# US 12,215,092 B2 · Pleiotropic pathway modifier compounds and method of treating diseases

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- Number: US 12,215,092 B2
- Document ID: US12215092B2
- Status: Granted
- Kind: B2
- Application number: 18/586,920
- Filed: 2024-02-26
- Published: 2024-09-12
- Granted: 2025-02-04
- Earliest claimed: 2023-02-24
- Assignees: Ppm Biopharma LLC
- Applicants: Ppm Biopharma LLC
- Inventors: Mingwen Wang; Linghua Zhang
- Web page: https://patentgrep.com/patent/US12215092B2

## CPC

- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- A61P 35/00: Antineoplastic agents
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

This patent document reveals a class of pleiotropic pathway modifier (known as PPM) compounds that facilitate the degradation of multiple targeted proteins and regulate various signaling events involved in cancer cell survival and proliferation, as well as immune response. These compounds effectively recruit disease-causing proteins for swift destruction through the ubiquitin-proteasome pathway, exhibiting potent anti-cancer, immunomodulatory, and anti-inflammatory properties. Additionally, disclosed herein are methods for treating diseases encompassing cancers, autoimmune disorders, infections, inflammations, and other ailments.

## Claims

### Claim 1

A compound represented by Formula I,
wherein
X is CH2 or C═O,
R1 in each instance is independently selected from the group consisting of 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, C1-4alkyl, OC1-4alkyl, NRaRb, halo C1-4alkyl, halogen, OH, CN, phenyl and 5- or 6-membered heteroaryl, wherein the phenyl and 5- or 6-membered heteroaryl are optionally substituted with one or more substituents selected from the group consisting of C1-4alkyl, OC1-4alkyl, NRaRb, halo C1-4alkyl, halogen, OH, and CN;
R2 is OH;
Ra and Rb in each instance is independently H or C1-4alkyl;
A is C1-3alkylene or void,
M is O, OC1-3alkylene, NRa, NHC(O)NH, O(CO)NH, NHC(O)O, or NHC(O), wherein O of OC1-3alkylene is bonded to A or the B ring when A is void;
L1 is NH, 3-6 membered heterocyclic, 6-membered aryl or 6-membered heteroaryl, haloC1-2alkylene, C1-3alkylene or void, wherein the aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of C1-4alkyl, ORa, SH, NRaRb, 3-6 membered cycloalkyl, COORa, CN, halogen, 3-6 membered cycloalkyl, OC1-4alkyl, and haloC1-4alkyl,
L2 in each instance is independently selected from the group consisting of 3-6 membered heterocylic, 6-membered aryl, 6-membered heteroaryl, —(CH2)aC(O)NRa—, —C(O)NRa—, —(CH2)aC(O)NRa(CH2)b—, —(CH2)a—, —(CH2)aO(CH2CH2O)c—, —(CH2)aS, —(CH2)aheterocyclyl-, —(CH2)aC(O)—, —(CH2)a NRa—, —CRa═N—NRa—, —CRa═N—O—, —CRa═N—NRb—CO—, —N═N—CO—, —S—S—, and any combination thereof, wherein a, b, and c are each an integer selected from 0 to 25, all subunits included;
L3 is C1-20alkylene, halo-C1-20alkylene, C2-20alkenlene, C2-20alkynlene or void;
m is 0, 1, 2 or 3;
n is an integer selected from 0 to 25, all subunits included;
or a pharmaceutically acceptable salt thereof,
provided that when A, L1 and (L2)n are void and M is NHC(O)NH, or NHC(O), M is not in an ortho position to X.

### Claim 2 (depends on 1)

The compound or the pharmaceutically acceptable salt thereof of claim 1, wherein X is CH2.

### Claim 3 (depends on 1)

The compound or the pharmaceutically acceptable salt thereof of claim 1, wherein
X is CH2;
A is C1-3alkylene;
M is NHC(O);
(L2)n optionally comprises —(CH2)aO(CH2CH2O)c—.

### Claim 4 (depends on 3)

The compound or the pharmaceutically acceptable salt thereof of claim 3, wherein L1 is NH, 3-6 membered heterocyclic, 6-membered aryl, 6-membered heteroaryl, or haloC1-2alkylene,
wherein the compound is represented by Formula I-a.

### Claim 5 (depends on 1)

The compound or the pharmaceutically acceptable salt thereof of claim 1, wherein A is methylene or void,
X is CH2
M is NHC(O),
L1 is NH, haloC1-2alkylene, C1-3alkylene or void,
(L2)n comprises optionally substituted phenyl,
n is an integer selected from 1 to 25, all subunits included.

### Claim 6 (depends on 1)

The compound or the pharmaceutically acceptable salt thereof of claim 1, wherein A is methylene or void,
X is CH2
M is NHC(O),
L1 is halo-methylene, C1-3alkylene or void,
(L2)n comprises optionally substituted phenyl,
n is an integer selected from 1 to 25, all subunits included.

### Claim 7 (depends on 6)

The compound or the pharmaceutically acceptable salt thereof of claim 6, wherein
L1 is CF2, CH2, or void.

### Claim 8 (depends on 6)

The compound or the pharmaceutically acceptable salt thereof of claim 6, wherein L1 is CH2, or void, A is CH2.

### Claim 9 (depends on 8)

The compound or the pharmaceutically acceptable salt thereof of claim 8,
wherein the compound is represented by Formula I-b.

### Claim 10 (depends on 8)

The compound or the pharmaceutically acceptable salt thereof of claim 8, wherein L1 is NH, halo-methylene or C1-3alkylene, (L2)n comprises optionally substituted phenyl.

### Claim 11 (depends on 1)

The compound or the pharmaceutically acceptable salt thereof of claim 1,
wherein the compound is represented by Formula I-c.

### Claim 12 (depends on 1)

The compound or the pharmaceutically acceptable salt thereof of claim 1, wherein the compound is represented by Formula I-j,
Wherein
p is an integer from 1 to 20,
A is C1-2alkylene or void,
R1a, R1b, and R1c in each instance are independently selected from the group consisting of 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, C1-4alkyl, OC1-4alkyl, NRaRb, halo C1-4alkyl, halogen, OH, and CN;
R4 and R5, are each independently H, halogen or C1-4alkyl.

### Claim 13 (depends on 12)

The compound or the pharmaceutically acceptable salt thereof of claim 12, wherein R4 and R5 are each independently H or halogen.

### Claim 14 (depends on 1)

The compound or the pharmaceutically acceptable salt thereof of claim 1, wherein the compound is represented by Formula I-k,
Wherein
p is an integer from 1 to 20,
A is C1-2alkylene or void,
R1a, R1b, and R1c in each instance are independently selected from the group consisting of 3-6 membered cycloalkyl, 3-6 membered heterocycloalkyl, C1-4alkyl, OC1-4alkyl, NRaRb, halo C1-4alkyl, halogen, OH, and CN; and
R4 and R5, are each independently H, halogen or C1-4alkyl.

### Claim 15 (depends on 14)

The compound or the pharmaceutically acceptable salt thereof of claim 14, wherein the nitrogen of NHC(O)NH, O(CO)NH, NHC(O)O or NHC(O) in M is bonded to L1.

### Claim 16 (depends on 1)

The compound or the pharmaceutically acceptable salt thereof of claim 1, wherein the compound is selected from the group consisting of

### Claim 17 (depends on 1)

A pharmaceutical composition comprising a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof of claim 1.

### Claim 18 (depends on 4)

The compound or the pharmaceutically acceptable salt thereof of claim 4, wherein A is bonded to M via nitrogen of the NHC(O).

### Claim 19 (depends on 4)

The compound or the pharmaceutically acceptable salt thereof of claim 4, wherein A is CH2.

### Claim 20 (depends on 19)

The compound or the pharmaceutically acceptable salt thereof of claim 19, wherein L1 is optionally substituted phenyl.

### Claim 21 (depends on 19)

The compound or the pharmaceutically acceptable salt thereof of claim 19, wherein L1 is phenyl, L3 is C3-9alkylene, and n is 0.

### Claim 22 (depends on 1)

The compound or the pharmaceutically acceptable salt thereof of claim 1, wherein the compound is selected from the group consisting of

### Claim 23 (depends on 1)

The compound or the pharmaceutically acceptable salt thereof of claim 1, wherein L1 is halo-methylene.

### Claim 24 (depends on 1)

A method of treating a disease in a subject comprising administering to the subject a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof of claim 1, wherein the disease is selected from blood cancers, solid tissue cancers, autoimmune diseases, and other diseases involved in carcinogenesis, angiogenesis, immune dysregulation and infection.

### Claim 25 (depends on 24)

The method of claim 24, wherein the disease is cancer selected from the group consisting of bladder cancer, breast cancer, colorectal adenocarcinoma, hepatoma, ovarian cancer, pancreatic cancer, prostate cancer, lung cancer and other solid tissue cancers, as well as blood cancer such as leukemia, lymphoma, and myeloma.

### Claim 26 (depends on 1)

A method of degrading a target protein, comprising the target protein with a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof of claim 1, wherein the target protein is selected from the group consisting of c-MYC (cellular myelocytomatosis), n-MYC (also known as basic helix-loop-helix protein 37), CRBN (cereblon), HDAC (histone deacetylases), IKZF1 (Ikaros Zinc Finger Transcription Factor, Ikaros) IKZF2 (helios), IKZF3 (aiolos), IKZF4 (Eos), IRF4 (Interferon regulatory factor 4), NFκB (Nuclear factor kappa-light-chain-enhancer of activated B cells), p21 (CDK-interacting protein 1), p53 (tumor protein P53), and TNF-α (tumor necrosis factor alpha).