CN-121974884-A - RAS inhibitors

Abstract

The present invention relates to RAS inhibitors. The present disclosure provides macrocyclic compounds capable of inhibiting Ras proteins, as well as pharmaceutical compositions and protein complexes thereof, and their use in cancer treatment.

Inventors

• J. CRAIG
• Y.LIU

Assignees

• 锐新医药公司

Dates

Publication Date

20260505

Application Date

20201104

Priority Date

20191104

Claims (20)

1. 1. A compound having the structure of formula Int-1: Or a salt thereof, wherein: q is hydrogen, -B (OH) 2 , Or halogen; Z is hydrogen or optionally substituted C 1 -C 6 alkyl; Y is halogen, -B (OH) 2 , -CO 2 H、-CO 2 -(C 1 -C 6 alkyl) or-CN; e is 、 、 Or (b) And (C) sum PNG is a protecting group.
2. 2. The compound of claim 1, wherein E is 。
3. 3. The compound of claim 1, wherein E is 。
4. 4. The compound of claim 3, wherein E is 。
5. 5. The compound of claim 1, wherein E is 。
6. 6. The compound of claim 1, wherein E is 。
7. 7. The compound of claim 1, wherein the compound has the structure of formula Int-1 a: 。
8. 8. the compound of claim 1, wherein the compound has the structure of formula Int-1 b: 。
9. 9. The compound of claim 1, wherein the compound has the structure of formula Int-1 c: 。
10. 10. The compound of claim 1, wherein the compound has the structure of formula Int-1 d: 。
11. 11. The compound of claim 1, wherein the compound has the structure of formula Int-1 e: 。
12. 12. the compound of claim 1, wherein the compound has the structure of formula Int-1 f: 。
13. 13. the compound of any one of claims 1 to 12, wherein Q is H.
14. 14. The compound of any one of claims 1 to 12, wherein Q is halogen.
15. 15. The compound of any one of claims 1 to 12, wherein Z is H or C 1 -C 6 alkyl optionally substituted with halo.
16. 16. The compound of any one of claims 1 to 12, wherein Z is H or optionally substituted ethyl.
17. 17. The compound of claim 16, wherein Z is 。
18. 18. The compound of claim 16, wherein Z is 。
19. 19. The compound of claim 13, wherein Z is H.
20. 20. The compound of claim 13, wherein Z is optionally substituted C 1 -C 6 alkyl.

Description

RAS inhibitors The application is a divisional application of an application patent application with the name of RAS inhibitor, wherein the application date is 2022, 7, 22 and the application number is 202080076129.4. Cross Reference to Related Applications The present application claims the priority benefits of U.S. application Ser. No. 62/930,355, filed on Ser. No. 62/951,652, filed on Ser. No. 26, and 2020, ser. No. 63/011,636, filed on Ser. No. 17, and Ser. No. 63/043,588, filed on Ser. No. 24, and 2020, both of which are incorporated herein by reference in their entirety. Background Most small molecule drugs act by binding to functionally important pockets on the target protein, thereby modulating the activity of the protein. For example, cholesterol lowering drugs known as statins bind to the enzyme active site of HMG-CoA reductase, thereby preventing the enzyme from binding to its substrate. The fact that many such drug/target interaction pairs are known may mislead some to believe that small molecule modulators for most, if not all, proteins may be found, which provides a reasonable amount of time, effort and resources. But this is far from the case. Currently, it is estimated that only about 10% of all human proteins can be targeted by small molecules. Bojadzic and Buchwald, curr Top Med Chem 18:674-699 (2019). The other 90% are currently considered to be difficult to cure or handle for the small molecule drug discovery described above. Such targets are commonly referred to as "non-patentable (undruggable)". These non-patentable targets include a large and largely undeveloped medically important human protein reservoir. Thus, there is great interest in finding new molecular modalities that can modulate the function of such non-pharmaceutically acceptable targets. It is well established in the literature that Ras proteins (K-Ras, H-Ras and N-Ras) play a vital role in a variety of human cancers and are therefore suitable targets for anticancer therapies. Indeed, in the united states, about 30% of all human cancers are caused by mutations in the Ras protein, many of which are fatal. Ras protein deregulation by activating mutations, overexpression or upstream activation is common in human tumors, and activating mutations in Ras are often found in human cancers. For example, activating mutations at codon 12 in Ras proteins act by inhibiting GTPase Activating Protein (GAP) dependence and the rate of intrinsic GTP hydrolysis, significantly biasing the Ras mutein population towards the "ON" (GTP-binding) state (Ras (ON)), resulting in oncogenic MAPK signaling. Notably, ras exhibits an affinity for GTP at a picomolar concentration, and even in the presence of such low nucleotide concentrations, ras can be activated. Mutations at codon 13 (e.g., G13D) and codon 61 (e.g., Q61K) of Ras also cause oncogenic activity in some cancers. Despite extensive drug discovery efforts directed to Ras over the past decades, drugs that directly target Ras have not been approved. More effort is needed to find additional drugs against cancers driven by various Ras mutations. Disclosure of Invention Provided herein are Ras inhibitors. The methods described herein require the formation of a high affinity three-component complex between a synthetic ligand and two intracellular proteins that do not interact under normal physiological conditions, a target protein of interest (e.g., ras), and a cytoplasmic chaperone protein (presentation protein) that is widely expressed in cells (e.g., cyclophilin a). More specifically, in some embodiments, the Ras inhibitors described herein induce a new binding pocket in Ras by driving the formation of a high affinity triple complex or conjugate between a Ras protein and the widely expressed cytosolic chaperone protein cyclophilin a (CYPA). Without being bound by theory, the present inventors believe that one way in which the compounds of the present invention, and complexes or conjugates formed thereby, exert an inhibitory effect on Ras is to sterically block the site of interaction between Ras and downstream effector molecules such as RAF and PI3K that are required for the transmission of oncogenic signals. Accordingly, in some embodiments, the present disclosure provides a compound of structural formula I, or a pharmaceutically acceptable salt thereof: wherein the dashed lines represent zero, one, two, three or four non-adjacent double bonds; A is-N (H or CH 3)C(O)-(CH2) -, wherein the amino nitrogen is bound to a carbon atom of-CH (R 10) -, optionally substituted 3-to 6-membered cycloalkylene, optionally substituted 3-to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5-to 10-membered heteroarylene; B is absent, is-CH (R 9)-、>C=CR9R9' or > CR 9R9' wherein the carbon is bound to the carbonyl carbon of-N (R 11) C (O) -optionally substituted 3-to 6-membered cycloalkylene, optionally substituted 3-to 6-membered heterocycloalkylene, optionally s