthio-6-(1,4-oxazepane-4-yl)pyrimidine-5-carboxylic acid ethyl ester (1.75g, 4.76mmol) and 2.5M HCl (15mL) in acetone (36mL) was stirred overnight at room temperature under N2.The mixture was concentrated in vacuo and purified by silica gel column (10 / 1 to 2 / 1 petroleum ether / EtOAc) to obtain 4-acetyl-2-methylthio-6-(1,4-oxazepane-4-yl)pyrimidine-5-carboxylic acid ethyl ester (23g, 65% yield).

[1116] UPLC-MS(ES + , Method 4): 1.70 min, m / z 340.10 [M+H] +

[1117] Step D, 4-ethylimino-2-methylthio-6-(1,4-oxazepan-4-yl)pyrimidine-5-carboxylic acid. A mixture of ethyl 4-acetyl-2-methylthio-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 NH 3 .MeOH (100 mL) was stirred at room temperature for 4 h. The solvent was removed under reduced pressure, and the crude material 4-ethylimino-2-methylthio-6-(1,4-oxazepan-4-yl)pyrimidine-5-carboxylic acid was used directly in the next step.

[1118] UPLC-MS(ES + , Method 4): 1.06 min, m / z 311.05 [M+H] + .

[1119] Step E, 7-methyl-2-methylthio-4-(1,4-oxazepan-4-yl)-6,7-dihydropyrrolo[3,4-d]pyrimidin-5-one. A mixture of 4-ethylimino-2-methylthio-6-(1,4-oxazepan-4-yl)pyrimidine-5-carboxylic acid (20 g, 64.44 mmol) in 7N NH3.MeOH (50 mL) was cooled to 0°C, followed by the addition of NaBH4 (7.3 g, 193.32 mmol). The resulting mixture was warmed to room temperature and stirred overnight. The mixture was quenched with water, extracted into EtOAc, dried (Na2SO4), filtered and 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.

[1120] UPLC-MS(ES + , Method 4): 1.278 min, m / z 295.10 [M+H] + .

[1121] 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), Cs2CO3 (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), extracted with EtOAc (50 mL x 3), the combined organic layers were washed with brine, dried over Na2SO4 and 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.

[1122] UPLC-MS(ES + , Method 3):1.969min,m / z 481.2[M+H] + .

[1123] Step G, 6-[3-(methoxymethoxy)-1-naphthyl]-7-methyl-2-methanesulfonyl-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-methylthio-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, and then m-chloroperbenzoic acid (118.49 mg, 0.69 mmol) was added and stirred at room temperature for 2 h. Saturated aqueous Na2SO3 solution (30 mL) was added. After stirring for 15 min, the mixture was diluted with DCM (50 mL), the phases were separated, and the organic layer was washed with saturated aqueous bicarbonate solution (2×50 mL) and brine (300 mL). The combined organics 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-methanesulfonyl-4-(1,4-oxazepan-4-yl)-7H-pyrrolo[3,4-d]pyrimidin-5-one (100 mg, 85% yield) as a light yellow solid.

[1124] UPLC-MS(ES + , Method 3): 2.09 min, m / z 513.2 [M+H] + .

[1125] 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-hexahydropyrrolizin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one. A mixture of ((2R,7aS)-2-fluorohexahydro-1H-pyrrolazin-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, followed by the addition of 6-[3-(methoxymethoxy)-1-naphthyl]-7-methyl-2-methanesulfonyl-4-(1,4-oxazepan-4-yl)-7H-pyrrolo[3,4-d]pyrimidin-5-one (100 mg, 0.2 mmol) and stirring at room temperature for 1 h. The reaction was poured into saturated ammonium chloride solution at 0°C, diluted with water (100 mL), and extracted with DCM (30 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated in vacuo and purified by column chromatography on silica gel (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-hexahydropyrrolazin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one (40 mg, 34% yield) as a white solid.

[1126] UPLC-MS(ES + , Method 4): 1.247 min, m / z 592.2 [M+H] + .

[1127] 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-hexahydropyrrolizin-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-hexahydropyrrolizin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one (35 mg, 0.06 mmol) and 4N HCl in dioxane (1.5 mL) in methanol (1 mL) was stirred at room temperature for 1 h. The pH of the resulting mixture was adjusted to 8 with saturated sodium carbonate solution and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give the crude material, 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-hexahydropyrrolizin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one (7 mg, 21% yield) as a white solid.

[1128] UPLC-MS(ES + , Method 4): 0.97 min, m / z 548.3 [M+H] + .

[1129] 1 H NMR(400MHz, DMSO-d6)δ / ppm:10.79(s,1H),7.78(dd,J=18.1,8.4Hz,1H),7.62–7.38(m,2H),7.31–6.97(m,3H),5.59(d,J=52.3Hz,1H),4.91(d d,J=115.2,7.1Hz,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=49.7,7.1Hz,3H).

[1130] Example 166, 6-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-4-(1,4-oxazepan-4-yl)-2-prop-2-ynyloxy-7H-pyrrolo[3,4-d]pyrimidin-5-one.

[1131]

[1132] Example 166 was synthesized according to the reaction conditions in Step D of Example 1 (Scheme 15), replacing 6-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-4-(1,4-oxaazepan-4-yl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizine-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one with I-16.

[1133] UPLC-MS(ES + , Method 1): 3.68 min, m / z 477.7 [M+H] + .

[1134] 1 H NMR(400MHz,DMSO-d6)δ / ppm:9.94(br.s,1H),7.73(dd,J=6.0,9.1Hz,1H),7.33(t,J =9.4Hz,1H),7.26(d,J=2.6Hz,1H),7.17(d,J=2.6Hz,1H),5.03(br.s,2H),4.74-4.5 3(m,3H),4.42-4.21(m,1H),4.10-3.75(m,3H),3.71-3.60(m,3H),3.56(t,J=2.4Hz, 1H),2.93-2.83(m,1H),2.76-2.66(m,1H),2.07-1.76(m,2H),1.02(t,J=7.4Hz,3H).

[1135] Example 172, 6-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-4-phenyl-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one.

[1136]

[1137] Step A, tert-butyl 2-chloro-4-phenyl-5,7-dihydropyrrolo[3,4-d]pyrimidine-6-carboxylate. To 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 tripotassium phosphate (1097.37 mg, 5.17 mmol) in degassed 1,4-dioxane (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 mixture was diluted with EtOAc, separated by phase separation filter paper and concentrated to dryness. The crude material was then purified by column chromatography, eluted with 100% petroleum ether to 100% EtOAc to give 2- chloro- 4- phenyl -5,7- dihydropyrrolo [3,4-d] pyrimidine -6- carboxylic acid tert-butyl esters (349 mg, 1.05 mmol, 61% yield), as a white solid.

[1138] UPLC-MS(ES + , Method 2): 2.24 min, m / z 332.2 [M+H] + .

[1139] Step B, 2-chloro-5-oxo-4-phenyl-7H-pyrrolo[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester. To 2-chloro-4-phenyl-5,7-dihydropyrrolo[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester (349 mg, 1.05 mmol) and sodium periodate (674.93 mg, 3.16 mmol) in ethyl acetate (30 mL) and water (30 mL), ruthenium chloride (32.73 mg, 0.16 mmol) was added and the reactants were stirred for 4 h. The reactants were filtered through a diatomaceous earth pad, washed with EtOAc, and each phase was separated. The organic matter was passed through a phase separation filter paper and concentrated to dryness. The crude material was then purified by column chromatography eluting with 100% petroleum ether to 50% EtOAc in petroleum ether to afford 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.

[1140] UPLC-MS(ES + , Method 2): 2.04 min, m / z 368.0 [M+Na] + .

[1141] Step C, tert-butyl 5-oxo-4-phenyl-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate. To 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 h. The reaction was diluted with EtOAc, passed through a phase separation filter paper and concentrated to dryness. The crude material was then purified by column chromatography eluting with 100% DCM to 20% MeOH in DCM to afford tert-butyl 5-oxo-4-phenyl-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolazin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (176 mg, 0.38 mmol, 88% yield) as a yellow solid.

[1142] UPLC-MS(ES + , Method 2): 1.53 min, m / z 469.2 [M+H] + .

[1143] Step D, 4-phenyl-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolazin-8-yl]methoxy]-6,7-dihydropyrrolo[3,4-d]pyrimidin-5-one. To tert-butyl 5-oxo-4-phenyl-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolazin-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 min. The reaction was concentrated under reduced pressure and purified by flash column chromatography on a KP-NH column eluting with 100% DCM to 20% MeOH in DCM to give 4-phenyl-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolazin-8-yl]methoxy]-6,7-dihydropyrrolo[3,4-d]pyrimidin-5-one (95 mg, 0.26 mmol, 69% yield) as an orange oil.

[1144] UPLC-MS(ES + , Method 2): 1.23 min, m / z 369.1 [M+H] + .

[1145] Step E, 6-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-4-phenyl-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one. To 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 N2 degassed toluene (4 mL) was added XantPhos PdG3 (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 phase separation filter paper and concentrated. The crude material was then purified by column chromatography eluting with 100% petroleum ether to 100% DCM to 20% MeOH in DCM to afford 6-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-4-phenyl-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one (72 mg, 0.12 mmol, 46% yield) as an orange oil.

[1146] UPLC-MS(ES + , Method 2): 1.79 min, m / z 601.3 [M+H] + .

[1147] Step F, 6-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-4-phenyl-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one. To 6-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-4-phenyl-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-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 and loaded onto an SCX column, washed with MeOH, and eluted with 1M NH3 in MeOH. The elution was concentrated to dryness. The material was then purified by column chromatography on a KP-NH column eluting with 100% DCM to 10% MeOH in 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-hexahydropyrrolazin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one (47 mg, 0.08 mmol, 70% yield) as a beige solid.

[1148] UPLC-MS(ES + , method 1): 2.80 min, m / z 557.6 [M+H] + .

[1149] 1 H NMR(400MHz,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=7.5Hz,3H).

[1150] Example 181, 6-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-2-[[(2S,8R)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-4-(3-oxo-1,4-diazepan-1-yl)-7H-pyrrolo[3,4-d]pyrimidin-5-one

[1151] PI-3 was synthesized according to the same procedure as Example 69 (Scheme 22), substituting 1-[(4-methoxyphenyl)methyl]-1,4-diazepan-2-one for N-Boc-4-(methylamino)piperidine in step B.

[1152] Example 181 was prepared analogously to Example 176, replacing 6-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-2-[[(2S,8R)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-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) with PI-3.

[1153] UPLC-MS(ES + , method 1): 2.53 min, m / z 593.5 [M+H] + .

[1154] 1 H NMR(400MHz,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,2 H),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).

[1155] Example 196, 6-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidin-5-one.

[1156]

[1157] Step A, 2-chloro-5,7-dihydropyrrolo[3,4-d]pyrimidine-6-carboxylic acid tert-butyl ester. To 2,4-dichloro-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylic acid tert-butyl ester (1000mg, 3.45mmol) and zinc powder (901.36mg, 13.79mmol) in methanol (30mL) was added acetic acid (1.97mL, 34.47mmol), and the reactants were stirred at 65 °C for 2h. The reactants were cooled, decanted and concentrated to dryness. The crude material was then stirred in EtOAc: water and filtered through a diatomaceous earth pad. The organic matter was extracted, passed through a phase separation filter paper and concentrated to dryness. The crude material was purified by column chromatography (petroleum ether to EtOAc) to give 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.

[1158] UPLC-MS(ES + , Method 2): 1.71 min, m / z 256.0 [M+H] + .

[1159] Step B, 2- chloro-5- oxo -7H- pyrrolo [3,4-d] pyrimidine -6- carboxylic acid tert-butyl ester. To 2- chloro-5,7- dihydro pyrrolo [3,4-d] pyrimidine -6- carboxylic acid tert-butyl ester (251mg, 0.98mmol) and ruthenium chloride (30.54mg, 0.15mmol) in ethyl acetate (6mL) and water (6mL) was added sodium periodate (629.88mg, 2.94mmol), and the reactants were stirred at room temperature for 4h. The reactants were diluted with EtOAc and passed through a diatomaceous earth pad. The organic matter was extracted, passed through a phase separation filter paper and concentrated to dryness. The crude material was then purified by column chromatography (petroleum ether to EtOAc) to obtain 2- chloro-5- oxo -7H- pyrrolo [3,4-d] pyrimidine -6- carboxylic acid tert-butyl ester (180mg, 0.67mmol, 68% yield) as a white solid.

[1160] UPLC-MS (ES+, method 2): 1.70 min, m / z 291.9 [M+Na] + .

[1161] Step C, tert-butyl 5-oxo-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate. To tert-butyl 2-chloro-5-oxo-7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (90 mg, 0.33 mmo...

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: Z 1 Independently selected from -O- and -NR 5 -; Z 2 Independently absent or selected from -O- and -NR 6 -; L 1 Selected from bonds and -C(R 18 )2- X 1 Selected from -C(R 3a )2 and -NR 3b -; R 1 Independently selected from C0-C3-alkylene-R 1a and C2-C6-alkylene-R 1b ; where R 1a independently selected from a 4- to 7-membered heterocycloalkyl ring; a benzene ring; and optionally NR 7 R 8 wherein the heterocycloalkyl ring, the benzene ring or the cycloalkyl ring is optionally substituted with 1 to 4 R 9 Group substitution; R 1b Independently selected from: NR 7 R 8 , OR 8 SR 8 、SOR 8 、SO2R 8 and SO(NH)R 8 ; or R 1 and R 5 Together with the nitrogen to which they are attached, they form a ring system selected from: optionally substituted by 1 to 4 R 9 a monocyclic 4 to 7 membered heterocycloalkyl group substituted with a group; and optionally substituted with 1 to 4 R 9 a substituted fused, spirofused or bridged bicyclic 6- to 11-membered heterocyclyl; 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 ; R 2a is independently selected from monocyclic 4 to 7 membered heterocycloalkyl; fused, spirofused or bridged bicyclic 6 to 11 membered heterocycloalkyl; 5, 6, 9 or 10 membered monocyclic or bicyclic heteroaryl; phenyl; C3-C7-cycloalkyl; wherein any heterocycloalkyl or cycloalkyl R 2a The group is optionally substituted by 1 to 6 R 10 group substituted, and any heteroaryl or phenyl R 2a The group is optionally substituted by 1 to 6 R 11 group substitution; where R 2b Independently selected from CONR 12 R 12 and CO2R 12 ; where R 2c Independently selected from NR 12 R 13 and OR 12 ; or R 2 and R 6 Together with the nitrogen to which they are attached, they form a ring system selected from the group consisting of: monocyclic 4 to 7 membered heterocycloalkyl; and fused, spirofused or bridged bicyclic 6 to 11 membered heterocycloalkyl; the heterocycloalkyl being optionally substituted by 1 to 6 R 10 group substitution; R 3a In each occurrence, independently selected from the group consisting of: H, C1-C4-alkyl, C1-C4-haloalkyl, 12 R 13 Substituted C1-C4-alkyl, 12 Substituted C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl; or two of R 3a The groups, together with the carbon to which they are attached, form a spiro-fused cyclopropyl group; R 3b independently selected from H, C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl; R 4 independently selected from the group consisting of: 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 Optionally 1 to 4 R 14 group substitution; R 5 、R 6 、R 8 and R 12 is independently selected at each occurrence from H, C1-C4-haloalkyl, cyclopropyl and C1-C4-alkyl; R 7 and R 13 are 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, they form a ring system selected from the group consisting of: monocyclic 4 to 7 membered heterocycloalkyl; and fused, spirofused or bridged bicyclic 6 to 11 membered heterocycloalkyl; the heterocycloalkyl being optionally substituted by 1 to 6 R 10 group substitution; R 9 is independently selected at each occurrence from the group consisting of: oxo, halogen, cyano, NR 12 R 13 , OR 12 、COR 12 、CO2R 12 、CONR 12 R 12 、CONR 12 R 13 、C1-C4-alkyl、NR 12 R 13 Substituted C1-C4-alkyl, 12 Substituted C1-C4-alkyl, C1-C4-alkyl substituted by cyano, C1-C4-alkyl substituted by phenyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl; R 10 is independently selected at each occurrence from the group consisting of: oxo, halogen, cyano, NR 12 R 13 , OR 12 、COR 12 、CO2R 12 、CONR 12 R 12 、C1-C4-alkyl、NR 12 R 13 Substituted C1-C4-alkyl, 12 Substituted C1-C4-alkyl, C1-C4-alkyl substituted by cyano, C1-C4-alkyl substituted by phenyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl; R 11 Independently selected from the following: halogen, cyano, nitro, NR 12 R 13 , OR 12 、CO2R 12 、CONR 12 R 12 、C1-C4-alkyl、NR 12 R 13 Substituted C1-C4-alkyl, 12 substituted C1-C4-alkyl, monocyclic 4- to 7-membered cycloalkyl or heterocycloalkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl; R 14 is independently selected at each occurrence from the group consisting of: H, halogen, cyano, nitro, NR 12 R 13 , OR 12 、CO2R 12 、CONR 12 R 12 、C1-C4-alkyl、NR 12 R 13 Substituted C1-C4-alkyl, 12 substituted C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, phenyl and cyclopropyl; R 18 is independently selected at each occurrence from the group consisting of: H, halogen, cyano, nitro, NR 12 R 13 , OR 12 、CO2R 12 、CONR 12 R 12 、C1-C4 alkyl、NR 12 R 13 Substituted C1-C4-alkyl, 12 Substituted C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl; or two of R 18 The groups, together with the carbon to which they are attached, form a spiro-fused cyclopropyl group; wherein any of the above alkyl, alkylene, phenyl or cyclopropyl groups is optionally substituted, where chemically possible, by 1 to 5 substituents, said substituents being independently selected at each occurrence from the group consisting of: C1-C4-alkyl, substituted by OR a Substituted C1-C4-alkyl, halogen, nitro, cyano, NR a R b , OR a SR 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; and 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 according to claim 1, wherein R 1 and R 5 , making NR 1 R 5 Contains no more than a monoamine, wherein the monoamine can be a primary, secondary or tertiary amine.

3. The compound according to claim 1 or 2, wherein R 1 and R 5 Together with the nitrogen to which they are attached, they form a ring system selected from the group consisting of: optionally substituted by 1 to 4 R 9 monocyclic 4 to 7 membered heterocycloalkyl substituted with a group; optionally substituted with 1 to 4 R 9 a fused or spirofused bicyclic 6- to 11-membered heterocyclic group substituted with a group; and optionally substituted with 1 to 4 R 9 a bridged bicyclic 6- to 11-membered heterocyclic group substituted by a group; wherein R 1 and R 5 The attached nitrogen is the only nitrogen in the ring system.

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

5. The compound according to claim 4, wherein R 1 and R 5 Together with the nitrogen to which they are attached, they form a ring system having the following structure: where R 9a Selected from NR 12 R 13 and NR 12 R 13 substituted C1-C4-alkyl; p1 is selected from the group consisting of 0, 1, 2, and 3, q1 is selected from the group consisting of 0, 1, and 2; and r1 is selected from the group consisting of 0, 1, 2, and 3.

6. The compound according to claim 4, wherein R 1 and R 5 Together with the nitrogen to which they are attached, they form a ring system having the following structure: where Z 6 Independently selected from C(O)NR 9b NR 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.

7. The compound according to claim 6, wherein R 1 and R 5 Together with the nitrogen to which they are attached, they form a ring system having the following structure: where Z 6 Independently selected from C(O)NR 9b ,O,S,S(O)2,S(O),S(O)(NR 9b ), S(O)(NH) and NR 9b ; 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.

8. The compound according to claim 7, wherein Z 6 It can be O.

9. The compound according to any one of claims 1 to 8, wherein R 2 Has the following structure: where R 15 are independently selected from H, C1-C4-alkyl; wherein R 16 are independently selected from H, C1-C4-alkyl and cyclopropyl; or wherein R 15 and R 16 Together with the atoms to which they are attached, they form a 5- or 6-membered heterocycloalkyl ring, which is optionally substituted by 1 or 2 R 10 and y is independently selected from 0, 1, 2, 3 and 4.

10. The compound according to claim 9, wherein R 2 Has the following structure: wherein z is independently selected from 0, 1, 2, 3 and 4.

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

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

13. The compound according to claim 12, wherein R 18 It is H at every occurrence.

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

15. The compound according to claim 14, wherein R 3a are independently selected at each occurrence from H, C1-C4-alkyl, C1-C4-haloalkyl and cyclopropyl; or wherein two R 3a The groups, together with the carbon to which they are attached, form a spiro-fused cyclopropyl.

16. The compound according to claim 13 or 14, wherein R 3a It is H at every occurrence.

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

18. The compound according to claim 17, wherein R 3b is selected from H and C1-C4-alkyl.

19. A compound according to any one of claims 1 to 18, wherein R 4 is a phenyl group, said phenyl group being optionally fused to a C5-C7-cycloalkyl ring, wherein R 4 Optionally 1 to 4 R 14 Group substitution.

20. A compound according to any one of claims 1 to 18, wherein R 4 Has the following structure: wherein x is independently selected from 0, 1, 2, 3 and 4.

21. The compound according to claim 20, wherein R 4 Has the following structure: where R 12a is independently H or C1-C4-alkyl; x2 is independently selected from 0, 1, 2 and 3.

22. A compound according to any one of claims 1 to 18, wherein R 4 is a 5-, 6-, 9- or 10-membered monocyclic or bicyclic heteroaryl group, which is optionally substituted by 1 to 4 R 14 Group substitution.

23. The compound according to claim 1, wherein the compound of formula (I) is selected from the group consisting of:

24. A compound according to any one of claims 1 to 23 for use in medical treatment.

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

26. The compound of claim 25, wherein the cancer is selected from the group consisting of pancreatic cancer, colorectal cancer, rectal cancer, endometrial cancer, non-small cell lung cancer, gastric cancer, ovarian cancer, and small cell lung cancer.

27. The compound of claim 25 or 26, wherein the subject being treated has a cancer with wild-type KRAS.

28. The compound of claim 25 or 26, wherein the subject being treated has a cancer having a KRAS mutation selected from the group consisting of 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.

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