# US 10,370,346 B2 · KDM1A inhibitors for the treatment of disease

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- Number: US 10,370,346 B2
- Document ID: US10370346B2
- Status: Granted
- Kind: B2
- Application number: 15/667,166
- Filed: 2017-08-02
- Published: 2017-11-23
- Granted: 2019-08-06
- Earliest claimed: 2013-08-06
- Assignees: Imago Biosciences, Inc.
- Applicants: Imago Biosciences, Inc.
- Inventors: John M. McCall; Hugh Y. Rienhoff, Jr.; Michael Clare
- Web page: https://patentgrep.com/patent/US10370346B2

## CPC

- C07D 295/192: from aromatic carboxylic acids
- A61K 31/166: having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
- A61K 31/40: having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K 31/4453: only substituted in position 1, e.g. propipocaine, diperodon
- A61K 31/454: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
- A61K 31/4545: containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
- A61K 31/47: Quinolines; Isoquinolines
- A61K 31/495: having six-membered rings with two {or more} nitrogen atoms as the only ring heteroatoms, e.g. piperazine {or tetrazines}(A61K31/48 takes precedence {; with three nitrogen atoms A61K31/53})
- A61K 31/5375: 1,4-Oxazines, e.g. morpholine
- A61K 31/54: having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 7/06: Antianaemics
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07C 237/22: having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated (peptides C07K)
- C07D 213/81: Amides; Imides
- C07D 215/14: Radicals substituted by oxygen atoms
- C07D 233/90: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 295/185: from aliphatic carboxylic acids
- C07D 295/26: Sulfur atoms
- C07C 2601/02: with a three-membered 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
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS

## Abstract

Disclosed herein are new compounds and compositions and their application as pharmaceuticals for the treatment of diseases. Methods of inhibition of KDM1A, methods of increasing gamma globin gene expression, and methods to induce differentiation of cancer cells in a human or animal subject are also provided for the treatment of diseases such as acute myelogenous leukemia.

## Claims

### Claim 1

A method of treatment of cancer comprising the administration of a therapeutically effective amount of a compound of Formula I:
or a salt thereof, wherein:
Y is chosen from a bond, NR4a, O, C(O)NH, NHC(O), S, SO2, and CH2;
Z is chosen from a bond, NR4b, O, C(O)NH, NHC(O), S, SO2, and CH2;
m is an integer from 0 to 5;
n is an integer from 0 to 3;
R1 and R2 are each independently chosen from, alkyl, aminoalkyl, alkylsulfonylalkyl, alkoxyalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, phenyl, biphenyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl and R1 and R2, together with the nitrogen to which they attach, form a nitrogen-containing heterocycloalkyl or heteroaryl ring, which may be optionally substituted with between 0 and 3 R6 groups; or R1 and R2, together with the nitrogen to which they attach, form
R3 is chosen from alkylamino, cycloalkylamino, arylamino, heteroarylamino, heterocycloalkylamino, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, and heterocycloalkylalkyl any of which may be optionally substituted with between 0 and 3 R6 groups;
R4, R4a, and R4b are independently chosen from hydrogen, alkyl, alkenyl, alkynyl, and cycloalkyl;
R5 is chosen from aryl and heteroaryl, any of which may be optionally substituted with between 0 and 3 R6 groups;
each R6 is independently chosen from hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, haloalkoxy, aryl, aralkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, cyano, alkoxy, amino, alkylamino, dialkylamino, COR7, SO2R7, NHSO2R7, NHSO2NHR7, NHCOR7, NHCONHR7, CONHR7, and CONR7R8; and
R7 and R8 are independently chosen from hydrogen, and lower alkyl; or R7 and R8 may be taken together to form a nitrogen-containing heterocycloalkyl or heteroaryl ring, which may be optionally substituted with lower alkyl,
to a patient in need thereof.

### Claim 2 (depends on 1)

The method as recited in claim 1, wherein the cancer is a hematologic cancer.

### Claim 3 (depends on 2)

The method as recited in claim 2, wherein the hematologic cancer is selected from multiple myeloma, Myelodysplastic Syndrome, Acute Myelogenous Leukemia (AML), Acute Lymphocytic Leukemia (ALL), Chronic Lymphocytic Leukemia (CLL), and Chronic Myelogenous Leukemia (CML), Hodgkin's lymphoma and non-Hodgkin's lymphoma.

### Claim 4 (depends on 2)

The method as recited in claim 2, wherein the cancer is chosen from Myelodysplastic Syndrome (MDS), Acute Myelogenous Leukemia (AML), and Chronic Myelogenous Leukemia (CML).

### Claim 5 (depends on 1)

The method as recited in claim 1, wherein the cancer is a non-hematologic cancer.

### Claim 6 (depends on 5)

The method as recited in claim 5, wherein the non-hematologic cancer is a solid tumor.

### Claim 7 (depends on 1)

The method as recited in claim 1, wherein Z is NR4b.

### Claim 8 (depends on 7)

The method as recited in claim 7, wherein R4b is chosen from methyl and hydrogen.

### Claim 9 (depends on 8)

The method as recited in claim 8, wherein the alkyl, whether by itself or as a named part of another non-cyclic substituent, is C1-C8 alkyl.

### Claim 10 (depends on 9)

The method as recited in claim 9, wherein R3 is chosen from aryl, arylalkyl, heteroaryl, and heteroarylalkyl, any of which may be optionally substituted with between 0 and 3 R6 groups.

### Claim 11 (depends on 10)

The method as recited in claim 10, wherein R3 is chosen from aryl and heteroaryl, any of which may be optionally substituted with between 0 and 3 R6 groups.

### Claim 12 (depends on 11)

The method as recited in claim 11, wherein m is an integer from 0 to 1; Y is chosen from NR4a, O, S, SO2, and CH2; n is an integer from 1 to 3; and R4a is chosen from hydrogen and alkyl.

### Claim 13 (depends on 12)

The method as recited in claim 12, wherein m is 0; Y is CH2; and n is an integer from 1 to 2.

### Claim 14 (depends on 13)

The method as recited in claim 13, wherein R3 is 5-6 membered monocyclic or 8-12 membered bicyclic heteroaryl, in which between one and five ring members may be heteroatoms chosen from N, O, and S, and which may be optionally substituted with between 0 and 3 R6 groups.

### Claim 15 (depends on 14)

The method as recited in claim 14, wherein R3 is 5-6 membered monocyclic heteroaryl, in which between one and four ring members may be heteroatoms chosen from N, O, and S, and which may be optionally substituted with between 0 and 3 R6 groups.

### Claim 16 (depends on 15)

The method as recited in claim 15, wherein each R6 is chosen from lower alkyl, halogen, lower alkoxy, OCF3 and CF3.

### Claim 17 (depends on 16)

The method as recited in claim 16, wherein R3 is chosen from

### Claim 18 (depends on 17)

The method as recited in claim 17, wherein R4 is hydrogen.

### Claim 19 (depends on 18)

The method as recited in claim 18, wherein the nitrogen-containing heterocycloalkyl or heteroaryl ring formed by R1 and R2 together with the nitrogen to which they are attached contains 3 to eight atoms.

### Claim 20 (depends on 19)

The method as recited in claim 19, wherein R1 and R2 are taken together to form a nitrogen-containing heterocycloalkyl, which may be optionally substituted with between 0 and 3 R6 groups.

### Claim 21 (depends on 20)

The method as recited in claim 20, wherein the nitrogen-containing heterocycloalkyl is chosen from:

### Claim 22 (depends on 21)

The method as recited in claim 21, wherein the nitrogen-containing heterocycloalkyl is chosen from:

### Claim 23 (depends on 22)

The method as recited in claim 22, wherein n is 2.

### Claim 24 (depends on 23)

The method as recited in claim 23, wherein R5 is aryl, which may be optionally substituted with between 0 and 3 R6 groups.

### Claim 25 (depends on 24)

The method as recited in claim 24, wherein R5 is phenyl, which may be optionally substituted with between 0 and 3 R6 groups.

### Claim 26 (depends on 12)

The method as recited in claim 12, wherein R3 is aryl, optionally substituted with between 0 and 3 R6 groups.

### Claim 27 (depends on 26)

The method as recited in claim 26, wherein R3 is chosen from phenyl and biphenyl, either of which may be optionally substituted with between 0 and 3 R6 groups.

### Claim 28 (depends on 27)

The method as recited in claim 27, wherein m is an integer from 0 to 1; Y is chosen from NR4a, O, S, SO2, and CH2; n is an integer from 1 to 3; and R4a is chosen from hydrogen and alkyl.

### Claim 29 (depends on 28)

The method as recited in claim 28, wherein m is 0; Y is CH2; and n is an integer from 1 to 2.

### Claim 30 (depends on 28)

The method as recited in claim 28, wherein each R6 is chosen from lower alkyl, halogen, lower alkoxy, OCF3 and CF3.

### Claim 31 (depends on 30)

The method as recited in claim 30, wherein R4 is hydrogen.

### Claim 32 (depends on 31)

The method as recited in claim 31, wherein n is 2.

### Claim 33 (depends on 32)

The method as recited in claim 32, wherein the nitrogen-containing heterocycloalkyl or heteroaryl ring formed by R1 and R2 together with the nitrogen to which they are attached contains 3 to eight atoms.

### Claim 34 (depends on 33)

The method as recited in claim 33, wherein R1 and R2 are taken together to form a nitrogen-containing heterocycloalkyl, which may be optionally substituted with between 0 and 3 R6 groups.

### Claim 35 (depends on 34)

The method as recited in claim 34, wherein the nitrogen-containing heterocycloalkyl is chosen from:

### Claim 36 (depends on 35)

The method as recited in claim 35, wherein the nitrogen-containing heterocycloalkyl is chosen from:

### Claim 37 (depends on 36)

The method as recited in claim 36, wherein n is 2.

### Claim 38 (depends on 37)

The method as recited in claim 37, wherein R5 is aryl, which may be optionally substituted with between 0 and 3 R6 groups, each of which is independently chosen from lower alkyl, halogen, lower alkoxy, OCF3 and CF3.

### Claim 39 (depends on 38)

The method as recited in claim 38, wherein R5 is phenyl, which may be optionally substituted with between 0 and 3 R6 groups, each of which is independently chosen from lower alkyl, halogen, lower alkoxy, OCF3 and CF3.

### Claim 40 (depends on 1)

The method as recited in claim 1, further comprising the administration of a second therapeutic agent.

### Claim 41 (depends on 40)

The method as recited in claim 40, wherein the second therapeutic agent is selected from all-trans retinoic acid (ATRA), arsenic trioxide, an inhibitor of DNA methytransferases, an inhibitor of NFκB signaling, a conventional anti-neoplastic agent, a nucleoside analogue, and a checkpoint inhibitor.

### Claim 42 (depends on 41)

The method as recited in claim 41, wherein the checkpoint inhibitor is a PD-1 inhibitor.

### Claim 43 (depends on 42)

The method as recited in claim 42, wherein the PD-1 inhibitor is selected from pembrolizumab (KEYTRUDA®), nivolumab (OPDIVO®), pidilizumab, and BMS-936559.

### Claim 44 (depends on 41)

The method as recited in claim 41, wherein the checkpoint inhibitor is a PD-L1 inhibitor.

### Claim 45 (depends on 44)

The method as recited in claim 44, wherein the PD-L1 inhibitor is selected from atezolizumab (TECENTRIQ®), avelumab (BAVENCIO®), durvalumab (IMFINZI®), atezolizumab, and avelumab.

### Claim 46 (depends on 41)

The method as recited in claim 41, wherein the second therapeutic agent is all-trans retinoic acid (ATRA).

### Claim 47

A method of treatment of cancer comprising the administration of a therapeutically effective amount of a compound of Formula I:
or a salt thereof, wherein:
Y is CH2;
Z is NR4b;
m is 0;
n is 2;
R1 and R2, together with the nitrogen to which they attach, form
R3 is chosen from phenyl and biphenyl, either of which may be optionally substituted with between 0 and 3 R6 groups;
R4, R4a, and R4b are hydrogen;
R5 is phenyl, which may be optionally substituted with between 0 and 3 groups each chosen from lower alkyl, halogen, lower alkoxy, OCF3 and CF3;
each R6 is independently chosen from hydrogen, halogen, alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, haloalkoxy, aryl, aralkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, cyano, alkoxy, amino, alkylamino, dialkylamino, COR7, SO2R7, NHSO2R7, NHSO2NHR7, NHCOR7, NHCONHR7, CONHR7, and CONR7R8; and
R7 and R8 are independently chosen from hydrogen, and lower alkyl; or R7 and R8 may be taken together to form a nitrogen-containing heterocycloalkyl or heteroaryl ring, which may be optionally substituted with lower alkyl.

### Claim 48 (depends on 47)

The method as recited in claim 47 further comprising the administration of all trans-retinoic acid (ATRA).