# US 10,441,581 B2 · Substituted pyrazolo[1,5-A]pyridine compounds as RET kinase inhibitors

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- Number: US 10,441,581 B2
- Document ID: US10441581B2
- Status: Granted
- Kind: B2
- Application number: 15/860,894
- Filed: 2018-01-03
- Published: 2018-05-17
- Granted: 2019-10-15
- Earliest claimed: 2016-10-10
- Assignees: Array BioPharma Inc.
- Applicants: Array BioPharma, Inc.
- Inventors: Steven W. Andrews; Sean Aronow; James F. Blake; Barbara J. Brandhuber; James Collier; Adam Cook; Julia Haas; Yutong Jiang; Gabrielle R. Kolakowski; Elizabeth A. McFaddin; Megan L. McKenney; Oren T. McNulty; Andrew T. Metcalf; David A. Moreno; Ginelle A. Ramann; Tony P. Tang; Li Ren; Shane M. Walls
- Web page: https://patentgrep.com/patent/US10441581B2

## CPC

- A61K 31/4545: containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
- A61K 31/4162: condensed with heterocyclic ring systems
- A61K 31/444: containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
- A61K 31/497: containing further heterocyclic rings
- A61K 31/501: not condensed and containing further heterocyclic rings
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/12: Antidiarrhoeals
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- C07D 471/04: Ortho-condensed systems
- 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
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Provided herein are compounds of the Formula I: or pharmaceutically acceptable salt or solvate thereof, wherein A, B, X1, X2, X3, X4, Ring D, E, Ra, Rb, n and m have the meanings given in the specification, which are inhibitors of RET kinase and are useful in the treatment and prevention of diseases which can be treated with a RET kinase inhibitor, including RET-associated diseases and disorders.

## Claims

### Claim 1

A method for treating a RET-associated cancer, the method comprising:
(a) detecting dysregulation of a RET gene, a RET kinase, or the expression or activity or level of any of the same in a sample from a patient; and
(b) administering to the patient a therapeutically effective amount of a compound having Formula I or a pharmaceutically acceptable salt or solvate thereof:
and pharmaceutically acceptable salts and solvates thereof, wherein:
X1, X2, X3 and X4 are independently CH or N, wherein zero, one or two of X1, X2, X3 and X4 is N;
A is CN;
B is:
(b) C1-C6 alkyl optionally substituted with 1-3 fluoros,
(c) hydroxyC2-C6 alkyl- wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring, or
(i) (hetCyca)C1-C3 alkyl-;
hetCyca is a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with one or more substituents independently selected from OH, C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyC1-C6 alkyl, halogen, (C1-C6 alkyl)C(═O)—, C1-C6 alkoxy, oxo, and (C1-C6 alkoxy)C(═O)—;
Ring D is
a saturated monocyclic 4-7 membered heterocyclic ring having one ring heteroatom which is nitrogen;
each Ra is independently C1-C6 alkyl (optionally substituted with 1-3 fluoros);
Rb is (a) hydroxy;
n is 0 or 1;
m is 0 or 1;
E is:
(e) hetAr2C1-C6 alkyl-,
(h) hetAr2—O—,
(k) R3C(═O)NRg— where Rg is H or C1-C6 alkyl,
(l) Ar1C(═O)NRg— where Rg is H or C1-C6 alkyl, or
(m) hetAr2C(═O)NRg(CH2)p— where p is 0 or 1 and Rg is H or C1-C6 alkyl;
Ar1 is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C1-C6 alkyl- (optionally substituted with 1-3 fluoros), C3-C6 cycloalkyl, hydroxyC1-C6 alkyl, (C1-C6 alkyl)SO2—, ReRfN— and (ReRfN)C1-C6 alkyl- where each Re and Rf is independently H or C1-C6 alkyl;
hetAr2 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S, or a 9-10 membered bicyclic heteroaryl having 1-2 ring nitrogen atoms, wherein hetAr2 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy (optionally substituted with 1-3 fluoros), (C1-C6 alkoxy)C1-C6 alkyl- (optionally substituted with 1-3 fluoros) and hydroxyC1-C6 alkoxy-;
R3 is C1-C6 alkyl (optionally substituted with 1-3 fluoros), hydroxyC1-C6 alkyl-, C1-C6 alkoxy, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)CH2—, (C3-C6 cycloalkyl)O—, (C3-C6 cycloalkyl)CH2O—, hetCyc7O—, Ph-O—, or (C1-C6 alkoxy)C1-C6 alkyl-; wherein each of said C3-C6 cycloalkyl moieties is optionally substituted with C1-C6 alkyl (optionally substituted with 1-3 fluoros), C1-C6 alkoxy, OH, or R′R″N— where R′ and R″ are independently hydrogen or C1-C6 alkyl; and
hetCyc7 is a 5-7 membered heterocyclic ring having 1-3 ring heteroatoms independently selected from N, O and S.

### Claim 2 (depends on 1)

The method of claim 1, wherein Ring D is
wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X1, X2, X3 and X4, and the asterisk indicates the point of attachment of Ring D to the E group.

### Claim 3 (depends on 2)

The method of claim 2, wherein D is
wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X1, X2, X3 and X4, and the asterisk indicates the point of attachment of Ring D to the E group.

### Claim 4 (depends on 3)

The method of claim 3, wherein D is
wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X1, X2, X3 and X4, and the asterisk indicates the point of attachment of Ring D to the E group.

### Claim 5 (depends on 3)

The method of claim 3, wherein D is
wherein the wavy line indicates the point of attachment of Ring D to the ring comprising X1, X2, X3 and X4, and the asterisk indicates the point of attachment to the E group.

### Claim 6 (depends on 3)

The method of claim 3, wherein E is:
(e) hetAr2C1-C6 alkyl-,
(h) hetAr2—O—,
(l) ArlC(═O)NRg— where Rg is H or C1-C6 alkyl, or
(m) hetAr2C(═O)NRg(CH2)p— where p is 0 or 1 and Rg is H or C1-C6 alkyl.

### Claim 7 (depends on 3)

The method of claim 3, wherein B is C1-C6 alkyl optionally substituted with 1-3 fluoros, or hydroxyC2-C6 alkyl wherein the alkyl portion is optionally substituted with a C3-C6 cycloalkylidene ring.

### Claim 8 (depends on 3)

The method of claim 3, wherein X1 is N, and X2, X3 and X4 are CH.

### Claim 9 (depends on 1)

The method of claim 1, wherein the compound of Formula I is selected from the group consisting of:
N-(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)benzamide;
6-ethoxy-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile;
6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-(pyridin-2-yloxy)azetidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile;
6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-((6-methoxypyridazin-3-yl)oxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile;
(S)-6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-(pyridin-2-yloxy)pyrrolidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile;
N-(1-(5-(3-cyano-6-((3-fluoro-1-methylazetidin-3-yl)methoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-5-fluoro-2-methylbenzamide;
3-chloro-N-(1-(5-(3-cyano-6-((3-fluoro-1-methylazetidin-3-yl)methoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide;
N-((3S,4S)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-hydroxypiperidin-4-yl)-3-methylbutanamide;
6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile; and
3-chloro-N-((3S,4S)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-3-hydroxypiperidin-4-yl)picolinamide;
or a pharmaceutically acceptable salt or solvate thereof.

### Claim 10 (depends on 1)

The method of claim 1, wherein the compound of Formula I is
N-(1-(5-(3-cyano-6-(2-hydroxy-2-methylpropoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)benzamide, or a pharmaceutically acceptable salt or solvate thereof.

### Claim 11 (depends on 1)

The method of claim 1, wherein the compound of Formula I is
6-ethoxy-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile, or a pharmaceutically acceptable salt or solvate thereof.

### Claim 12 (depends on 1)

The method of claim 1, wherein the compound of Formula I is
6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-(pyridin-2-yloxy)azetidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile, or a pharmaceutically acceptable salt or solvate thereof.

### Claim 13 (depends on 1)

The method of claim 1, wherein the compound of Formula I is
6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-((6-methoxypyridazin-3-yl)oxy)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile, or a pharmaceutically acceptable salt or solvate thereof.

### Claim 14 (depends on 1)

The method of claim 1, wherein the compound of Formula I is
(S)-6-(2-hydroxy-2-methylpropoxy)-4-(6-(3-(pyridin-2-yloxy)pyrrolidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile, or a pharmaceutically acceptable salt or solvate thereof.

### Claim 15 (depends on 1)

The method of claim 1, wherein the compound of Formula I is
N-(1-(5-(3-cyano-6-((3-fluoro-1-methylazetidin-3-yl)methoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)-5-fluoro-2-methylbenzamide, or a pharmaceutically acceptable salt or solvate thereof.

### Claim 16 (depends on 1)

The method of claim 1, wherein the compound of Formula I is
3-chloro-N-(1-(5-(3-cyano-6-((3-fluoro-1-methylazetidin-3-yl)methoxy)pyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-4-methylpiperidin-4-yl)picolinamide, or a pharmaceutically acceptable salt or solvate thereof.

### Claim 17 (depends on 1)

The method of claim 1, wherein the compound of Formula I is
N-((3S,4S)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyridin-2-yl)-3-hydroxypiperidin-4-yl)-3-methylbutanamide, or a pharmaceutically acceptable salt or solvate thereof.

### Claim 18 (depends on 1)

The method of claim 1, wherein the compound of Formula I is
6-(2-hydroxy-2-methylpropoxy)-4-(6-(4-hydroxy-4-(pyridin-2-ylmethyl)piperidin-1-yl)pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonitrile, or a pharmaceutically acceptable salt or solvate thereof.

### Claim 19 (depends on 1)

The method of claim 1, wherein the compound of Formula I is
3-chloro-N-((3S,4S)-1-(5-(3-cyano-6-ethoxypyrazolo[1,5-a]pyridin-4-yl)pyrazin-2-yl)-3-hydroxypiperidin-4-yl)picolinamide, or a pharmaceutically acceptable salt or solvate thereof.

### Claim 20 (depends on 1)

The method of claim 1, wherein the cancer is selected from the group consisting of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), breast cancer, cervical cancer, colorectal cancer, ganglioneuromatosis of the gastroenteric mucosa, gastric cancer, gastrointestinal stromal tumors, glioma, leukemia, lung cancer, lymphoma, multiple endocrine neoplasia type 2A or 2B (MEN2A or MEN2B, respectively), multiple myeloma, non-Hodgkin's lymphoma, non-small cell lung cancer, ovarian cancer, papillary renal cell carcinoma, paraganglioma, parathyroid hyperplasia, pheochromocytoma, and thyroid cancer.

### Claim 21 (depends on 20)

The method of claim 20, wherein the cancer is leukemia.

### Claim 22 (depends on 1)

The method of claim 1, wherein the dysregulation of a RET gene, a RET kinase, or the expression or activity or level of any of the same results in the translation of a RET fusion protein or a mutation of a RET kinase.

### Claim 23 (depends on 22)

The method of claim 22, wherein the RET fusion protein is selected from the group consisting of BCR-RET, CLIP1-RET, KIF5B-RET, CCDC6-RET, NCOA4-RET, TRIM33-RET, ERC1-RET, FGFR1OP-RET, RET-MBD1, RET-RAB61P2, RET-PRKAR1A, RET-TRIM24, RET-GOLGA5, HOOK3-RET, KTN1-RET, TRIM27-RET, AKAP13-RET, FKBP15-RET, SPECC1L-RET, TBL1XR1/RET, CEP55-RET, CUX1-RET, KIAA1468-RET, RFG8/RET, ACBD5-RET, PTClex9-RET, MYH13-RET, PIBF1-RET, KIAA1217-RET, MPRIP-RET, HRH4-RET, Ria-RET, RET-PTC4, FRMD4A-RET, SQSTM1-RET, AFAP1L2-RET, PPFIBP2-RET, EML4-RET, PARD3-RET, MYH10-RET, HTIF1/RET, AFAP1-RET, RASGEF1A-RET, TEL-RET, RUFY1-RET, UEVLD-RET, DLG5-RET, FOXP4-RET, TIF1G-RET, H4L-RET, OFLM4-RET, and RRBP1-RET.

### Claim 24 (depends on 22)

The method of claim 22, wherein the mutation is one or more point mutations in a RET gene.

### Claim 25 (depends on 24)

The method of claim 24, wherein the one or more point mutation results in the translation of a RET protein comprising an amino acid substitution at an amino acid position selected from the group consisting of 32, 34, 40, 56, 64, 67, 114, 145, 292, 321, 330, 338, 360, 393, 423, 446, 510, 511, 513, 515, 525, 531, 532, 533, 550, 591, 593, 595, 600, 602, 603, 606, 609, 611, 616, 618, 619, 620, 623, 624, 630, 631, 632, 634, 635, 636, 640, 641, 648, 649, 664, 665, 666, 675, 686, 689, 691, 694, 700, 706, 713, 732, 736, 748, 750, 765, 766, 768, 769, 770, 771, 777, 778, 781, 788, 790, 791, 804, 805, 806, 810, 818, 819, 823, 826, 833, 836, 841, 843, 844, 848, 852, 865, 870, 873, 876, 881, 883, 884, 886, 891, 897, 898, 900, 901, 904, 905, 907, 908, 911, 912, 918, 919, 921, 922, 930, 961, 972, 981, 982, 1009, 1015, 1017, 1041, 1064, and 1096.

### Claim 26 (depends on 24)

The method of claim 24, wherein the one or more point mutations results in the translation of a RET protein comprising an amino acid substitution selected from the group consisting of S32L, D34S, L40P, L56M, P64L, R67H, R114H, V145G, V292M, G321R, R330Q, T338I, R360W, F393L, G423R, G446R, A510V, E511K, G513D, C515S, C515W, R525W, C531R, G533C, G533S, G550E, V591I, G593E, E595D, E595A, R600Q, I602V, K603Q, K603E, Y606C, C609C, C609Y, C609S, C609G, C609R, C609F, C609W, C611R, C611S, C611G, C611Y, C611F, C611W, E616Q, C618S, C618Y, C618R, C618G, C618F, C618W, F619F, C620S, C620W, C620R, C620G, C620L, C620Y, C620F, E623K, D624N, C630A, C630R, C630S, C630Y, C630F, C630W, D631N, D631Y, D631A, D631G, D631V, D631E, E632K, E632G, C634W, C634Y, C634S, C634R, C634F, C634G, C634L, C634A, C634T, R635G, T636P, T636M, A640G, A641S, A641T, V648I, S649L, A664D, H665Q, K666E, K666M, K666N, K666R, T675T S686N, S689T, G691S, R694Q, M700L, V706M, V706A, E713K, E732K, G736R, G748C, A750P, S765P, P766S, P766M, E768Q, E768D, L769L, R770Q, D771N, N777S, V778I, Q781R, I788I, L790F, Y791F, Y791N, V804L, V804M, V804E, E805K, Y806E, Y806F, Y806S, Y806G, Y806C, Y806H, Y806N, Y806Y, G810R, G810S, G810A, E818K, S819I, G823E, Y826M, Y826S, R833C, S836S, P841L, P841P, E843D, R844W, R844Q, R844L, M848T, I852M, L865V, L870F, R873W, A876V, L881V, A883F, A883S, A883T, E884K, R886W, S891A, S891S, R897Q, D898V, Y900F, E901K, S904F, S904S, S904C, Y905F, K907E, K907M, R908K, G911D, R912P, R912Q, M918T, M918V, M918L, A919V, E921K, S922P, S922Y, T930M, F961L, R972G, Y981F, R982C, M1009V, Y1015F, D1017N, V1041G, M1064T, and Y1096F.

### Claim 27 (depends on 1)

The method of claim 1, further comprising administering an additional therapy or therapeutic agent to the patient.

### Claim 28 (depends on 27)

The method of claim 27, wherein the additional therapy or therapeutic agent is selected from the group consisting of radiotherapy, cytotoxic chemotherapeutics, kinase targeted therapeutics, apoptosis modulators, signal transduction inhibitors, immune-targeted therapies, and angiogenesis-targeted therapies.

### Claim 29 (depends on 27)

The method of claim 27, wherein the additional therapy is a second RET inhibitor, an immunotherapy, or a combination thereof.