# US 2020/0399265 A1 · Highly active csf1r inhibitor compound

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- Number: US 2020/0399265 A1
- Document ID: US20200399265A1
- Status: Published application
- Kind: A1
- Application number: 16/977,093
- Filed: 2019-05-24
- Published: 2020-12-24
- Earliest claimed: 2018-06-01
- Assignees: Adlai Nortye Biopharma Co., Ltd.
- Applicants: Adlai Nortye Biopharma Co., Ltd.
- Inventors: Shifeng LIU; Zhiyong YU; Wei PANG; Ji WANG; Peng CHEN
- Web page: https://patentgrep.com/patent/US20200399265A1

## CPC

- C07D 417/14: containing three or more hetero rings
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61P 35/00: Antineoplastic agents
- A61P 37/00: Drugs for immunological or allergic disorders
- C07D 401/14: containing three or more hetero rings
- C07D 471/10: Spiro-condensed systems
- C07D 487/10: Spiro-condensed systems
- C07D 491/107: with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to a CSF1R inhibitor, and in particular to a highly active CSF1R inhibitor compound having the structure of formula (I). Said compound of the present invention has high inhibitory activity on CSF1R.

## Claims

### Claim 1

A compound of formula I or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, a mixture of stereoisomers or a racemic mixture of stereoisomers:
wherein, X represents CRaRa′,
NRa, —C(O)—, O, S, S(O), S(O)2;
R1 and R2, together with the carbon atom directly attached thereto form a saturated or unsaturated 3 to 12 membered cycloalkyl or cycloheteroalkyl ring, the heterocycloalkyl group contains at least one heteroatom selected from O, N and S, the cycloalkyl group or heterocycloalkyl group can be optionally substituted by 0, 1, 2, 3 or 4 substituents each independently selected from the following halogen, hydroxy, C1-C8 alkyl, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 haloalkyl, C1-C8 alkoxy, C1-C8 haloalkoxy, C3-C8 cycloalkoxy, C3-C8 heterocyclic alkoxy, —S—(C1-C8) alkyl, —S—(C3-C8) cycloalkyl, —S—(C3-C8) heterocycloalkyl, cyano, nitro, —(C0-C8)alkyl-NR9Ra′, —C═NRa, —O—Cy1, —O—(C0-C8)alkyl-Cy1, —(C2-C8)alkenyl-Cy1, —(C2-C8)alkynyl-Cy1, —C(O)ORa, —C(O)Ra, —OC(O)Ra, —C(O)—NRaRa′, —NRa—C(O)—Ra, —NRa—C(O)—ORa, —(C1-C8)alkyl-NRa—C(O)Ra, —SO2—NRaRa′ and —SO2Ra;
R3 and R5 each independently represent hydrogen, halogen, C1-C8 alkyl, C1-C8 alkoxy, C3-C8 cycloalkyl, C3-C8 heterocycloalkyl, halogenated C1-C8 alkyl, hydroxyl, amino, nitro, cyano, —C(O)ORa, —OC(O)Ra, —C(O)—NRaRa′, —NRa—C(O)—Ra, —NRa—C(O)—ORa, —(C1-C8)alkyl-NRa—C(O)Ra, —SO2—NRaRa′ or —SO2Ra;
R4 represents Cy2, —NHC(O)Ra, —NHC(O)NRaRa′, —C(O)Ra, —c(O)NRaRa′, —S(O)2Ra, —S(O)2NRaRa′, NHS (O)2Ra or —NHS(O)2NRaRa′;
wherein, Cy1 and Cy2 each independently represent a 5-12 membered ring which was independently substituted by 0, 1, 2, 3 or 4 substituents, preferably a 5-12 membered aryl group or a 5-12 membered heteroaryl group; more preferably a 5-6 membered aryl group or a 5-6 membered heteroaryl group, wherein the substituents are halogen, C1-C8 alkyl, C1-C8 alkoxy, C3-C9 cycloalkyl, C3-C9 heterocycle alkyl, halogenated C1-C8 alkyl, hydroxy, nitro, cyano, —C(O)ORa, —OC(O)Ra, —C(O)—NRaRa′, —NRa—C(O)—Ra, —NRa—(O)—ORa, —(C1-C8)alkyl-NRa—C(O)Ra, —SO2—NRaRa′ and —SO2Ra;
wherein, Ra and Ra′ independently represent hydrogen, C1-C8 alkyl, C3-C9 cycloalkyl, hydroxyl, halogen, amino, C1-C8 haloalkyl, C1-C8 alkylamino, alkylamino group or Ra, Ra′ together with the atom directly attached thereto form a 3-9 membered cycloalkyl or heterocycloalkyl ring, preferably hydrogen, C1-C8 alkyl or C3-C8 cycloalkyl;
n is 1, 2 or 3, preferably 1; m and o independently represent 0, 1, 2 or 3,
for the above-defined alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups, can further be substituted with the substituents selected from the following: C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, 5-12 membered aryl, 5-12 membered heteroaryl, C1-C8 haloalkyl, C1-C8 alkoxy, C1-C8 alkylthio, halogen, hydroxyl, cyano, sulfonic and nitro;
for the above-defined substituents, each of the different substituents Ra or Ra′ has its own independent definition.

### Claim 2 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, mixture of stereoisomers or racemic mixture of stereoisomers, wherein R1, R2 together with the carbon atom directly attached thereto form a saturated or unsaturated 3-6 membered cycloalkyl or cycloheteroalkyl ring, and the said cycloalkyl or heterocycloalkyl, and the heterocycloalkyl contains at least one heteroatom selected from O, N and S atoms, the cycloalkyl or heterocycloalkyl group may be optionally substituted with 0, 1, 2, 3, or 4 substituents each independently selected from the following R6, wherein R6 is as defined in claim 1.

### Claim 3 (depends on 1, 2)

The compound of claim 1 or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, mixture of stereoisomers or racemic mixture of stereoisomers, wherein R1, R2 and together with the carbon atom directly attached thereto form the following structures:
wherein, Rc is selected from hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, —C(O)Ra, —C(O)ORa, —C(O)—NRaRa′, —SO2—NRaRa′, and —SO2Ra;
* represents the binding site of R1 and R2 and the carbon atom connected to them;
and the above-mentioned groups may be optionally substituted by 0, 1, 2, 3, 4 substituents independently selected from the following R6 Substitution, wherein Ra, Ra′ and R6 are as defined in claim 1 or 2.

### Claim 4 (depends on 1)

The compound according to claim 1 or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, mixture of stereoisomers or racemic mixture of stereoisomers, wherein X is selected from CRaRa′, NRa, O and S, preferably O; wherein, Ra and Ra′ are selected from hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl, hydroxyl, halogen, C1-C8haloalkyl, C1-C8 alkylamino, di-(C1-C8) alkylamino, or Ra, Ra′ together with the atom directly attached thereto form a 3-9 membered cycloalkyl or heterocycloalkyl ring, preferably hydrogen, halogen or C1-C8 alkyl.

### Claim 5 (depends on 1, 2, 3, 4)

The compound of claim 1 or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, mixture of stereoisomers or racemic mixture of stereoisomers thereof, wherein: R4 is preferably Cy2, —NHC(O)Ra, —C(O)NRaRa′ or —NHC(O)NRaRa′, wherein Cy2, Ra, Ra′ are as defined in any one of claims 1-4.

### Claim 6 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, mixture of stereoisomers or racemic mixture of stereoisomers thereof, wherein: Cy2 is selected from phenyl, pyridyl, pyrazinyl, cyclopropyl, cyclopentyl, cyclohexyl, furyl, thiazolyl, piperidinyl, piperazinyl, oxazolyl, imidazolyl and thienyl;
more preferably, Cy2 is selected from pyrazolyl, imidazolyl, oxazolyl, thiazolyl, phenyl and pyridyl;
and the Cy2 can be optionally substituted by C1-C8 alkyl, C1-C8 alkoxy, C3-C9 cycloalkane Group, C3-C9 heterocyclic group, C1-C8 haloalkyl, halogen, cyano, sulfonic acid, nitro or hydroxy.

### Claim 7 (depends on 1)

The compound according to claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, mixture of stereoisomers or racemic mixture of stereoisomers thereof, wherein: Ra and Ra′ are preferably hydrogen, halogen or C1-C8 alkyl.

### Claim 8 (depends on 1)

The compound according to claim 1 or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, mixture of stereoisomers or racemic mixture of stereoisomers, wherein the compound has a structure selected from:
NO.
Structure
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### Claim 9 (depends on 8)

A pharmaceutical composition comprising the compound of claim 8 or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, mixture of stereoisomers or stereoisomers thereof A racemic mixture, and a pharmaceutically acceptable carrier.

### Claim 10 (depends on 9)

The pharmaceutical composition or pharmaceutical preparation according to claim 9, which further comprises an additional therapeutic agent and/or an immune checkpoint inhibitor, the additional therapeutic agent is preferably selected from chlorambucil, melphalan, cyclophosphamide, ifosfamide, busulfan, carmustine, lomustine, streptozotocin, cisplatin, carboplatin, oxaliplatin, Dacarbazine, temozolomide, procarbazine, methotrexate, fluorouracil, cytarabine, gemcitabine, mercaptopurine, fludarabine, vinblastine, vincristine, vinorelbine, paclitaxel, docetaxel, Topotecan, irinotecan, etoposide, trabectedin, probiotic, doxorubicin, epirubicin, daunorubicin, mitoxantrone, bleomycin, mitomycin C, ixabepilone, tamoxifen, flutamide, gonadorelin analogs, megestrol, prednisone, dexamethasone, methylprednisolone, thalidomide, interferons, alcium Folinate, sirolimus, sirolimus lipid, everolimus, afatinib, alisertib, amuvatinib, apatinib, axitinib, bortezomib, bosutinib, Brivanib, Carbotinib, Cediranib, crenolanib, crizotinib, Dabrafenib, Dacomitinib, danusertib, dasatinib, dovitinib , Erlotinib, foretinib, ganetespib, gefitinib, ibrutinib, icotinib, imatinib, iniparib, lapatinib, lenvatinib, linifanib, linsitinib, masitinib, momelotinib, Motesanib, lenatinib, nilotinib, niraparib, oprozomib, olaparib, pazopanib, pictilisib, ponatinib, quizartinib, Regorafenib, rigosertib, rucaparib, ruxolitinib, saracatinib, saridegib, sorafenib, sunitinib, tilatinib, tivantinib, Tivozanib, tofacitinib, trametinib, vandetanib, Veliparib, Vemurafenib , Vismodegib, Volasertib, Alemtuzumab, Bevacizumab, brentuximab vedotin, Victorin, Catumaxomab, Cetuximab, Denosumab, Getuzumab, ipilimumab, nimotuzumab, ofatumumab, panitumumab, rituximab, Tositumomab, trastuzumab, DO inhibitor, anti-PD-1 antibody, anti-PD-L1 antibody, LAG3 antibody, TIM-3 antibody and anti-CTLA-4 antibody.

### Claim 11 (depends on 8)

A method of preventing and/or treating tumors, cancers, viral infections, organ transplant rejections, neurodegenerative diseases, attention-related diseases or autoimmune diseases by inhibiting CSF1R in a subject in need thereof, comprising administering a compound according to claim 8 or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, mixture of stereoisomers or racemic mixture of stereoisomers thereof to the subject.

### Claim 12 (depends on 11)

The method according to claim 11, wherein the tumor or cancer is selected from skin cancer, bladder cancer, Ovarian cancer, breast cancer; gastric carcinoma, pancreatic cancer; prostatic cancer, colorectal carcinoma, Lung Cancer, bone cancer, brain cancer, Neurocytoma, rectal cancer, colon cancer, familial adenomatous polyposis, hereditary nonpolyposis colorectal cancer, esophageal carcinoma, lip cancer, laryngocar, hypopharyngeal carcinoma, tongue cancer, salivary gland carcinoma, gastric carcinoma, adenocarcinoma, medullary thyroid carcinoma, papillary thyroid cancer, kidney cancer, carcinoma of renal pelvis, Ovarian Carcinoma, cervical carcinoma, carcinoma of the corpus uteri, endometrial carcinoma, choriocarcinoma, prostatic cancer, pancreatic cancer, testicular cancer, Urinary cancer, melanoma, Brain tumors such as glioblastoma and astrocytoma, meningeoma, Neuroblastoma and peripheral neuroectodermal tumor, Hodgkin's lymphoma, Non Hodgkin's lymphoma, Burkitt's lymphoma, acute lymphoid leukemia, Acute lymphoblastic leukemia (ALL), Chronic Lymphocytic Leukemia (CLL), Acute myeloid leukemia (AML), Chronic myelogenous leukemia (CML), Adult T-cell leukemia lymphoma, Diffuse large B cell lymphoma (DLBCL), hepatic cellular cancer, gallbladder cancer, bronchogenic carcinoma, small-cell lung carcinoma, non-small-cell lung cancer, multiple myeloma, Basaloma, Teratoma, retinoblastoma, choroidal melanoma, seminoma, rhabdomyosarcoma, craniopharyngioma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing's sarcoma, plasmacytoma.

### Claim 13

(canceled)

### Claim 14 (depends on 1)

A method for inhibiting CSF1R, which comprises making the compound or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, mixture of stereoisomers or stereoisomers thereof of claim 1 exposed to the CSF1R.

### Claim 15 (depends on 1)

A method for preventing and/or treating diseases that can be prevented and/or treated by inhibiting CSF1R, which comprises administering a subject in need thereof a compound or a pharmaceutically acceptable salts, solvates, hydrates, stereoisomers, mixtures of stereoisomers or racemic mixtures of stereoisomers of claim 1.