Inhibitors of menin-MLL interaction

Abstract

To provide novel agents that inhibit the menin-MLL interaction.SOLUTION: A compound of formula I or a pharmaceutically acceptable salt thereof is provided.SELECTED DRAWING: None

Description

Technical Field

[0001] The present invention relates to inhibitors of the interaction between menin and MLL and MLL fusion proteins, pharmaceutical compositions containing the same, and their use in the treatment of cancers and other diseases mediated by the menin-MLL interaction.

Background Art

[0002] The mixed-lineage leukemia (MLL) protein is a histone methyltransferase mutated in a clinically and biologically distinct subset of acute leukemias. Recombinant mixed-lineage leukemia (MLL-r) is associated with recurrent translocations at the 11q23 chromosomal locus, leading to an aggressive form of acute leukemia with limited treatment options. These translocations target the MLL gene and generate oncogenic fusion proteins containing the amino terminus of MLL fused in-frame with over 60 different fusion protein partners. Menin, a ubiquitously expressed nuclear protein encoded by the multiple endocrine neoplasia type 1 (MEN1) tumor suppressor gene, has a high-affinity binding interaction with MLL fusion proteins and is an essential cofactor for oncogenic MLL-r fusion proteins (Yokoyama et al., 2005, Cell, 123:207-18; Cierpicki & Grembecka, 2014, Future Med. Chem., 6:447-462). Disruption of this interaction results in selective growth inhibition and apoptosis of MLL-r leukemia cells in vitro (Grembecka et al., 2012, Nat. Chem. Biol., 8:277-284) and in vivo (Yokoyama et al., 2005, op. cit.; Borkin et al., 2015, Cancer Cell, 27:589-602).

Summary of the Invention

Problems to be Solved by the Invention

[0003] The Menin-MLL complex plays a role in castration-resistant / progressive prostate cancer, and Menin-MLL inhibitors have been shown to reduce tumor growth in vivo (Malik et al., 2015, Nat. Med., 21:344-352). Also, Menin-MLL inhibitors have been shown to enhance human β-cell proliferation (Chamberlain et al., 2014, J. Clin. Invest., 124:4093-4101), supporting a role for Menin-MLL interaction inhibitors in the treatment of diabetes (Yang et al., 2010, Proc Natl Acad Sci U S A., 107:20358-20363). The interaction between Menin and MLL or MLL fusion proteins is an attractive target for therapeutic intervention, and new agents that inhibit the Menin-MLL interaction are needed for the treatment of various diseases and conditions, including leukemia, other cancers, and diabetes.

Means for Solving the Problems

[0004] The present invention provides an inhibitor of the Menin-MML interaction, such as a compound of formula I:

Chemical Formula

[0005] or a pharmaceutically acceptable salt thereof, wherein the constituent variables are defined herein.

[0006] The present invention further provides a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier. The present invention further provides a pharmaceutically acceptable salt form of a compound of formula I. The present invention further provides a crystalline form of a compound of formula I.

[0007] The present invention further provides a method for inhibiting the interaction between Menin and MLL, comprising contacting Menin and MLL with a compound of formula I or a pharmaceutically acceptable salt thereof. The present invention further provides a method for treating cancer in a patient, comprising administering to the patient a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. The present invention further provides a method for treating insulin resistance, prediabetes, diabetes, diabetes risk, or hyperglycemia in a patient, comprising administering to the patient a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0008]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

Figure 9

Figure 10

Figure 11

Figure 12

Figure 13

Figure 14

Figure 15

Figure 16

Figure 17

Figure 18

Figure 19

Figure 20

Figure 21

Figure 22

Figure 23

[0009] (Detailed explanation) The present invention provides inhibitors of menin-MLL interaction, such as compounds of formula I: [ka]

[0010] or a pharmaceutically acceptable salt thereof,

[0011] A, B, D, and E each independently represent -C(R A1 )(R A2 ), -C(R A1 )(R A2 )-C(R A1 )(R A2 ), -C(R A1 )(R A2 )-O-, -C(R A1 )(R A2 )-NR A3 -, -C(=O)-, -C(R A1 )(R A2 )—C(═O)—, and —N═C(NH)—, wherein not more than one of A, B, D, and E is selected from —C(R A1 )(R A2 )-O-, -C(R A1)(R A2 )-NR A3 -、 -C(R A1 )(R A2 )-C(=O)-、 -C(=O)-, or -N=C(NH2)-;

[0012] U is N or CR U where R U is H, halo, CN, OH, C 1-4 alkyl, C 1-4 alkoxy, amino, C 1-4 alkylamino, or C[[ID=2T]] 2-8 dialkylamino;

[0013] W is N or CR W where R W is H, halo, CN, OH, C 1-4 alkyl, C 1-4 alkoxy, amino, C 1-4 alkylamino, or C 2-8 dialkylamino;

[0014] X is N or CR X where R X is H, halo, CN, OH, C 1-4 alkyl, C 1-4 alkoxy, amino, C 1-4 alkylamino, or C 2-8 dialkylamino, and when X is N, the atom of L directly bonded to X is other than N, O, or S;

[0015] [[ID=GO]]L is selected from -C 1-6 alkylene- and -(C 1-4 alkylene) a -Q-(C 1-4 alkylene) b -, where -(C 1-4 alkylene) a -Q-(C 1-4 alkylene) b - group's C 1-6 alkylene group and any -(C 1-4 alkylene) b - group is halo, CN, OH, C1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, Amino, C 1-3 Alkylamino and di(C 1-3 optionally substituted with 1, 2, or 3 substituents independently selected from (alkyl)amino;

[0016] Q is -O-, -S-, -S(=O)-, -S(=O)2-, -C(=O)-, -C(=O)NR q1 -, -C(=O)O-, -OC(=O)NR q1 -, -NR q1 -, -NR q1 C(=O)O-, -NR q1 C(=O)NR q1 , -S(=O)2NR q1 -, -C(=NR q2 )- or -C(=NR q2 )-NR q1 - where R q1 is H, C 1-6 alkyl, and wherein R q2 is H, C 1-6 independently selected from alkyl and CN;

[0017] Cy is a concatenated C 6-14 Aryl, C 3-18 cycloalkyl, 5- to 16-membered heteroaryl, or 4- to 18-membered heterocycloalkyl group, each of which is R Cy optionally substituted with 1, 2, 3, or 4 substituents independently selected from

[0018] Each R Cy Ha, Halo, C 1-6 Alkyl, C 1-4 Haloalkyl, C 1-4 Cyanoalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, NO2, OR a1, SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , NR c1 C(=NR e1 )NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 C(O)NR c1 R d1 , NR c1 S(O)R b1 , NR c1 S(O)2R b1 , NR c1 S(O)2NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 , and S(O)2NR c1 R d1 is independently selected from, where C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are each, CN, NO2, OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1, NR c1 C(=NR e1 )NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 C(O)NR c1 R d1 , NR c1 S(O)R b1 , NR c1 S(O)2R b1 , NR c1 S(O)2NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O)2R b1 , and S(O)2NR c1 R d1 optionally substituted with 1, 2, 3, or 4 substituents independently selected from; )

[0019] R 1 is H, Cy 1 , halo, C 1-6 alkyl, C 1-4 haloalkyl, C 1-4 cyanoalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CN, NO2, OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , C(=NR e2 )NR c2 R d2 , NR c2 , C(=NR e2 )NR c2 R d2 , NR c2 R d2 , NR c2 , C(O)R b2 , NRc2 C(O)OR a2 , N.R. c2 C(O)NR c2 R d2 , N.R. c2 S(O)R b2 , N.R. c2 S(O)2R b2 , N.R. c2 S(O)NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O)2R b2 , and S(O)NR c2 R d2 where C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl is halo, CN, NO, OR a2 , S.R. a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 ,OC(O)R b2 , OC(O)NR c2 R d2 , C(=NR e2 )NR c2 R d2 , N.R. c2 C(=NR e2 )NR c2 R d2 , N.R. c2 R d2 , N.R. c2 C(O)R b2 , N.R. c2 C(O)OR a2 , N.R. c2 C(O)NR c2 R d2 , N.R. c2 S(O)R b2 , N.R. c2 S(O)2R b2 , N.R. c2 S(O)NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O)2Rb2 and S(O)2NR c2 R d2 optionally substituted with 1, 2, 3, or 4 substituents independently selected from;

[0020] Y is O, S, CR Y1 R Y2 , or NR Y3 , where R Y1 , R Y2 , and R Y3 are each independently selected from H and C 1-4 alkyl;

[0021] Z is Cy 2 , halo, C 1-6 alkyl, C 1-4 haloalkyl, C 1-4 cyanoalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CN, NO2, OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , C(=NR e3 )NR c3 R d3 , NR c3 C(=NR e3 )NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)OR a3 , NR c3 C(O)NR c3 R d3 , NR c3 S(O)R b3 , NR c3 S(O)2R b3 , NR c3 S(O)2NR c3 R d3 , S(O)R b3, S(O)NR c3 R d3 , S(O)2R b3 , S(O)NR c3 R d3 , and P(O)R c3 R d3 where C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Alkynyl is Cy 2 , Halo, CN,NO2, CN,NO2, OR a3 , S.R. a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 ,OC(O)R b3 , OC(O)NR c3 R d3 , C(=NR e3 )NR c3 R d3 , N.R. c3 C(=NR e3 )NR c3 R d3 , N.R. c3 R d3 , N.R. c3 C(O)R b3 , N.R. c3 C(O)OR a3 , N.R. c3 C(O)NR c3 R d3 , N.R. c3 S(O)R b3 , N.R. c3 S(O)2R b3 , N.R. c3 S(O)NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O)2R b3 , and S(O)NR c3 R d3 optionally substituted with 1, 2, 3, or 4 substituents independently selected from

[0022] Each R 2 and R 3 H, halo, C1-6 Alkyl, C 1-4 Haloalkyl, C 1-4 Cyanoalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, CN, NO2, OR a4 , SR a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , OC(O)R b4 , OC(O)NR c4 R d4 , C(=NR e4 )NR c4 R d4 , NR c4 C(=NR e4 )NR c4 R d4 , NR c4 R d4 , NR c4 C(O)R b4 , NR c4 C(O)OR a4 , NR c4 C(O)NR c4 R d4 , NR c4 S(O)R b4 , NR c4 S(O)2R b4 , NR c4 S(O)2NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O)2R b4 , and S(O)2NR c4 R d4 independently selected from, wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each, halo, CN, NO2, OR a4 , SR a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , OC(O)R b4 , OC(O)NR c4 Rd4 , C(=NR e4 )NR c4 R d4 , NR c4 C(=NR e4 )NR c4 R d4 , NR c4 R d4 , NR c4 C(O)R b4 , NR c4 C(O)OR a4 , NR c4 C(O)NR c4 R d4 , NR c4 S(O)R b4 , NR c4 S(O)2R b4 , NR c4 S(O)2NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O)2R b4 , and S(O)2NR c4 R d4 is optionally substituted with 1, 2, 3, or 4 substituents independently selected from;

[0023] each R A1 is independently selected from H, halo, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, amino, C 1-4 alkylamino, C 2-8 dialkylamino, CN, NO2, and OH;

[0024] each R A2 is independently selected from H, halo, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, amino, C 1-4 alkylamino, C 2-8 dialkylamino, CN, NO2, and OH;

[0025] Each R A3 is independently selected from H, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C(O)R z , and C(O)OR z , and is independently selected, where said C 1-4 alkyl is optionally substituted by phenyl, C 1-4 alkoxy, C 1-4 haloalkoxy, CN, NO2, or OH;

[0026] R z is H, C 1-4 alkyl, or phenyl;

[0027] Each Cy 1 is independently selected from C 6-14 aryl, C 3-18 cycloalkyl, 5- to 16-membered heteroaryl, and 4- to 18-membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from RC y1 ;

[0028] Each Cy 2 is independently selected from C 6-14 aryl, C 3-18 cycloalkyl, 5- to 16-membered heteroaryl, and 4- to 18-membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from RC y2 ;

[0029] Each RC y1 and RC y2 is halo, C 1-6 alkyl, C 1-4 haloalkyl, C 1-4 cyanoalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl, CN, NO2, OR a5 , SR a5 , C(O)Rb5 、 C(O)NR c5 R d5 、 C(O)OR a5 、 OC(O)R b5 、 OC(O)NR c5 R d5 、 C(=NR e5 )NR c5 R d5 、 NR c5 C(=NR e5 )NR c5 R d5 、 NR c5 R d5 、 NR c5 C(O)R b5 、 NR c5 C(O)OR a5 、 NR c5 C(O)NR c5 R d5 、 NR c5 S(O)R b5 、 NR c5 S(O)2R b5 、 NR c5 S(O)2NR c5 R d5 、 S(O)R b5 、 S(O)NR c5 R d5 、 S(O)2R b5 、 and S(O)2NR c5 R d5 are independently selected from, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl are each, CN, NO2, OR a5 、 SR a5 、 C(O)R b5 、 C(O)NR c5 R d5 、 C(O)OR a5 、 OC(O)R b5 、 OC(O)NR c5 R d5 、 C(=NR e5 )NR c5 R d5 、 NR c5 C(=NR e5 )NRc5 R d5 、 NR c5 R d5 、 NR c5 C(O)R b5 、 NR c5 C(O)OR a5 、 NR c5 C(O)NR c5 R d5 、 NR c5 S(O)R b5 、 NR c5 S(O)2R b5 、 NR c5 S(O)2NR c5 R d5 、 S(O)R b5 、 S(O)NR c5 R d5 、 S(O)2R b5 、 and S(O)2NR c5 R d5 is optionally substituted with 1, 2, 3, or 4 substituents independently selected from;

[0030] each R a1 、 R b1 、 R c1 、 R d1 、 R a2 、 R b2 、 R c2 、 R d2 、 R a3 、 R b3 、 R c3 、 R d3 、 R a4 、 R b4 、 R c4 、 R d4 、 R a5 、 R b5 、 R c5 、 and R d5 is H, C 1-6 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl, C 3-10 cycloalkyl-C1-6 Alkyl, (5- to 10-membered heteroaryl)-C 1-6 Alkyl, and (4- to 10-membered heterocycloalkyl)-C 1-6 Independently selected from alkyl, said C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 6-10 Allyl, C 3-10 Cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 Aryl-C 1-6 Alkyl, C 3-10 Cycloalkyl-C 1-6 Alkyl, (5- to 10-membered heteroaryl)-C 1-6 Alkyl, and (4- to 10-membered heterocycloalkyl)-C 1-6 Alkyl is each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R g- ;

[0031] Each R e1 R e2 R e3 R e4 And R e5 Is independently selected from H, C 1-4 Alkyl, and CN;

[0032] Each R g Is OH, NO2, CN, halo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-4 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, cyano-C 1-3 Alkyl, HO-C 1-3 Alkyl, amino, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, thiol, C 1-6 Alkylthio, C 1-6 Alkylsulfinyl, C 1-6 Alkylsulfonyl, carboxy, aminocarbonyl, C 1-6 Alkylcarbonyl, and C1-6 selected independently of alkoxycarbonyl;

[0033] n is 0 or 1; m is 0 or 1; p is 0, 1, 2, or 3; q is 0, 1, or 2; a is 0 or 1; and b is 0 or 1, wherein any cycloalkyl or heterocycloalkyl group is optionally further substituted with 1 or 2 oxo groups.

[0034] In some embodiments, Y is O. In some embodiments, Y is NR Y3 . In some embodiments, Y is NH. In some embodiments, U is CR U . In some embodiments, U is CH. In some embodiments, W is N. In some embodiments, W is CR W . In some embodiments, W is CH. In some embodiments, X is N. In some embodiments, X is CR X . In some embodiments, X is selected from CH or CNH2.

[0035] In some embodiments, A, B, D, and E are each independently, -C(R A1 )(R A2 )-, -C(R A1 )(R A2 )-C(R A1 )(R A2 )-, -C(R A1 )(R A2 )-O-, -C(R A1 )(R A2 )-C(=O)-, and -C(=O)-, wherein one or less of A, B, D, and E is -C(RA1 )(R A2 )-O-, -C(R A1 )(R A2 )-C(=O)-, or -C(=O)-.

[0036] In some embodiments, A, B, D, and E are each independently -C(R A1 )(R A2 )-, -C(R A1 )(R A2 )-C(R A1 )(R A2 )-, and -C(R A1 )(R A2 )-O-, where one or fewer of A, B, D, and E is -C(R A1 )(R A2 )-O-.

[0037] In some embodiments, A, B, D, and E are each independently -C(R A1 )(R A2 )- or -C(R A1 )(R A2 )-C(R<( A1 )(R A2 )-.

[0038] In some embodiments, each R A1 and R A2 is independently selected from H, OH, and NH2. In some embodiments, A, B, D, and E are each independently selected from -CH2-, -CH2-CH2-, and -CH2O-. In some embodiments, A, B, D, and E are each independently selected from -CH2- or -CH2-CH2-.

[0039] In some embodiments, the following formula:

Chemical formula

[0040] (Here, e and f represent the bonding points to the remaining part of the molecule) The spiro moiety represented by is selected from the following:

Chem.

[0041] In some embodiments, the following formula:

Chem.

[0042] (Here, e and f represent the bonding points to the remaining part of the molecule) The spiro moiety represented by is selected from the following:

Chem.

[0043] In some embodiments, the following formula:

Chem.

[0044] (Here, e and f represent the bonding points to the remaining part of the molecule) The spiro moiety represented by is selected from the following:

Chem.

[0045] In some embodiments, L is one, two, or three substituents independently selected from halo, CN, OH, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy, amino, C 1-3 alkylamino, and di(C 1-3 alkyl)amino, and is optionally substituted with -C 1-6 alkylene-.

[0046] In some embodiments, L is selected from methylene, ethylene, and -CH2-CH(OH)-. In some embodiments, L is methylene.

[0047] In some embodiments, L is -(C 1-4 alkylene) a -Q-(C 1-4 alkylene) b -selected from, where -(C 1-4 alkylene) a -Q-(C 1-4 alkylene) b -the C of the group 1-4 alkylene group is optionally substituted with one, two, or three substituents independently selected from halo, CN, OH, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy, amino, C 1-3 alkylamino, and di(C 1-3 alkyl)amino.

[0048] In some embodiments, a is 1. In some embodiments, a is 0. In some embodiments, b is 1. In some embodiments, b is 0. In some embodiments, a and b are each 1. In some embodiments, a and b are each 0. In some embodiments, a is 1 and b is 0. In some embodiments, a is 0 and b is 1.

[0049] In some embodiments, L is selected from -C(O)-CH2-, -C(O)-CH2-CH2-, C(O), -NH-CH2-, NH, -C(O)-CH(NH2)-, -NH-CH(CH3)-, -N(CH3)-C(O)-, N(CH3)-CH2-, -CH2-CH2-O-, and -C(O)-NH-.

[0050] In some embodiments, Cy is a linking phenyl, C 3-18 cycloalkyl, 5- to 10-membered heteroaryl, or 4- to 9-membered heterocycloalkyl group, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R Cy .

[0051] In some embodiments, Cy is a linking phenyl, C 3-18 cycloalkyl, 5- to 10-membered heteroaryl, or 4- to 9-membered heterocycloalkyl group, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R Cy .

[0052] In some embodiments, Cy is a linking group having the following formula:

Chemical formula

[0053] each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R Cy .

[0054] In some embodiments, Cy is a linking group having the following formula:

Chemical formula

[0055] In some embodiments, Z is Cy 2 or C(O)NR c3 R d3 . In some embodiments, each Cy 2 is independently selected from C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R Cy2 .

[0056] In some embodiments, each Cy 2 is independently selected from phenyl, C 3-10 cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R Cy2 .

[0057] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, q is 0. In some embodiments, q is 1.

[0058] In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is a compound of Formula IIa, IIb, IIIa, or IIIb:

Chemical formula

[0059] or a pharmaceutically acceptable salt thereof.

[0060] In some embodiments, the compound of Formula I, or a pharmaceutically acceptable salt thereof, is a compound of Formula IVa, IVb, IVc, IVd, IVe, or IVf: [Chemistry] [Chemistry]

[0061] is a compound of formula I or a pharmaceutically acceptable salt thereof.

[0062] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof provided herein is crystalline. As used herein, "crystalline" or "crystalline form" means a particular lattice arrangement of a crystalline substance. Different crystalline forms of the same substance typically have different crystal lattices (e.g., unit cells) that result in different physical properties characteristic of each of the crystalline forms. In some examples, the different lattice structures have different water or solvent contents.

[0063] Different crystalline forms of the same compound or salt can have different bulk properties, for example, with respect to hygroscopicity, solubility, stability, etc. Forms with high melting points often have good thermodynamic stability, which is advantageous in extending the shelf life of pharmaceutical formulations containing the solid form. Forms with lower melting points are often not thermodynamically stable, but are advantageous in that they increase water solubility and lead to increased drug bioavailability. Forms with low hygroscopicity are desirable for their stability to heat and humidity and are resistant to degradation during long-term storage.

[0064] Different crystalline forms can be identified by solid-state characterization methods such as X-ray powder diffraction (XRPD). Other characterization methods such as differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), dynamic vapor sorption (DVS), etc. are further useful for specifying the form and for determining stability and solvent / water content.

[0065] The XRPD pattern of the reflection (peak) is typically considered the fingerprint of a particular crystalline form. It is well known that the relative intensities of XRPD peaks can vary significantly depending particularly on the sample preparation technique, crystal size distribution, various filters used, sample mounting procedure, and the particular equipment used. In some cases, depending on the type and settings of the equipment, new peaks may be observed or existing peaks may disappear. As used herein, the term "peak" refers to a reflection having a relative height / intensity of at least about 5% of the maximum peak height / intensity. Additionally, equipment variations and other factors can affect the 2θ value. Accordingly, peak assignments as reported herein vary by ± about 0.2° (2θ), and the terms "substantially" and "about" as used in the context of XRPD in this specification are intended to encompass such measurement variations.

[0066] Similarly, temperature readings associated with DSC, TGA, or other thermal experiments can vary by about ±3 °C depending on the apparatus, specific settings, sample preparation, etc. Accordingly, in the crystalline forms reported herein having DSC thermograms, the terms "substantially" or "about" as shown in any of the figures are understood to take such variations into account.

[0067] The present invention provides a crystalline form of a particular compound or a salt thereof. In some embodiments, the compound of formula I is 5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide, or a pharmaceutically acceptable salt thereof.

[0068] In some embodiments, the present invention provides crystalline 5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide, characterized, for example, by an XRPD profile substantially as shown in Figure 5.

[0069] In some embodiments, crystalline 5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide has at least 1, at least 2, at least 3, or at least 4 XRPD peaks selected from about 6.2°, about 8.3°, about 16.1°, about 16.6°, about 17.3°, about 19.0°, about 23.5°, about 25.3°, and about 26.9° at the 2θ point.

[0070] In some embodiments, crystalline 5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide has at least 1, at least 2, at least 3, or at least 4 XRPD peaks selected from about 6.2°, about 8.3°, about 16.1°, about 16.6°, and about 19.0° at the 2θ point.

[0071] In some embodiments, 5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide can be isolated as a crystalline bis-methanesulfonate that has an XRPD profile substantially as shown in Figure 6.

[0072] In some embodiments, the crystalline form of 5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide bis-methanesulfonate has at least 1, at least 2, at least 3, or at least 4 XRPD peaks selected from about 5.6°, about 8.8°, about 10.2°, about 12.6°, about 13.8°, about 15.3°, about 16.2°, about 16.8°, about 17.6°, about 18.6°, about 20.3°, about 20.9°, about 21.2°, about 22.7°, and about 24.6° from the 2θ point.

[0073] In some embodiments, the crystalline form of 5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide bis-methanesulfonate has at least 1, at least 2, at least 3, or at least 4 XRPD peaks selected from about 5.6°, about 8.8°, about 10.2°, about 12.6°, about 13.8°, about 15.3°, about 16.2°, about 16.8°, about 17.6°, about 18.6°, about 20.3° from the 2θ point.

[0074] In some embodiments, 5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide can be isolated as a crystalline bis-hydrochloride that has an XRPD profile substantially as shown in Figure 8.

[0075] In some embodiments, 5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide can be isolated as a fumarate salt, such as a sesquifumarate salt, which can be crystalline. The crystalline sesquifumarate salt can be a hydrate (e.g., monohydrate), a solvate (e.g., including a solvent other than water), or an anhydrate and a nonsolvate. In some embodiments, the crystalline form of the sesquifumarate salt is substantially an anhydrate or substantially a nonsolvate. In some embodiments, the crystalline form of the sesquifumarate salt is a hydrate or a solvate. In some embodiments, the crystalline form of the sesquifumarate salt is a hydrate. In some embodiments, the crystalline form of the sesquifumarate salt is a monohydrate.

[0076] In some embodiments, the crystalline form of the sesquifumarate salt of 5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide has an XRPD profile substantially as shown in Figure 7.

[0077] In some embodiments, the crystalline form of the 5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide sesquifumarate salt has at least 1, at least 2, at least 3, or at least 4 XRPD peaks selected from the points of 2θ at about 2.9°, about 5.8°, about 8.7°, about 13.2°, about 16.0°, about 17.6°, about 19.1°, about 20.3°, about 20.4°, about 20.8°, about 21.8°, about 22.9°, about 23.0°, about 23.3°, about 24.9°, and about 26.0°.

[0078] In some embodiments, the crystalline form of 5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide sesquifumarate has at least 1, at least 2, at least 3, or at least 4 XRPD peaks selected from the points of 2θ of about 2.9°, about 5.8°, about 8.7°, about 13.2°, about 16.0°, about 17.6°, about 19.1°, about 20.3°, about 20.4°, about 20.8°, about 21.8°, about 23.0°, about 23.3°, about 24.9°, and about 26.0°.

[0079] In some embodiments, the crystalline form of 5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide sesquifumarate has at least 1, at least 2, at least 3, or at least 4 XRPD peaks selected from the points of 2θ of about 2.9°, about 5.8°, about 8.7°, about 13.2°, about 16.0°, about 19.1°, about 21.8°, about 24.9°, and about 26.0°.

[0080] In some embodiments, the crystalline form of 5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide sesquifumarate has at least 1, at least 2, at least 3, or at least 4 XRPD peaks selected from the points of 2θ of about 2.9°, about 5.8°, about 8.7°, about 13.2°, about 16.0°, about 19.1°, and about 21.8.

[0081] In some embodiments, the crystalline form of 5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide sesquifumarate is selected from crystalline form A, crystalline form B, crystalline form C, crystalline form D, crystalline form E, and crystalline form F.

[0082] In some embodiments, crystalline form A of 5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide sesquifumarate monohydrate has an XRPD profile substantially as shown in Figure 10.

[0083] In some embodiments, crystalline form A of 5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide sesquifumarate has at least 1, at least 2, at least 3, or at least 4 XRPD peaks selected from about 5.8°, about 13.2°, about 15.9°, about 19.2°, about 20.3°, about 21.8°, about 23.0°, and about 23.3° at 2θ.

[0084] In some embodiments, crystalline form A of 5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide sesquifumarate monohydrate is characterized by a DSC thermogram having an endothermic peak at about 183°C.

[0085] In some embodiments, the crystalline form A of 5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide sesquifumarate monohydrate is characterized substantially by thermogravimetric analysis (TGA) as shown in Figure 12.

[0086] In some embodiments, the crystalline form A of 5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide sesquifumarate monohydrate is characterized substantially by dynamic vapor sorption analysis as shown in Figure 13.

[0087] In some embodiments, the crystalline form B of 5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide sesquifumarate has an XRPD profile substantially as shown in Figure 15.

[0088] In some embodiments, the crystalline form B of 5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide sesquifumarate has at least 1, at least 2, at least 3, or at least 4 XRPD peaks selected from the points of 2θ of about 6.2°, about 7.8°, about 8.5°, about 10.9°, about 12.6°, about 13.2°, about 13.5°, about 16.1°, about 19.0°, about 19.3°, about 21.2°, about 21.4°, about 21.6°.

[0089] In some embodiments, crystalline Form D of 5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide sesquifumarate has an XRPD profile substantially as shown in Figure 23.

[0090] In some embodiments, crystalline Form D of 5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide sesquifumarate has at least 1, at least 2, at least 3, or at least 4 XRPD peaks selected from about 7.2°, about 8.5°, about 11.8°, about 14.5°, about 16.0°, about 17.4°, about 19.3°, about 19.7°, and about 21.8° in terms of 2θ.

[0091] In some embodiments, crystalline Form D of 5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide sesquifumarate is characterized by a DSC thermogram having an endothermic peak at about 167 °C.

[0092] In some embodiments, crystalline Form D of 5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide sesquifumarate is characterized by thermographic analysis (TGA) substantially as shown in Figure 18.

[0093] In some embodiments, the crystalline form E of 5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide sesquifumarate has an XRPD profile substantially as shown in Figure 9.

[0094] In some embodiments, the crystalline form F of 5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide sesquifumarate has an XRPD profile substantially as shown in Figure 9.

[0095] In some embodiments, the crystalline form F of 5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide sesquifumarate is characterized by thermographic analysis (TGA) substantially as shown in Figure 18.

[0096] In some embodiments, 5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide is a benzenesulfonate (besylate) that can be crystalline.

[0097] In some embodiments, 5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide is a naphthalenedisulfonic acid (napsylic acid) salt that may be crystalline. In some embodiments, 5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide is a naphthalene-1,5-disulfonate salt that may be crystalline.

[0098] In some embodiments, 5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide is a toluenesulfonic acid (tosylic acid) salt that may be crystalline.

[0099] The present invention further provides a crystalline form of the compound N-ethyl-2-((4-(7-(((1r,4r)-4-(ethylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide, or a pharmaceutically acceptable salt thereof.

[0100] In some embodiments, the present invention provides a crystalline form of N-ethyl-2-((4-(7-(((1r,4r)-4-(ethylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide having an XRPD profile substantially as shown in, for example, FIG. 1.

[0101] In some embodiments, the crystalline form of N-ethyl-2-((4-(7-(((1r,4r)-4-(ethylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide has at least 1, at least 2, at least 3, or at least 4 XRPD peaks selected from about 9.7°, 11.6°, about 12.6°, about 16.6°, about 17.5°, about 18.8°, about 19.2°, about 19.8°, about 21.0°, and about 25.3° in terms of 2θ points.

[0102] In some embodiments, N-ethyl-2-((4-(7-(((1r,4r)-4-(ethylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide can be isolated as a fumarate, such as a sesquifumarate, which may be crystalline. In some embodiments, the crystalline form of the sesquifumarate is substantially anhydrous. In some embodiments, the crystalline form of the sesquifumarate is hydrated or solvated. In some embodiments, the crystalline form of the sesquifumarate is hydrated. In some embodiments, the crystalline form of the sesquifumarate is a monohydrate.

[0103] In some embodiments, the N-ethyl-2-((4-(7-(((1r,4r)-4-(ethylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide sesquifumarate has an XRPD profile substantially as shown in Figure 2.

[0104] In some embodiments, the crystalline form of N-ethyl-2-((4-(7-(((1r,4r)-4-(ethylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide sesquifumarate has at least 1, at least 2, at least 3, or at least 4 XRPD peaks selected from the points of 2θ of about 5.8°, about 8.7°, about 13.2°, about 16.0°, about 17.4°, about 17.6°, about 19.1°, about 20.3°, about 21.8°, about 23.0°, about 23.3°, about 24.9°, and about 26.0°.

[0105] In some embodiments, the crystalline form of N-ethyl-2-((4-(7-(((1r,4r)-4-(ethylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide sesquifumarate has at least 1, at least 2, at least 3, or at least 4 XRPD peaks selected from the points of 2θ of about 5.8°, about 8.7°, about 13.2°, about 16.0°, about 17.4°, about 17.6°, about 19.1°, about 20.3°, about 21.8°, and about 23.0°.

[0106] In some embodiments, the crystalline form of N-ethyl-2-((4-(7-(((1r,4r)-4-(ethylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide sesquifumarate has at least 1, at least 2, at least 3, or at least 4 XRPD peaks selected from the points of 2θ of about 5.8°, about 8.7°, about 13.2°, about 16.0°, about 17.4°, about 17.6°, and about 19.1°.

[0107] In some embodiments, N-ethyl-2-((4-(7-(((1r,4r)-4-(ethylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide is a bis-methanesulfonate that can be crystalline, having an XRPD profile substantially as shown, for example, in Figure 3.

[0108] In some embodiments, the crystalline form of N-ethyl-2-((4-(7-(((1r,4r)-4-(ethylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide bis-methanesulfonate has at least 1, at least 2, at least 3, or at least 4 XRPD peaks selected from the points of 2θ of about 5.6°, about 11.0°, about 13.3°, about 16.7°, about 20.1°, about 20.9°, about 22.1°, about 23.6°, about 24.9°, and about 29.6°.

[0109] In some embodiments, the crystalline form of N-ethyl-2-((4-(7-(((1r,4r)-4-(ethylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide bis-methanesulfonate has at least 1 XRPD peak selected from the points of 2θ of about 5.6 and about 16.7°.

[0110] In some embodiments, N-ethyl-2-((4-(7-(((1r,4r)-4-(ethylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide is a bis-hydrochloride that can be crystalline, having an XRPD profile substantially as shown, for example, in Figure 4.

[0111] In some embodiments, the crystalline form of N-ethyl-2-((4-(7-(((1r,4r)-4-(ethylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide bis-hydrochloride has at least 1, at least 2, at least 3, or at least 4 XRPD peaks selected from about 4.7°, about 10.7°, about 13.4°, about 15.9°, about 17.0°, about 19.5°, about 20.1°, about 23.8°, about 25.8°, and about 28.1° in terms of 2θ points.

[0112] In some embodiments, the crystalline form of N-ethyl-2-((4-(7-(((1r,4r)-4-(ethylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide bis-hydrochloride has at least 1 or 2 XRPD peaks selected from about 4.7°, about 17.0°, and about 19.5° in terms of 2θ points.

[0113] It is understood that the specific features of the invention described in the context of separate embodiments may be provided in combination in a single embodiment. Conversely, the various features of the invention described in the context of a single embodiment for the sake of brevity may also be provided separately or in any suitable sub-combination.

[0114] As used herein, the phrase "optionally substituted" means unsubstituted or substituted. As used herein, the term "substituted" means that a hydrogen atom is removed and replaced by a substituent. The term "substituted" may also mean that two hydrogen atoms are removed and replaced by a divalent substituent such as an oxo or sulfide group. It should be understood that substitution at a particular atom is limited by valence.

[0115] Throughout various portions of this specification, substituents of the compounds of the invention are disclosed in groups or ranges. The invention is specifically intended to include each and every sub-combination of the members of such groups and ranges. For example, the term "C 1-6 alkyl" is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl.

[0116] The term "z-membered" (where z is an integer) typically represents the number of ring-forming atoms in a moiety where the number of ring-forming atoms is z. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.

[0117] Throughout various portions of this specification, linking substituents are described. Each linking substituent is specifically intended to include both the forward and reverse forms of the linking substituent. For example, -NR(CR'R”) n - includes both -NR(CR'R”) n - and -(CR'R”) n NR-. When the structure clearly requires a linking group, the Markush variables listed for that group are understood to be linking groups. For example, when the structure requires a linking group and the definition of the Markush group of its variable lists "alkyl" or "aryl", it is understood that "alkyl" or "aryl" represents a linking alkylene group or arylene group, respectively.

[0118] Throughout various portions of this specification, various aryl rings, heteroaryl rings, cycloalkyl rings, and heterocycloalkyl rings are described. Unless otherwise specified, these rings can be attached to the remainder of the molecule by any ring member, where valence permits. For example, the term "pyridine ring" or "pyridinyl" can refer to a pyridin-2-yl ring, a pyridin-3-yl ring, or a pyridin-4-yl ring.

[0119] For compounds of the present invention in which a variable appears multiple times, each variable can be a different moiety selected independently from the groups that define the variable. For example, if a structure having two R groups simultaneously present on the same compound is described, the two R groups can represent different moieties selected independently from the groups defined for R.

[0120] As used herein, the term "C" used alone or in combination with other terms i-j "alkyl" refers to a saturated hydrocarbon group that may be straight-chain or branched-chain and has i to j carbon atoms. In some embodiments, the alkyl group contains 1 to 6 carbon atoms, or 1 to 4 carbon atoms, or 1 to 3 carbon atoms. Examples of alkyl moieties include, but are not particularly limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, and t-butyl. In some embodiments, when the alkyl group is a linking group, it may be referred to as "C" i-j "alkylene".

[0121] As used herein, the term "C" used alone or in combination with other terms i-j "alkoxy" refers to a group of the formula -O-alkyl in which the alkyl group has i to j carbon atoms. Examples of alkoxy groups include methoxy, ethoxy, and propoxy (e.g., n-propoxy and isopropoxy). In some embodiments, the alkyl group has 1 to 3 carbon atoms.

[0122] As used herein, "C" used alone or in combination with other terms i-j "alkenyl" refers to an unsaturated hydrocarbon group having one or more carbon-carbon double bonds and having i to j carbon atoms. In some embodiments, the alkenyl moiety contains 2 to 6 or 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not particularly limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, and the like.

[0123] As used herein, "C" used alone or in combination with other termsi-j "Alkynyl" refers to an unsaturated hydrocarbon group having one or more carbon-carbon triple bonds and having i to j carbons. Examples of alkynyl groups include, but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl, and the like. In some embodiments, the alkynyl moiety contains 2 to 6 or 2 to 4 carbon atoms.

[0124] As used herein, the term "C i-j "Alkylamino" refers to a group of the formula -NH(alkyl) in which the alkyl group has i to j carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms.

[0125] As used herein, the term "di-C i-j -alkylamino" refers to a group of the formula -N(alkyl)2 used alone or in combination with other terms, where each of the two alkyl groups independently contains i to j carbon atoms. In some embodiments, each alkyl group independently has 1 to 6 or 1 to 4 carbon atoms. In some embodiments, the dialkylamino group is -N(C 1-4 alkyl)2 such as, for example, dimethylamino or diethylamino.

[0126] As used herein, the term "C i-j "Alkylthio" refers to a group of the formula S-alkyl in which the alkyl group has i to j carbon atoms. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. In some embodiments, the alkylthio group is C 1-4 alkylthio such as, for example, methylthio or ethylthio.

[0127] As used herein, the term "thiol" refers to -SH.

[0128] As used herein, the term "amino," used alone or in combination with other terms, refers to a group of the formula -NH2-.

[0129] As used herein, the term "C" used alone or in combination with other terms i-j "haloalkoxy" refers to a group of the formula -O-haloalkyl having i to j carbon atoms. An example of a haloalkoxy group is OCF3. A further example of a haloalkoxy group is OCHF2. In some embodiments, the haloalkoxy group is fluorinated only. In some embodiments, the alkyl group has 1 to 6 or 1 to 4 carbon atoms. In some embodiments, the haloalkoxy group is C 1-4 haloalkoxy.

[0130] As used herein, the term "halo," used alone or in combination with other terms, refers to a halogen atom selected from F, Cl, I, or Br. In some embodiments, "halo" refers to a halogen atom selected from F, Cl, or Br. In some embodiments, the halo substituent is F.

[0131] As used herein, the term "C" used alone or in combination with other terms i-j "haloalkyl" refers to an alkyl group having from 1 halogen atom to 2s + 1 or more halogen atoms (which may be the same or different), where "s" is the number of carbon atoms in the alkyl group and the alkyl group has from i to j carbon atoms. In some embodiments, the haloalkyl group is fluorinated only. In some embodiments, the haloalkyl group is fluoromethyl, difluoromethyl, or trifluoromethyl. In some embodiments, the haloalkyl group is trifluoromethyl. In some embodiments, the haloalkyl group is 2,2,2-trifluoroethyl. In some embodiments, the haloalkyl group is 2,2-difluoroethyl. In some embodiments, the haloalkyl group has 1 to 6 or 1 to 4 carbon atoms.

[0132] As used herein, the term "C i-j cyanoalkyl", whether used alone or in combination with other terms, refers to a group of the formula CN-(C i-j alkyl)-.

[0133] As used herein, the term "aryl", whether used alone or in combination with other terms, includes monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) aromatic hydrocarbons such as phenyl, 1-naphthyl, 2-naphthyl, anthracenyl, phenanthrenyl. In some embodiments, aryl is C 6-10 aryl. In some embodiments, aryl is C 6-14 aryl. In some embodiments, the aryl group is a naphthalene ring or a phenyl ring. In some embodiments, the aryl group is phenyl.

[0134] As used herein, the term "C i-j cycloalkyl", whether used alone or in combination with other terms, refers to a non-aromatic cyclic hydrocarbon moiety having i to j ring-forming carbon atoms, which may optionally include one or more alkenylene groups as part of the ring structure. The cycloalkyl group may include a monocyclic or polycyclic ring system. The polycyclic ring system may include a fused ring system and a spiro ring. Also included in the definition of cycloalkyl are moieties having one or more aromatic rings fused to the cycloalkyl ring (i.e., having a common bond), such as benzo or pyrido derivatives of cyclopentane, cyclopentene, cyclohexane, etc. A heterocycloalkyl group containing a fused aromatic (e.g., aryl or heteroaryl) moiety can be attached to the molecule through an atom from either the aromatic or non-aromatic moiety. One or more of the ring-forming carbon atoms of the cycloalkyl group can be oxidized to form a carbonyl bond. In some embodiments, cycloalkyl is C 3-10 cycloalkyl, C 3-7 cycloalkyl, or C 5-6It is a cycloalkyl. Typical cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, etc. Further exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Further cycloalkyl groups in which the cycloalkyl group has a fused aryl or heteroaryl moiety include tetrahydronaphthalen-2-yl, 2,3-dihydro-1H-inden-2-yl; 2,3,4,9-tetrahydro-1H-carbazol-7-yl; 2,6,7,8-tetrahydrobenzo[cd]indazol-4-yl; and 5,6,7,8,9,10-hexahydrocyclohepta[b]indol-3-yl.

[0135] As used herein, the term "heteroaryl," used alone or in combination with other terms, refers to a monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) aromatic heterocyclic moiety having one or more heteroatom ring members selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl group has 1, 2, 3, or 4 heteroatom ring members. In some embodiments, the heteroaryl group has 1, 2, or 3 heteroatom ring members. In some embodiments, the heteroaryl group has 1 or 2 heteroatom ring members. In some embodiments, the heteroaryl group has 1 heteroatom ring member. In some embodiments, the heteroaryl group is 5- to 10-membered or 5- to 6-membered. In some embodiments, the heteroaryl group is 5-membered. In some embodiments, the heteroaryl group is 6-membered. In some embodiments, the heteroaryl group is a 9- or 10-membered bicyclic. In some embodiments, the heteroaryl is a 9-membered bicyclic. When the heteroaryl group contains more than one heteroatom ring member, the heteroatoms may be the same or different. A nitrogen atom in the ring of the heteroaryl group can be oxidized to form an N-oxide. Examples of heteroaryl groups include, but are not particularly limited to, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, azolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, furanyl, thiophenyl, triazolyl, tetrazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, indolyl, benzothiophenyl, benzofuranyl, benzoisoxazolyl, benzimidazolyl, imidazo[1,2-b]thiazolyl, purinyl, triazinyl, and the like. In some embodiments, the heteroaryl group is 9H-carbazol-2-yl; 1H-benzo[d]imidazol-6-yl; 1H-indol-6-yl; 1H-indazol-6-yl; 2H-indazol-4-yl; 1H-benzo[d][1,2,3]triazol-6-yl; benzo[d]oxazol-2-yl; quinolin-6-yl; or benzo[d]thiazol-2-yl.

[0136] As used herein, the term "heterocycloalkyl," used alone or in combination with other terms, can optionally include one or more unsaturations as part of the ring structure and refers to a non-aromatic heterocyclic ring system having at least one heteroatom ring member independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heterocycloalkyl group has 1, 2, 3, or 4 heteroatom ring members. In some embodiments, the heterocycloalkyl group has 1, 2, or 3 heteroatom ring members. In some embodiments, the heterocycloalkyl group has 1 or 2 heteroatom ring members. In some embodiments, the heterocycloalkyl group has 1 heteroatom ring member. When the heterocycloalkyl group contains more than two heteroatoms in the ring, the heteroatoms may be the same or different. Examples of ring-forming members include CH, CH2, C(O), N, NH, O, S, S(O), and S(O)2. The heterocycloalkyl group can include a monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) ring system. The polycyclic ring can include both fused systems and spiro rings. The definition of heterocycloalkyl includes moieties having one or more aromatic rings fused to a non-aromatic ring (i.e., having a common bond), such as 1,2,3,4-tetrahydroquinolinyl, dihydrobenzofuranyl, etc. A heterocycloalkyl group containing a fused aromatic moiety can be attached to the molecule via an atom from either the aromatic moiety or the non-aromatic moiety. The carbon atoms or heteroatoms of the ring of the heterocycloalkyl group can be oxidized to form a carbonyl, sulfinyl, or sulfonyl group (or other oxidized bond), or the nitrogen atom can be quaternized. In some embodiments, the heterocycloalkyl is 5- to 10-membered, 4- to 10-membered, 4- to 7-membered, 5-membered, or 6-membered. Examples of heterocycloalkyl groups include 1,2,3,4-tetrahydroquinolinyl, dihydrobenzofuranyl, azetidinyl, azepanyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and pyranyl.Examples of heterocycloalkyl groups containing one or more condensed aromatic groups (e.g., aryl or heteroaryl) include N-(2'-oxospiro[cyclohexane-1,3'-indoline]-6'-yl; 1,2,3,4-tetrahydroisoquinolin-6-yl; 2,3-dihydro-1H-benzo[d]imidazol-5-yl; 1,3-dihydrospiro[indene-2,3'-indoline]-6'-yl; 2,3-dihydrobenzoxazol-5-yl; 1,2-dihydroquinolin-7-yl; indolin-6-yl; spiro[cyclopentane-1,3'-indoline]-6'-yl; spiro[cyclohexane-1,3'-indoline]-6'-yl; chroman-6-yl; 3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl; and benzo[d][1,3]dioxol-5-yl.

[0137] As used herein, the term "arylalkyl," used alone or in combination with other terms, refers to an alkyl group substituted with an aryl group. As used herein, the term "cycloalkylalkyl," used alone or in combination with other terms, refers to an alkyl group substituted with a cycloalkyl group. As used herein, the term "heteroarylalkyl," used alone or in combination with other terms, refers to an alkyl group substituted with a heteroaryl group. As used herein, the term "heterocycloalkylalkyl," used alone or in combination with other terms, refers to an alkyl group substituted with a heterocycloalkyl group.

[0138] As used herein, the term "C" i-j alkylsulfinyl," used alone or in combination with other terms, refers to a group of the formula -S(=O)-(C i-j alkyl). As used herein, the term "C" i-j alkylsulfonyl," used alone or in combination with other terms, refers to a group of the formula -S(=O)2-(C i-j alkyl). As used herein, the term "carboxy" used alone or in combination with other terms refers to a -C(=O)OH group.

[0139] As used herein, the term "C i-j alkylcarbonyl" used alone or in combination with other terms refers to a group of the formula -C(=O)-(C i-j alkyl). As used herein, the term "C i-j alkoxycarbonyl" used alone or in combination with other terms refers to a group of the formula -C(=O)O-(C i-j alkyl). As used herein, the term "aminocarbonyl" used alone or in combination with other terms refers to a group of the formula -C(=O)NH2.

[0140] The compounds described herein may be asymmetric (e.g., having one or more stereocenters). Unless otherwise specified, all stereoisomers such as enantiomers and diastereoisomers are intended. When the name or structure of a compound does not represent the stereochemistry of a stereocenter, all possible configurations at the stereocenter are intended. Compounds of the present invention containing an asymmetrically substituted carbon atom can be isolated in optically active form or in racemic form. Methods for preparing optically active forms from optically inactive starting materials are known in the art, such as the resolution of racemic mixtures or stereoselective synthesis. Geometric isomers of olefins, C=N double bonds, etc. can also be present in the compounds described herein, and all such stable isomers are intended in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and can be isolated as mixtures of isomers or as separated isomers.

[0141] When the compounds of the present invention contain chiral centers, the compounds can be any of the possible stereoisomers. In a compound having a single chiral center, the stereochemistry of the chiral center can be (R) or (S). In a compound having two chiral centers, since the stereochemistry of each chiral center can independently be (R) or (S), the stereoconfiguration of the chiral centers includes (R) and (R), (R) and (S), (S) and (R), or (S) and (S). In a compound having three chiral centers, since the stereochemistry of each of the three chiral centers can independently be (R) or (S), the stereoconfiguration of the chiral centers can be (R), (R), (R); (R), (R), (S); (R), (S), (R); (R), (S), (S); (S), (R), (R); (S), (R), (S); (S), (S), (R); or (S), (S), (S).

[0142] The resolution of a racemic mixture of compounds can be carried out by any of a number of methods known in the art. Exemplary methods include the fractional recrystallization method using a chiral resolution acid, which is an optically active salt-forming organic acid. Resolving agents suitable for the fractional recrystallization method include, for example, optically active acids such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, or various optically active camphorsulfonic acids such as the D and L forms of β-camphorsulfonic acid. Other resolving agents suitable for the fractional crystallization method include stereochemically pure forms of α-methylbenzylamine (e.g., the S and R forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

[0143] The resolution of a racemic mixture can also be carried out by elution on a column charged with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). A suitable elution solvent composition can be determined by those skilled in the art.

[0144] If the disclosed compound is named or described without indicating the stereochemistry of one or more stereocenters, each stereoisomer resulting from the possible stereochemistry at the undefined stereocenters is intended to be included. For example, if a stereocenter is not designated as R or S, either or both are intended.

[0145] The compounds of the present invention also include tautomers. Tautomers result from the exchange of a single bond adjacent to a double bond with concomitant proton shift. Tautomers include prototropic tautomers, which are isomeric protonation states having the same empirical formula and total charge. Examples of prototropic tautomers include keto-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, amide-imidic acid pairs, enamine-imine pairs, and cyclic forms in which a proton can occupy two or more positions of a heterocyclic system, such as 1H- and 3H-isoindole, 1H-, 2H-, and 4H-1,2,4-triazole, 1H- and 2H-imidazole, and 1H- and 2H-pyrazole. Tautomers may be in an equilibrium state or may be stereochemically fixed in one form by appropriate substitution.

[0146] The compounds of the present invention can also include all isotopes of atoms present in the intermediate or final compound. Isotopes include atoms having the same atomic number but different mass numbers. The isotopes of the constituent atoms of the compounds of the present invention can be present in natural or non-natural abundances. Examples of isotopes of hydrogen include deuterium and tritium. In some embodiments, the compounds of the present invention are deuterated, which means that at least one deuterium atom is present in place of a hydrogen atom. In some embodiments, 1, 2, 3, 4, 5, 6, 7, or 8 hydrogens in the compounds of the present invention are replaced by deuterium. Methods for replacing hydrogen in a molecule with deuterium are known in the art.

[0147] As used herein, the term "compound" is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the described structure. A compound identified herein by name or structure as a particular tautomer is meant to include other tautomers thereof as well, unless otherwise specified (e.g., in the case of a purine ring, unless otherwise specified, if the compound name or structure has the 9H tautomer, this is understood to also include the 7H tautomer).

[0148] All compounds and their pharmaceutically acceptable salts can be found with other substances such as water or solvents (e.g., hydrates and solvates), or can be isolated.

[0149] In some embodiments, the compounds of the invention or salts thereof, or crystalline forms of any of the foregoing, are purified or substantially isolated. "Substantially isolated" means that the compound is at least partially or substantially separated from the environment in which it was formed or detected. Partial separation can include, for example, a composition in which the compound of the invention is concentrated. Substantial separation can include a composition comprising at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% of the compound of the invention or a salt thereof. In some embodiments, the compounds of the invention or salts thereof, or crystalline forms of any of the foregoing, can be prepared with a purity of about 75% or greater, 80% or greater, 85% or greater, 90% or greater, 95% or greater, 98% or greater, or 99% or greater.

[0150] As used herein, the term "pharmaceutically acceptable" refers to compounds, materials, compositions, and / or dosage forms that are suitable for use in contact with the tissues of humans and animals within the scope of sound medical judgment, without excessive toxicity, irritation, allergic response, or other problems or complications, and commensurate with a reasonable benefit / risk ratio.

[0151] As used herein, the expressions "ambient temperature" and "room temperature" are understood in the art and generally refer to a temperature near the temperature of the room in which the reaction is carried out, for example, at a reaction temperature of about 20 °C to about 30 °C.

[0152] The present invention also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, "pharmaceutically acceptable salts" refers to derivatives of the disclosed compounds in which the parent compound is modified by converting an existing acidic or basic moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids. Pharmaceutically acceptable salts of the present invention include, for example, conventional non-toxic salts of the parent compounds formed from non-toxic inorganic or organic acids. Pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing basic or acidic moieties by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two. Generally, non-aqueous media such as ether, ethyl acetate, alcohols (e.g., methanol, ethanol, isopropanol, or butanol), or acetonitrile (MeCN) are preferred. A list of suitable salts is described in Remington's Pharmaceutical Sciences, 17th Ed., (Mack Publishing Company, Easton, 1985), p. 1418, Berge et al., J. Pharm. Sci., 1977, 66(1), 1-19, and Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (Wiley, 2002).

[0153] As used herein, the terms "subject" and "patient" can be used interchangeably and refer to mammals in need of treatment, such as pet animals (e.g., dogs, cats, etc.), livestock (e.g., cows, pigs, horses, sheep, goats, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.). Typically, the subject or patient is a human in need of treatment.

[0154] Synthesis The compounds of the present invention (including their salts) can be prepared using known organic synthesis techniques and can be synthesized according to any of a number of possible synthetic routes.

[0155] The reactions for preparing the compounds of the present invention can be carried out in a suitable solvent that can be readily selected by those skilled in the art of organic synthesis. A suitable solvent can be substantially non-reactive with the starting materials (reactants), intermediates, or products at the temperature at which the reaction is carried out, e.g., a temperature in the range from the freezing temperature to the boiling point of the solvent. A given reaction can be carried out in one solvent or a mixture of two or more solvents. Depending on the particular reaction step, those skilled in the art can select a solvent suitable for the particular reaction step.

[0156] The preparation of the compounds of the present invention can include the protection and deprotection of various chemical groups. The need for protection and deprotection and the selection of appropriate protecting groups ("Pg") can be readily determined by those skilled in the art. The chemistry of protecting groups ("Pg") can be found, for example, in P. G. M. Wuts and T. W. Greene, Protective Groups in Organic Synthesis, 4th Ed., Wiley & Sons, Inc., New York (2006), which is hereby incorporated by reference in its entirety.

[0157] The compounds of the present invention can be prepared using conventional methods that employ readily available reagents and starting materials. The reagents used in the preparation of the intermediates of the present invention are either commercially available or can be prepared by standard procedures described in the literature. Various techniques such as solid-phase chemistry, microwave chemistry, or flow chemistry can also be used to synthesize the intermediates or the final compounds. Further, other methods for preparing the compounds of the present invention will be readily apparent to those skilled in the art upon consideration of the following reactions and schemes and examples. Unless otherwise specified, all variables are defined below. Suitable synthetic methods are described in the following references: March, Advanced Organic Chemistry, 3rd edition, John Wiley & Sons, 1985; Greene and Wuts, Protective Groups in Organic Chemistry, 2nd edition, John Wiley & Sons 1991; and Larock, Comprehensive Organic Transformations, 4th edition, VCH publishers Inc., 1989; Further, in any synthesis, one or more of the reagents, intermediates, or chemical substances can be used in excess to ensure completion of the reaction. Suitable reaction temperatures generally range from about 0 °C to approximately the boiling point of the solvent. More typically, the temperature is high enough to allow reflux, for example, about 68 °C for tetrahydrofuran. In some cases, such as under microwave conditions, the reaction temperature may exceed the boiling point of the solvent.

[0158] The compounds of the present invention can be synthesized by the methods described in Schemes 1 to 3 below. Many of the synthetic steps are described in F.A. Carey, R.J. Sundberg, Advanced Organic Chemistry, 2nd ed., Plenum publication in 1983. The synthesis of various hydroxyl-substituted heterocycles is described in detail in the above literature and can be synthesized by the methods of known literature. For the general synthesis of useful heterocyclic rings, see The Handbook of Heterocyclic Chemistry, Alan R. Katritzky; Pergamon Press, NY, USA, 1st ed. 1986. The indicated intermediates are also available as commercially available reagents from a number of suppliers.

[0159] Scheme 1

Chemical formula

[0160] The compounds of the present invention can be synthesized by a number of methods based on retrosynthetic analysis of the final target. Exemplary methods are shown in Routes A, B, and C.

[0161] Route A: This method involves couplings of the amine intermediate I with various aldehydes, amines, acids, aryl halides, etc. Aldehydes and ketones can be condensed with intermediate I by reductive amination. This method involves the reaction of an aldehyde or ketone with an amine in the presence of a reducing agent (such as sodium cyanoborohydride or sodium triacetoxycyanoborohydride). Various alternative methods for the reaction of an amine with aldehydes and ketones under reducing conditions are known in the art. For example, these reactions can be carried out in various protic and aprotic solvents at temperatures ranging from -78 °C to the reflux temperature. One method involves the reaction of an amine with an aldehyde or ketone in a solvent such as methanol, ethanol, tetrahydrofuran, dichloromethane, or 1,2-dichloroethane, or a combination thereof, in the presence of a reducing agent (such as sodium triacetoxyborohydride or sodium cyanoborohydride), between room temperature and reflux conditions, in the presence or absence of a microwave reactor.

[0162] Route B: This method involves the coupling of Intermediate II and Intermediate III. Intermediate II (W = NH) can be synthesized, for example, from various spirocyclic amines using known synthetic procedures described in the literature and methods known to those skilled in the art. For example, Intermediate III can be synthesized by any of the various methods described below. The leaving group (LVG) can be, for example, a halogen, mesylate, tosylate, or any other group suitable for nucleophilic substitution or metal-catalyzed substitution catalyzed by a base (e.g., copper, palladium, etc.). These methods are described in detail in Handbook of Reagents for Organic Synthesis, Catalyst Components for Coupling Reactions; Gary Molander, 1st Edition, 2013; John Wiley & sons. One method involves the reaction of a halo derivative of Intermediate III with an amine at high temperature in the presence of an organic or inorganic base in a protic or aprotic solvent. A further example involves treating a chloro derivative of Intermediate III with an amine at high temperature in an aprotic solvent (e.g., DMF or DMSO) in the presence of an organic base (e.g., triethylamine or pyridine). For compounds of Intermediate II where W is carbon, the reaction can be carried out, for example, by a cross-coupling reaction of the vinyl boronic acid of the spiroamine with Intermediate III, followed by the formation of a carbon analog by hydrogenation.

[0163] Route C: The final compound can be synthesized from Intermediate IV by functional group modification. The functional group may be, for example, an acid, an alcohol, an amine, an aryl halide, etc. This reaction uses amines with various acylating agents (such as acyl chlorides, sulfonyl chlorides, isocyanates, etc.). Alternatively, a functional group such as an acid can be converted to an amide. The aryl halide can be converted to the desired product using conventional methods known for other functional groups, and many of these functional group conversions are well-known in the literature and are described in "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" by Richard C. Larock, 2nd Edition, 1999, Wiley & Sons. One functional group conversion involves the reaction of an amine with various acylating agents (such as acyl chloride or sulfonyl chloride) in the presence of an aprotic solvent and a base. Another example involves reacting sulfonyl chloride with an amine in dichloromethane in the presence of an organic base (such as pyridine, trimethylamine, etc.).

[0164] Scheme 2

Chemical Structure

[0165] Intermediate I can be synthesized by a number of methods as shown in Scheme 2. Exemplary methods are shown in Routes D, E, and F.

[0166] Route D: The method used in Route D is similar to the method used in Route B (Scheme 1). For spirodiamine, one of the amine functional groups can be selectively protected and the reaction can be carried out in a regioselective manner. The protecting group is selected to be compatible with other functional groups and their derivatives and can be selectively removed. Various amine protecting groups are known in the literature and are described in detail in Greene's Protective Groups in Organic Synthesis by Peter G. M. Wuts & Theodora W. Greene; 4th Edition,; 2006, Wiley-Interscience. Commonly used amine protecting groups include, for example, tert-butoxycarbonyl which is cleaved under acidic conditions in an aprotic solvent. One exemplary method involves using trifluoroacetic acid or hydrochloric acid gas in an aprotic solvent (such as 1,4-dioxane, dichloromethane, etc.) at room temperature.

[0167] Route E: The functional group Fg of intermediate V can undergo various functional group transformations to prepare intermediate I. Such transformations are described in detail, for example, in Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, by Jerry March, Wiley-Interscience; 6th Edition, 2007. Exemplary reactions include cross-couplings of aryl halides of intermediate V (e.g., where Fg is a halogen) with various borate salts, tin reagents, etc. These cross-coupling reactions can be carried out in various protic / aprotic solvents or combinations thereof, in the presence of inorganic or organic bases, at room temperature to high temperature, using various metal catalysts (e.g., copper, palladium, rhodium). In some cases, a microwave reactor can also be used. An exemplary method involves the reaction of a chloro- or bromo-derivative of intermediate V with an aryl Suzuki reagent in the presence of a palladium catalyst in various solvents (e.g., DMF, toluene / water), at high temperature, in the presence of an inorganic base (e.g., cesium carbonate or potassium phosphate). In certain cases, further functionalization can be carried out to reach the desired compound. For example, the Fg halo group of intermediate V can be converted to an acid and further to an amide, alcohol, ether, etc. Similarly, the Fg halo group of intermediate V can be converted to a cyano group, and the cyano group can be further converted to other functional groups as known in the art.

[0168] Route F: This method involves the reaction of phenols, thiols, anilines with 3-halopyridine or 5-halopyrimidine using a metal-mediated reaction. The nucleophilic substitution of 3-halopyridine or 5-halopyrimidine by phenols, anilines, and arylthiols is known in the literature as described, for example, in Copper-Mediated Cross-Coupling Reactions by Gwilherm Evano & Nicolas Blanchard by John Wiley & Sons, 1st Edition, 2013. For example, intermediate VII can be synthesized by reaction with a spiroamine from 3,4-dihalopyridine or 4,5-dihalopyrimidine using a method similar to that described in Route B. Further, carbon analogs can be synthesized by cross-coupling reactions of intermediate VII with various alkyl zinc halides in the presence of a metal catalyst as described, for example, in “Applied Cross-Coupling Reactions” by Yasushi Nishihara Springer Science Edition 1, 2013. The exemplary method involves reacting a palladium catalyst with benzyl zinc bromide in an aprotic solvent (such as diethyl ether or tetrahydrofuran) at a high temperature in the presence or absence of a microwave reactor. Fluoro-substituted phenols, anilines, and thiols are known in the literature and can be synthesized by various methods known to those skilled in the art.

[0169] Various methods can be used for the synthesis of intermediate III containing pyrimido-phenol ether. Some methods are shown in Scheme 3, Routes A and B.

[0170] Scheme 3, Route A

Chemical Structure

[0171] Route A of Scheme 3 involves the reaction of phenol with 2-haloacetate. This method is known in the literature and is described, for example, in Journal of Medicinal Chemistry (1980), 23(9), 1026-31. This reaction is achieved by converting phenol to the corresponding phenolate by reaction with a metal hydride in an aprotic solvent (e.g., DMF, THF). One example involves the reaction of phenol with sodium hydride in an aprotic solvent (e.g., DMF), followed by the addition of methyl chloroacetate in the same pot at a temperature varying from -78 °C to room temperature. The 2-phenoxyacetate intermediate is further condensed with formaldehyde in the presence of a metal hydride (e.g., NaH) in an aprotic solvent as described in the first step. This intermediate is then reacted with thiourea in a protic solvent (e.g., alcohol) at an elevated temperature to obtain a 2-thiopyrimidine intermediate. The thiopyrimidine can be reduced to pyrimidine or converted to a 2-substituted pyrimidine by various synthetic routes known in the literature. An exemplary method involves reducing the thiopyrimidine to pyrimidine under metal-catalyzed hydrogenation conditions (e.g., nickel in a protic solvent such as ethanol). The 4-pyrimidone intermediate can then be converted to 4-halopyrimidone by reaction with a chlorinating solvent (e.g., thionyl chloride, phosphorus trichloride) either as such or at an elevated temperature in an aprotic solvent (e.g., toluene, THF). Alternatively, 4-pyrimidone can be reacted with a sulfonyl chloride (e.g., methanesulfonyl chloride or trifluoromethanesulfonyl chloride) to generate a sulfonate as a leaving group suitable for nucleophilic substitution, which can further be used to prepare the desired compounds as described herein in Schemes 1 and 2.

[0172] Scheme 3, Route B

Chemical Structure

[0173] The first step of Route B of Scheme 3 involves the coupling of a phenol and a 5-halopyrimidine, as described, for example, in Organic Letters, 14(1), 170-173; 2012, or Journal of Organic Chemistry, 75(5), 1791-1794; 2010. The resulting pyrimidine can then be oxidized with a peracid in an aprotic solvent at room temperature to obtain a pyrimidine N-oxide. An exemplary method involves the reaction of a pyrimidine ether with meta-chloroperbenzoic acid in a halogenated solvent (e.g., dichloromethane, 1,2-dichloroethane), as described in J. Org. Chem., 1985, 50 (17), pp 3073-3076. The crude intermediate can be further treated with phosphorus oxychloride or phosphorus pentachloride to obtain Intermediate III, as described in International Publication No. WO 2009 / 137733.

[0174] Method of Use The compounds of the present invention are inhibitors of the interaction between menin and MLL and MLL fusion proteins. In some embodiments, the present invention relates to a method of inhibiting the interaction between menin and MLL or an MLL fusion protein by contacting menin with an MLL or an MLL fusion protein and a compound of the present invention. The contacting can be performed in vitro or in vivo. In some embodiments, the compounds of the present invention can bind to menin, thereby preventing the binding of MLL to menin. In some embodiments, the present invention provides a method of inhibiting the activity of menin by contacting menin with a compound of the present invention in the presence of an MLL or an MLL fusion protein. In a further embodiment, the present invention provides a method of inhibiting the binding between an MLL or an MLL fusion protein and menin, comprising contacting menin with a compound of the present invention in the presence of an MLL or an MLL fusion protein.

[0175] The compounds of the present invention are also useful for the treatment of diseases associated with menin-MLL interaction, or menin-MLL fusion protein interaction. For example, diseases and conditions treatable according to the methods of the present invention include cancers such as leukemia, and other diseases or disorders mediated by menin-MLL interaction or menin-MLL fusion protein interaction such as diabetes.

[0176] Accordingly, the compounds of the present invention are effective against a wide range of cancers including, but not limited to, blood cancers (such as leukemia and lymphoma), bladder cancer, brain cancer (such as glioma, diffuse intrinsic pontine glioma (DIPG)), breast cancer (such as triple negative breast cancer, estrogen receptor positive breast cancer (i.e., ER+ breast cancer)), colorectal cancer, cervical cancer, gastrointestinal cancer (such as colorectal cancer, gastric cancer), genitourinary cancer, head and neck cancer, liver cancer, lung cancer, melanoma, ovarian cancer, pancreatic cancer, prostate cancer (such as castration-resistant prostate cancer), kidney cancer (such as renal cell carcinoma), skin cancer, thyroid cancer (such as papillary thyroid cancer), testicular cancer, sarcoma (such as Ewing sarcoma), and AIDS-related cancer. In some embodiments, the cancer is associated with a rearranged MLL gene. In some embodiments, the pathophysiology of the cancer is dependent on the MLL gene. In some embodiments, the cancer is associated with a mutant p53 gain of function.

[0177] In some embodiments, specific cancers that can be treated by the compounds, compositions, and methods described herein include cardiac cancers such as sarcomas (e.g., angiosarcoma, fibrosarcoma, rhabdomyosarcoma, and liposarcoma), myxomas, rhabdomyomas, fibromas, lipomas, and teratomas; lung cancers such as bronchogenic carcinoma (e.g., squamous cell, undifferentiated small cell, undifferentiated large cell, and adenocarcinoma), alveolar and bronchioloalveolar carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma, non-small cell lung cancer, small cell lung cancer, bronchial adenoma / carcinoid, and pleuropulmonary blastoma; gastrointestinal cancers such as esophageal cancer (e.g., squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, and lymphoma), gastric cancer (e.g., carcinoma, lymphoma, and leiomyosarcoma), pancreatic cancer (e.g., ductal carcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, and hemangioma), small intestine cancer (e.g., adenocarcinoma, lymphoma, carcinoid tumor, Kaposi sarcoma, leiomyosarcoma, hemangioma, lipoma, neurofibroma, and fibroma), colorectal cancer (e.g., adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, and leiomyosarcoma), and other cancers of the gastrointestinal tract (e.g., anal cancer, rectal cancer, appendiceal cancer, anal canal cancer, tongue cancer, gallbladder cancer, gastrointestinal stromal tumor (GIST), colon cancer, colorectal cancer, extrahepatic bile duct cancer, intrahepatic bile duct cancer, rectal cancer, and small intestine cancer); genitourinary cancers such as kidney cancer (e.g., adenocarcinoma, Wilms tumor (nephroblastoma), lymphoma, and leukemia), bladder and urethral cancer (e.g., squamous cell carcinoma, transitional cell carcinoma, and adenocarcinoma), prostate cancer (e.g., adenocarcinoma and sarcoma), testicular cancer (e.g., seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, and lipoma), as well as transitional cell carcinoma, renal pelvis, and ureter, and other urothelial transitional cell carcinomas, urethral cancer, and bladder cancer; liver cancer such as hepatoma (e.g., hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma; bone cancer such as osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor, chordoma, osteochondroma (osteochondroma exostosis), benign chondroma, chondroblastoma, chondromyxofibroma, osteoblastoma, and giant cell tumor; cancers of the nervous system such as cranial cancers (e.g., osteoma, hemangioma, granuloma, xanthoma, and Paget's disease); cancers of the meninges (e.g., meningioma, meningiosarcoma, and gliomatosis);Brain cancer (e.g., astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal), glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, and congenital tumor); spinal cord cancer (e.g., neurofibroma, meningioma, glioma, and sarcoma), and other nervous system cancers (e.g., brainstem glioma, diffuse intrinsic pontine glioma (DIPG), brain tumor, central nervous system cancer, cerebellar astrocytoma, cerebral astrocytoma / malignant glioma, pediatric cerebellar astrocytoma, pediatric cerebral astrocytoma, primary central nervous system lymphoma, visual pathway and hypothalamic glioma, nervous system lymphoma, thoracic primitive neurogenic tumor, pineoblastoma, and thoracic primitive neurogenic tumor); gynecological cancer, e.g., uterine cancer (e.g., endometrial cancer), cervical cancer (e.g., cervical cancer and pre-tumor cervical dysplasia), ovarian cancer (e.g., ovarian cancer, e.g., serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma, granulosa cell tumor, sertoli-leydig cell tumor, dysgerminoma, and malignant teratoma), vulvar cancer (e.g., squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, and melanoma), vaginal cancer (e.g., clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma, and embryonal rhabdomyosarcoma) and fallopian tube cancer (e.g., carcinoma); other genital tract cancers, e.g., corpus cancer, endometrial carcinoma, germ cell tumor, gestational trophoblastic tumor, gestational trophoblastic tumor glioma, ovarian epithelial cancer, ovarian germ cell tumor, low-grade ovarian tumor, penile cancer, vaginal cancer, vulvar cancer, extracranial germ cell tumor, extragonadal germ cell tumor, uterine cancer, corpus cancer, uterine sarcoma; lymphatic and hematological cancers, e.g., blood cancer (e.g., acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative disorder, multiple myeloma, and myelodysplastic syndrome, Hodgkin lymphoma, non-Hodgkin lymphoma (malignant lymphoma), and Waldenström macroglobulinemia), and other lymphatic or hematological cancers, e.g., pediatric leukemia, myeloproliferative disorder (e.g., primary myelofibrosis), plasma cell neoplasm / multiple myeloma, myelodysplasia, myelodysplastic syndrome, cutaneous T-cell lymphoma, lymphoid neoplasm, AIDS-related lymphoma, thymoma, thymoma and thymic carcinoma, mycosis fungoides, and Sézary syndrome;Skin cancers, such as melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, lipomatous dysplastic nevus, lipoma, hemangioma, dermatofibroma, keloid, psoriasis, Merkel cell carcinoma, Merkel cell skin adenocarcinoma, melanoma, and carcinoid tumors; adrenal gland adenocarcinoma, such as neuroblastoma; other cancers related to the endocrine system, such as adrenocortical carcinoma, multiple endocrine neoplasia (e.g., multiple endocrine neoplasia type I), multiple endocrine neoplasia syndrome, parathyroid cancer, pituitary tumor, pheochromocytoma, islet cell pancreatic cancer, and islet cell tumors); connective tissue cancers (e.g., bone cancer, bone and joint cancer, osteosarcoma, and malignant fibrous histiocytoma); cancers related to the head, neck, and mouth (e.g., head and neck cancer, paranasal and nasal cavity cancer, metastatic squamous cell carcinoma, oral cancer, laryngeal cancer, esophageal cancer, laryngeal cancer, pharyngeal cancer, hypopharyngeal cancer, oral and oral cavity cancer, nasopharyngeal cancer, oral cancer, oral pharyngeal cancer, and salivary gland cancer); and cancers associated with the eye (e.g., eye cancer, intraocular melanoma). In some embodiments, the cancer is Ewing's sarcoma.;

[0178] In some embodiments, the cancer is a blood cancer such as leukemia or lymphoma. Examples of leukemias and lymphomas treatable by the compounds of the present invention include mixed lineage leukemia (MLL), MLL-related leukemia, MLL-related leukemia, MLL-positive leukemia, MLL-induced leukemia, rearranged mixed lineage leukemia (MLL-r), leukemia associated with MLL rearrangement or rearrangement of the MLL gene, acute leukemia, chronic leukemia, indolent leukemia, lymphoblastic leukemia, lymphocytic leukemia, myeloid leukemia, myelogenous leukemia, pediatric leukemia, acute lymphoblastic leukemia (ALL) (also referred to as acute lymphocytic leukemia or acute lymphoblastic leukemia), acute myeloid leukemia (AML) (also referred to as acute myelogenous leukemia or acute myeloblastic leukemia), acute granulocytic leukemia, acute non-lymphocytic leukemia, chronic lymphocytic leukemia (CLL) (also referred to as chronic lymphoblastic leukemia), chronic myelogenous leukemia (CML) (also referred to as chronic myeloid leukemia), therapy-related leukemia, myelodysplastic syndrome (MDS), myeloproliferative disorder (MPD) (e.g., primary myelofibrosis (PMF)), myeloproliferative neoplasm (MPN), plasma cell neoplasm, multiple myeloma, myelodysplasia, cutaneous T-cell lymphoma, lymphoma tumor, AIDS-related lymphoma, thymoma, thymic carcinoma, mycosis fungoides, Alibert-Bazin syndrome, granuloma polyps, Sézary syndrome, hairy cell leukemia, T-cell prolymphocytic leukemia (T-PLL), large granular lymphocytic leukemia, meningeal leukemia, leukemic leptomeningitis, leukemia meningitis, multiple myeloma, Hodgkin lymphoma, non-Hodgkin lymphoma (malignant lymphoma), and Waldenström macroglobulinemia. In some embodiments, acute myeloid leukemia (AML) is an abstract nucleophosmin (NPM1) mutant acute myeloid leukemia (i.e., NPM1 mut acute myeloid leukemia).

[0179] In certain embodiments, the compounds of the invention are used to treat leukemia associated with MLL rearrangement, acute lymphoblastic leukemia associated with MLL rearrangement, acute lymphoblastic leukemia associated with MLL rearrangement, acute lymphocytic leukemia associated with MLL rearrangement, acute myeloid leukemia associated with MLL rearrangement, or acute myeloblastic leukemia associated with MLL rearrangement. As used herein, "MLL rearrangement" means rearrangement of the MLL gene.

[0180] In some embodiments, the diseases and conditions treatable with the compounds of the invention include insulin resistance, prediabetes, diabetes (e.g., type 2 diabetes or type 1 diabetes), and diabetes risk. In some embodiments, the diseases and conditions treatable with the compounds of the invention include hyperglycemia. In some embodiments, hyperglycemia is associated with diabetes such as type 2 diabetes. In some embodiments, the compounds of the invention are used to treat loss of response to other antidiabetic drugs and / or decline in beta cell function in a patient or subject. In some embodiments, the compounds of the invention are used to restore response to other antidiabetic drugs, and / or restore beta cell function, and / or reduce insulin requirements in a patient or subject. In some embodiments, the compounds of the invention are used to reduce insulin resistance, or reduce the risk of diabetes, or reduce the increase in blood glucose caused by statins in a subject taking statins. In some embodiments, the compounds of the invention are used to treat diabetes in a subject taking statins or to prevent diabetes in a subject taking statins. The methods of the invention include reducing, inhibiting, suppressing, limiting, or controlling the increase in blood glucose levels of a patient. In a further aspect, the methods of the invention include increasing, stimulating, enhancing, promoting, inducing, or activating the insulin sensitivity of a subject. Statins include, but are not particularly limited to, atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin.

[0181] In some embodiments, a patient is treated (e.g., administered) with a compound of the invention in an amount sufficient (e.g., a therapeutically effective amount) to treat or ameliorate one or more of the above-described diseases and conditions. The compounds of the invention may also be useful in the prevention of one or more of the diseases listed therein.

[0182] Combination therapy The present invention further relates to combination therapies for treating the diseases or disorders described herein. In some embodiments, the combination therapy comprises administering at least one compound of the invention in combination with one or more other pharmaceutically active substances for treating cancer or other disorders mediated by menin / MLL. In some embodiments, the combination therapy comprises administering at least one compound of the invention in combination with, for example, one or more other pharmaceutically active substances for the treatment of cancer. The pharmaceutically active substances can be combined with the compounds of the invention in a single dosage form, or the therapeutic agents can be administered simultaneously or sequentially as separate dosage forms.

[0183] The compounds of the invention may also be used in combination with immunotherapies for the treatment of the diseases or disorders disclosed herein, including, but not limited to, cell-based therapies, antibody therapies, and cytokine therapies.

[0184] In certain embodiments, the compounds of the invention are used in combination with one or more passive immunotherapies including, but not limited to, naked monoclonal antibody drugs and conjugate-forming monoclonal antibody drugs. Examples of naked monoclonal antibody drugs that can be used include, but are not limited to, rituximab (Rituxan®), an antibody against the CD20 antigen; trastuzumab (Herceptin®), an antibody against the HER2 protein; alemtuzumab (Lemtrada®, Campath®), an antibody against the CD52 antigen; cetuximab (Erbitux®), an antibody against the EGFR protein; bevacizumab (Avastin®), an anti-angiogenic inhibitor of the VEGF protein.

[0185] Examples of conjugate-forming monoclonal antibodies that can be used include radiolabeled antibody ibritumomab tiuxetan (Zevalin®); radiolabeled antibody tositumomab (Bexxar®); gemtuzumab ozogamicin (Mylotarg®), an immunotoxin containing calicheamicin; anti-CD22 monoclonal antibody-immunotoxin conjugate BL22; radiolabeled antibodies such as OncoScint® and ProstaScint®; brentuximab vedotin (Adcetris®); ado-trastuzumab emtansine (Kadcyla®, also called TDM-1).

[0186] Further examples of therapeutic antibodies that may be used include, but are not particularly limited to, REOPRO® (abciximab), an antibody against the glycoprotein IIb / IIIa receptor on platelets; ZENAPAX® (daclizumab), an immunosuppressive humanized anti-CD25 monoclonal antibody; PANOREX™, a murine anti-17-1A cell surface antigen IgG2a antibody; BEC2, a murine anti-idiotype (GD3 epitope) IgG antibody; IMC-C225, a chimeric anti-EGFR IgG antibody; VITAXIN™, a humanized anti-αVβ3 integrin antibody; Campath 1H / LDP-03, a humanized anti-CD52 IgG1 antibody; SMART M195, a humanized anti-CD33 IgG antibody; LYMPHOCIDE™, a humanized anti-CD22 IgG antibody; LYMPHOCIDE™ Y-90; Lymphoscan; Nuvion® (against CD3); CM3, a humanized anti-ICAM3 antibody; IDEC-114, a primatized anti-CD80 antibody; IDEC-131, a humanized anti-CD40L antibody; IDEC-151, a primatized anti-CD4 antibody; IDEC-152, a primatized anti-CD23 antibody; SMART anti-CD3, a humanized anti-CD3 IgG; 5G1.1, a humanized anti-complement factor 5 (C5) antibody; D2E7, a humanized anti-TNF-α antibody; CDP870, a humanized anti-TNF-α Fab fragment; IDEC-151, a primatized anti-CD4 IgG1 antibody; MDX-CD4, a human anti-CD4 IgG antibody; CD20-streptavidin (+biotin-ytterbium 90); CDP571, a humanized anti-TNF-α IgG4 antibody; LDP-02, a humanized anti-α4β7 antibody; OrthoClone OKT4A, a humanized anti-CD4 IgG antibody; ANTOVA™, a humanized anti-CD40L IgG antibody; ANTEGREN™, a humanized anti-VLA-4 IgG antibody; and CAT-152, a human anti-TGF-β2 antibody.

[0187] In certain embodiments, the compounds of the invention are used in combination with one or more targeted immunotherapies that include toxins other than antibodies, such as denileukin diftitox (Ontak®), which is IL-2 conjugated to diphtheria toxin, although not particularly limited thereto.

[0188] The compounds of the invention may also be used in combination with adjuvant immunotherapies for the treatment of the diseases or disorders disclosed herein. Such adjuvant immunotherapies include, although not particularly limited thereto, granulocyte macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), macrophage inflammatory protein (MIP)-1α, interleukins (including IL-1, IL-2, IL-4, IL-6, IL-7, IL-12, IL-15, IL-18, IL-21, and IL-27), tumor necrosis factor (including TNF-alpha), and interferons (including IFN-alpha, IFN-beta, and IFN-gamma); aluminum hydroxide (alum); Bacillus Calmette-Guerin (BCG); keyhole limpet hemocyanin (KLH); incomplete Freund's adjuvant (IFA); QS-21; DETOX; levamisole; and dinitrophenyl (DNP); and combinations thereof, such as combinations of interleukins, such as IL-2 in combination with other cytokines such as IFN-alpha.

[0189] In certain embodiments, the compounds of the invention are used in combination with vaccine therapies including, although not particularly limited thereto, autologous and allogeneic tumor cell vaccines, antigen vaccines (including multivalent antigen vaccines), dendritic cell vaccines, and viral vaccines.

[0190] In another embodiment, the disclosure of the invention includes administering to a subject having cancer an effective amount of a compound of the invention and one or more additional anti-cancer therapies selected from surgery, anti-cancer agents / anticancer drugs, biological therapies, radiation therapies, anti-angiogenesis therapies, immunotherapies, adoptive transfer of effector cells, gene therapies, or hormonal therapies. Examples of anti-cancer agents / anticancer drugs are described below.

[0191] In some embodiments, the anti-cancer agent / anti-cancer drug is, for example, Adriamycin, Actinomycin, Bleomycin, Vinblastine, Cisplatin, Asibiicin; Aclarubicin; Acodazole Hydrochloride; Acronine; Adzelesin; Aldesleukin; Altretamine; Ambomycin; Ametantrone Acetate; Aminoglutethimide; Amsacrine; Anastrozole; Anthramycin; Asparaginase; Asperlin; Azacitidine; Azetepa; Azotomycin; Batimastat; Benzodepa; Bicalutamide; Bisantrene Hydrochloride; Bisnafide Dimesylate; Bizelesin; Bleomycin Sulfate; Brequinar Sodium; Broxuridine; Busulfan; Cactinomycin; Calusterone; Caracemide; Carbetimer; Carboplatin; Carmustine; Carboquone; Carzelesin; Cedefingol; Chlorambucil; Cirolemycin; Cladribine; Crisnatol Mesylate; Cyclophosphamide; Cytarabine; Dacarbazine; Daunorubicin Hydrochloride; Decitabine; Dexmaplatin; Dezaguanine; Dezaguanine Mesylate; Diaziridinylbenzoquinone; Doxorubicin; Doxorubicin Hydrochloride; Droloxifene; Droloxifene Citrate; Drostanolone Propionate; Duazomycin; Edatrexate; Efloxatin Hydrochloride; Elsamitrucin; Enloplatin; Epmate; Epipropidine; Epirubicin Hydrochloride; Erbulozole; Esorubicin Hydrochloride; Estramustine; Estramustine Phosphate Sodium; Ethanidazole; Etoposide; Etoposide Phosphate; Etoprine; Fadrozole Hydrochloride; Fazarabine; Fenretinide; Floxuridine; Fludarabine Phosphate; Fluorouracil; Flucytosine; Fosquidone; Fostriecin Sodium; Gemcitabine; Gemcitabine Hydrochloride; Hydroxyurea; Idarubicin Hydrochloride; Ifosfamide; Ilmofosine; Iproplatin; Irinotecan Hydrochloride; Lanreotide Acetate; Letrozole; Leuprolide Acetate; Liriomycine; Lomustine; Losoxantrone Hydrochloride; Masoprocol; Maytansine; Mechlorethamine Hydrochloride; Megestrol Acetate; Melenegestrol Acetate; Melphalan; Menogaril; Mercaptopurine; Methotrexate; Methotrexate Sodium; Metoprine; Metsulbrene; Mitindomide; Mitocarcin;Mitochromin; Mitogirin; Mitomarcin; Mitomycin; Mitosper; Mitotan; Mitoxantrone Hydrochloride; Mycophenolic Acid; Nocodazole; Nogalamycin; Ormaplatin; Oxirane; Pegaspargase; Periomycin; Pentostatin; Pepromycin Sulfate; Parfosfamide; Pipobroman; Piposulfan; Pyroxantrone Hydrochloride; Plicamycin; Promestane; Porfimer Sodium; Porfiromycin; Prednimustine; Procarbazine Hydrochloride; Puromycin; Puromycin Hydrochloride; Pyrazofurin; Riboprine; Rogletimide; Safingol; Safingol Hydrochloride; Semustine; Simtrazine; Sparfosate Sodium; Sparsomycin; Spirogermanium Hydrochloride; Spiro-mustine; Spiroplatin; Streptozocin; Streptozocin; Sulfofenur; Talisomycin; Tegafur Sodium; Tegafur; Teloxantrone Hydrochloride; Temoporfin; Teniposide; Teloxiron; Testolactone; Thiamiprine; Thioguanine; Thiotepa; Thiazofurin; Tirapazamine; Toremifene Citrate; Trestolone Acetate; Trisciribine Phosphate; Trimetrexate; Trimetrexate Glucuronate; Triptorelin; Tubulozole Hydrochloride; Uracil Mustard; Uredepa; Bapreotide; Verteporfin; Vinblastine Sulfate; Vincristine Sulfate; Vindesine; Vindesine Sulfate; Vinetepidine Sulfate; Vinglycinate Sulfate; Vinleurosine Sulfate; Vinorelbine Tartrate; Vinrosidine Sulfate; Vinzolidine Sulfate; Borozole; Zeniplatin; Dinostatin; Zorubicin Hydrochloride; Palbociclib; Yervoy (registered trademark) (ipilimumab); Mekinist (trademark) (trametinib); Peginterferon alpha-2b, recombinant interferon alpha-2b; Sylatron (trademark) (peginterferon alpha-2b); Tafinlar (registered trademark) (dabrafenib); Zelboraf (registered trademark) (vemurafenib); or nivolumab.;

[0192] The compounds of the present invention can be administered in combination with existing methods for treating cancer, such as chemotherapy, radiation therapy, or surgery. Accordingly, there is further provided a method of treating cancer comprising administering to a subject in need of such treatment an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof, wherein an effective amount of at least one additional cancer chemotherapeutic agent is administered to the subject. Examples of suitable cancer chemotherapeutic agents include abarelix, ado-trastuzumab emtansine, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, anastrozole, arsenic trioxide, asparaginase, azacitidine, bevacizumab, bexarotene, bleomycin, bortezomib, bortezomib, intravenous busulfan, oral busulfan, calusterone, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparin sodium, dasatinib, daunorubicin, decitabine, denileukin, denileukin diftitox, dexrazoxane, docetaxel, doxorubicin, drostanolone propionate, eculizumab, emtansine, epirubicin, eribulin, erlotinib, estramustine, etoposide phosphate, etoposide, everolimus, exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine, fluorouracil, fruquintinib, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib mesylate, interferon alpha 2a, irinotecan, ixabepilone, lapatinib ditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lomustine, mechlorethamine, megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone phenylpropionate, nelarabine, nolatrexed, oxaliplatin, paclitaxel, paclitaxel albumin-stabilized nanoparticle formulation, pamidronate, panitumumab,Pefaspalase, pegfilgrastim, pemetrexed disodium, pentostatin, pertuzumab, pipobroman, plicamycin, procarbazine, quinacrine, rasburicase, rituximab, sorafenib, streptozocin, sulfatinib, sunitinib, sunitinib maleate, tamoxifen, temozolomide, teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, volitinib, vorinostat, and zoledronate are included.,

[0193] In certain embodiments, the compounds of the present invention are used in combination with one or more anti-cancer agents selected from methotrexate, paclitaxel albumin-stabilized nanoparticle formulation, ado-trastuzumab emtansine, eribulin, doxorubicin, fluorouracil, everolimus, anastrozole, pamidronate disodium, exemestane, capecitabine, cyclophosphamide, docetaxel, epirubicin, toremifene, fulvestrant, letrozole, gemcitabine, gemcitabine hydrochloride, goserelin acetate, trastuzumab, ixabepilone, lapatinib ditosylate, megestrol acetate, tamoxifen citrate, pamidronate disodium, palbociclib, and pertuzumab for the treatment of breast cancer.

[0194] Other anti-cancer agents / anti-cancer drugs are not particularly limited, but include 20-epi-1,25-dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adesipenol; adozelesin; aldesleukin; ALL-TK antagonist; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; andrographolide; angiogenesis inhibitor; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein-1; anti-androgen; anti-estrogen; anti-neoplaston; antisense oligonucleotide; aphidicolin glycinate; apoptosis gene regulator; apoptosis regulator; appric acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azaseron; azatoxin; azatyrosine; baccatin III derivative; baranol; batimastat; BCR / ABL antagonist; benzochlorin; benzoyl staurosporine; beta-lactam derivative; beta-aretin; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinyl spermine; bisnafide; bistratin A; bizelesin; breflate; broxuridine; budotitane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivative; canarypox IL-2; capecitabine; carboxamide-amino-triazole; carboxamide triazole; CaRest M3; CARN 700; cartilage-derived inhibitor; carzelesin; casein kinase inhibitor; castanospermine; cecropin B; cetrorelix; chlorin; chloroquinoxaline sulfonamide; cicaprost; cisporphyrin; cladribine; clomifene analog; clotrimazole; corismycin A; corismycin B; combretastatin A4; combretastatin analog; conagenin; clavulbesidin 816; crisnatol; cryptophycin 8; cryptophycin A derivative; classin A; cyclin-dependent kinase inhibitor; cyclopentaanthraquinones; cycloplatam; sipeimine; cytarabine octophosphate;Cytolytic factors; Cytostatins; Daclizumab; Decitabine; Dehydrodidemnin B; Deslorelin; Dexamethasone; Dexifosfamide; Dexrazoxane; Dexbevacizumab; Diazquone; Didemnin B; Doxorubicin; Diethylnorspermine; Dihydro-5-azacytidine; 9-Dioxamycin; Diphenylspiromustin; Docosanol; Dolasetron; Doxifluridine; Droloxifene; Dronabinol; Duocarmycin SA; Ebselen; Ecostin; Edelfosine; Edrecolomab; Eflornithine; Elemen; Emitefur; Epirubicin; Epseride; Estramustine analogs; Estrogen agonists; Estrogen antagonists; Ethanidazole; Etoposide phosphate; Fadrozole; Fludarabine; Fazarabine; Fenretinide; Filgrastim; Finasteride; Flavopiridol; Fleserastin; Fluasterone; Fludarabine; Fluorodauorubicin hydrochloride; Formestane; Gallium nitrate; Gallocitabine; Ganirelix; Gelatinase inhibitors; Gemcitabine; Glutathione inhibitors; Hepsulfamide; Heregulin; Hexamethylenebisacetamide; Hypericin; Ibandronic acid; Idarubicin; Idoxifene; Idramantone; Ilmofosine; Iromastatin; Imidazoacridone; Imiquimod; Immunostimulatory peptides; Insulin-like growth factor-1 receptor inhibitors; Iobenguane; Iododoxorubicin; Ipomoeanol, 4-; Iroplact; Ilosgraine; Isobenzagol; Isohomohalicondrin B; Itasetron; Jasplakinolide; Kahalalide F; Lamellarin-N triacetate; Lanreotide; Lincomycin; Lenograstim; Sulfated lentinan; Leptostatin; Letrozole; Leukemia inhibitory factor; Leuprorelin + Estrogen + Progesterone; Leuprorelin; Levamisole; Rialoxazole; Linear polyamine analogs; Lipophilic disaccharide peptides; Lipophilic platinum compounds; Lysocline amide 7; Lobaplatin; Lomustine; Lometrexol; Lonidamine; Losoxantrone; Lovastatin; Roxifiban; Rutetecan; Lutetium texaphyrin; Lysophyllin; Lytic peptides; Maytansine; Mannostatin A; Marimastat; Masoprocol; Maspin;Matrix metalloproteinase inhibitor; Matrix metalloproteinase inhibitor; Menogaril; Melvalon; Meteclirine; Methioninase; Metoclopramide; MIF inhibitor; Mifepristone; Miltefosine; Miltimorestin; Mismatched double-stranded RNA; Mitoguazone; Mitolactol; Mitomycin analog; Mitonafide; Mitotoxin fibroblast growth factor-saporin; Mitoxantrone; Mofarotene; Molgramostim; Monoclonal antibody, human chorionic gonadotropin; Monophosphoryl lipid A + Mycobacterium cell wall sk; Mopidamol; Multidrug resistance gene inhibitor; Treatment based on multiple tumor suppressor 1; Mustard anticancer agent; Micaperoxide B; Mycobacterium cell wall extract; Myriaporon; N-acetyl dinarin; N-substituted benzamide; Nafarelin; Nagrestip; Naloxone + pentazocine; Napabucasin; Naftelpin; Nartograstim; Nedaplatin; Nemorubicin; Neridronic acid; Neutral endopeptidase; Nilutamide; Nisamycin; Nitric oxide regulator; Nitroxide antioxidant; Nitrilimine; O6-benzylguanine; Octreotide; Oxenone; Oligonucleotide; Onapristone; Ondansetron; Ondansetron; Orasin; Oral cytokine inducer; Ormaplatin; Osaterone; Oxaliplatin; Oxauromycin; Paraureamine; Palmitoyl lysine; Pamidronic acid; Panaxytriol; Panomifene; Parabactin; Pazelliptine; Pegaspargase; Perdesine; Pentosan polysulfate sodium; Pentostatin; Pentrozole; Perflubron; Perfosfamide; Perillyl alcohol; Phenazinomycin; Phenylacetic acid; Phosphatase inhibitor; Pivabanserin; Pilocarpine hydrochloride; Pirarubicin; Pyrithioxine; Placetin A; Placetin B; Plasminogen activator inhibitor; Platinum complex; Platinum compound; Platinum-triamine complex; Porfimer sodium; Porfiromycin; Prednisone; Propylbis-acridone; Prostaglandin J2; Proteasome inhibitor; Protein A-based immunomodulator; Protein kinase C inhibitor; Microalgae; Protein tyrosine phosphatase inhibitor; Purine nucleoside phosphorylase inhibitor; Purpurin; Pyrazoloacridine; Pyridoxylated hemoglobin polyoxyethylene conjugate;raf antagonist; raltitrexed; lamotrigine; ras farnesyl protein transferase inhibitor; ras inhibitor; ras-GAP inhibitor; reterptin demethylation; rhenium Re186 etidronate; lysokin; ribozyme; RII retinamide; logretimide; rohitukine; romurtide; roquinimex; rubidinoe B1; ruboxyl; saphingol; sintopine; SarCNU; sarcophytol A; sargramostim; Sdi1 mimetic; semustine; aging-derived inhibitor 1; sense oligonucleotide; signal transduction inhibitor; signal transduction regulator; single-chain antigen-binding protein; schizophyllan; sobuzoxan; sodium borocaptate; sodium phenylacetate; sorberol; somatomedin-binding protein; sonermin; sparfosic acid; spicamycin D; spiromustin; sprionpentine; spongistatin 1; squalamine; stem cell inhibitor; stem cell division inhibitor; stipiamide; stromelysin inhibitor; sulfinosine; superactive vasoactive intestinal peptide antagonist; sladidis; slamine; swine sonin; synthetic glycosaminoglycan; talimustine; tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; terlapirillium; telomerase inhibitor; temoporfin; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; taliblastine; thiocholin; thrombopoietin; thrombopoietin mimetic; timalphasin; thrombopoietin receptor agonist; timotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene dichloride; topsecentin; tretinoin; triacetyluridine; triciribine; trimethotrexate; tryptoreline; tropisetron; turosteride; tyrosine kinase inhibitor; tilostatin; UBC inhibitor; ubenimex; urogenital sinus-derived growth inhibitor; urokinase receptor antagonist; vapreotide; valiorin B; vector system, erythrocyte gene therapy; veraresol; veramine; verden; verteporfin; vinorelbine; vinca sulfate; vitaxin; zanoterone; zilastrub; dinostatin stimalamer; 5-fluorouracil; and leucovorin are included.;

[0195] In some embodiments, the anti-cancer agent / anti-cancer drug is an agent that stabilizes microtubules. As used herein, "microtubulin stabilizer" means an anti-cancer agent / anti-cancer drug that acts by arresting cells in the G2-M phase through the stabilization of microtubules. Examples of microtubulins include ACLITAXEL® and Taxol® analogs. Further examples of microtubulin stabilizers include, but are not particularly limited to, the following commercially available drugs and drugs in development: discodermolide (also known as NVP-XX-A-296); epothilones (epothilone A, epothilone B, epothilone C (also called desoxyepothilone A or dEpo-A); epothilone D (also called KOS-862, dEpoB, and desoxyepothilone B); epothilone E; epothilone F; epothilone B N-oxide; epothilone A N-oxide; 16-aza-epothilone B; 21-aminoepothilone B (also known as BMS-310705); 21-hydroxyepothilone D (also known as desoxyepothilone F and dEpoF); 26-fluoroepothilone); FR-182877 (Fujisawa, also known as WS-9885B), BSF-223651 (BASF, also known as ILX-651 and LU-223651); AC-7739 (Ajinomoto, also known as AVE-8063A and CS-39.HCl); AC-7700 (Ajinomoto, also known as AVE-8062, AVE8062A, CS-39-L-Ser.HCl, and RPR-258062A); physanolide B; laulimalide; calyculin B; calyculin; takanolide; eribulin; sarcodictyin; laulimalide; dictyostatin-1; jatrophane ester; and analogs and derivatives thereof.

[0196] In another embodiment, the anti-cancer agent / anti-cancer drug is an agent that inhibits microtubules. In the present invention, "microtubulin inhibitor" means an anti-cancer agent that acts by inhibiting tubulin polymerization or microtubule assembly. Examples of microtubulin inhibitors include, but are not particularly limited to, the following commercially available drugs and drugs under development: eribulin (also known as R-55104); dolastatin 10 (also known as DLS-10 and NSC-376128); mibolerone isethionate (also known as CI-980); vincristine; NSC-639829; ABT-751 (Abbott, also known as E-7010); altretamine (such as altretamine A and altretamine C); spongistatins (e.g., spongistatin 1, spongistatin 2, spongistatin 3, spongistatin 4, spongistatin 5, spongistatin 6, spongistatin 7, spongistatin 8, and spongistatin 9); semadotin hydrochloride (also known as LU-103793 and NSC-D-669356); auristatin PE (also known as NSC-654663); sobrivirtide (also known as TZT-1027), LS-4559-P (Pharmacia, also known as LS-4577); LS-4578 (Pharmacia, also known as LS-477-P). LS-4477 (Pharmacia), LS-4559 (Pharmacia): RPR-112378 (Aventis); vincristine sulfate; DZ-3358 (Daiichi); GS-164 (Takeda); GS-198 (Takeda); KAR-2 (Hungarian Academy of Sciences); SAH-49960 (Lilly / Novartis); SDZ-268970 (Lilly / Novartis); AM-97 (Armad / Kyowa Hakko); AM-132 (Armad); AM-138 (Armad / Kyowa Hakko); IDN-5005 (Indena); cryptophycin 52 (also known as LY-355703); bitubercinamide; tubulysin A; canadensol; centaureidin (also known as NSC-106969);T-138067 (also known as Tularik, T-67, TL-138067, and TI-138067); COBRA-1 (also known as Parker Hughes Institute, DDE-261, and WHI-261); H10 (Kansas State University); H16 (Kansas State University); Oncocidin A1 (also known as BTO-956 and DIME); DDE-313 (Parker Hughes Institute); SPA-2 (Parker Hughes Institute); SPA-1 (also known as Parker Hughes Institute and SPIKET-P); 3-IAABU (also known as Cytoskeleton / Mt-Sinai School of Medicine and MF-569); Narcosine (also known as NSC-5366); Noscapine, D-24851 (Asta Medica), A-105972 (Abbott); Hemiasterlin; 3-BAABU (also known as Cytoskeleton / Mt. Sinai School of Medicine and MF-191); TMPN (Arizona State University); Vanadocene acetylacetonate; T-138026 (Tularik); Monsatrol; Inanocine (also known as NSC-698666); 3-IAABE (Cytoskeleton / Mt. Sinai School of Medicine); A-204197 (Abbott); T-607 (also known as Tularik and T-900607); RPR-115781 (Aventis); Erolitinoids (e.g., desmethylerolitin, desacetylerolitin, isoerolitin A, and Z-erolitin); Halicondrin B; D-64131 (Asta Medica); D-68144 (Asta Medica); Diazonaide A; A-293620 (Abbott); NPI-2350 (Nereus); TUB-245 (Aventis); A-259754 (Abbott); Diosastatin; (-)-Phenylahistin (also known as NSCL-96F037);D-68838 (Asta Medica); D-68836 (Asta Medica); Myoseverin B; D-43411 (also known as Zentaris, D-81862); A289099 (Abbott); A-318315 (Abbott); HTI-286 (also known as SPA-110, trifluoroacetate) (Wyeth); D-82317 (Zentaris); D-82318 (Zentaris); SC-12983 (NCI); Rosuvastatin sodium phosphate; BPR-0Y-007 (National Health Research Institutes); SSR-250411 (Sanofi); Combretastatin A4; Eribulin (Halaven®); and analogs and derivatives thereof are included.;

[0197] In a further embodiment, the compounds of the invention are used in combination with one or more alkylating agents, antimetabolites, natural products, or hormones.;

[0198] Examples of alkylating agents useful in the methods of the invention include, but are not particularly limited to, nitrogen mustards (e.g., mechlorethamine, cyclophosphamide, chlorambucil, melphalan, etc.), ethyleneimines and methylmelamines (e.g., hexamethylmelamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomustine, semustine, streptozocin, etc.), or triazenes (e.g., dacarbazine, etc.).;

[0199] Examples of antimetabolites useful in the method of the present invention include, but are not particularly limited to, folic acid analogs (e.g., methotrexate), or pyrimidine analogs (e.g., fluorouracil, floxuridine, cytarabine), and purine analogs (e.g., mercaptopurine, thioguanine, pentostatin). Examples of natural products useful in the method of the present invention include, but are not particularly limited to, vinca alkaloids (e.g., vinblastine, vincristine), epipodophyllotoxins (e.g., etoposide, teniposide), antibiotics (e.g., actinomycin D, daunorubicin, doxorubicin, bleomycin, plicamycin, mitomycin), or enzymes (e.g., L-asparaginase).

[0200] Examples of hormones and antagonists useful for the treatment of cancer include, but are not particularly limited to, corticosteroids (e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate, megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., diethylstilbestrol, ethinyl estradiol), antiestrogens (e.g., tamoxifen), androgens (e.g., testosterone propionate, fluoxymesterone), antiandrogens (e.g., flutamide), and gonadotropin-releasing hormone analogs (e.g., leuprolide).

[0201] Other agents that can be used in combination with the compounds of the present invention for the treatment of cancer include platinum coordination complexes (e.g., cisplatin, carboplatin), anthraquinones (e.g., mitoxantrone), substituted ureas (e.g., hydroxyurea), methylhydrazine derivatives (e.g., procarbazine), and adrenocortical suppressants (e.g., mitotane, aminoglutethimide). Other anti-cancer agents / anti-cancer drugs that can be used in combination with the compounds of the present invention include, but are not particularly limited to, liver X receptor (LXR) modulators including LXR agonists and LXR beta-selective agonists; aryl hydrocarbon receptor (AhR) inhibitors; inhibitors of the enzyme poly ADP ribose polymerase (PARP) including olaparib, iniparib, rucaparib, veliparib; inhibitors of vascular endothelial growth factor (VEGF) receptor tyrosine kinase including cediranib; programmed cell death protein 1 (PD-1) inhibitors including nivolumab (Bristol-Myers Squibb Co.) and pembrolizumab (Merck&Co., Inc.; MK-3475); MEK inhibitors including cobimetinib; B-Raf enzyme inhibitors including vemurafenib; cytotoxic T lymphocyte antigen (CTLA-4) inhibitors including tremelimumab; programmed death-ligand 1 (PD-L1) inhibitors including MEDI4736 (AstraZeneca); inhibitors of the Wnt pathway; inhibitors of epidermal growth factor receptor (EGFR) including AZD9291 (AstraZeneca), erlotinib, gefitinib, panitumumab, and cetuximab; adenosine A2A receptor inhibitors; adenosine A2B receptor inhibitors; colony-stimulating factor-1 receptor (CSF1R) inhibitors including PLX3397 (Plexxikon), and inhibitors of CD73.

[0202] The compounds of the present invention can be used in combination with one or more treatment strategies including immune checkpoint inhibitors including inhibitors of PD-1, PD-L1, and CTLA-4.

[0203] The compounds of the present invention can be used in combination with one or more anticancer agents selected from the following: MCL-1 inhibitors such as homoharringtonine (HHT) and omacetaxine; BCL-2 inhibitors such as venetoclax (ABT-199), navitoclax (ABT-263), ABT-737, gossypol (AT-101), apogossypolone (ApoG2), and obatoclax; selective inhibitors of nuclear export (SINE) such as selinexor (KPT-330).

[0204] In certain embodiments, the compounds of the invention can be used in combination with one or more anti-cancer agents selected from the following: methotrexate (Abitrexate®; Folex®; Folex PFS®; Mexate®; Mexate-AQ®); nelarabine (Arranon®); blinatumomab (Blincyto®); rubidomycin hydrochloride or daunorubicin hydrochloride (Cerubidine®); cyclophosphamide (Clafen®; Cytoxan®; Neosar®); clofarabine (Clofarex®; Clolar®); cytarabine (Cytosar-U®; Tarabine PFS®); dasatinib (Sprycel®); doxorubicin hydrochloride; asparaginase Erwinia chrysanthemi (Elspar); imatinib mesylate (Gleevec®); ponatinib hydrochloride (Iclusig®); mercaptopurine (Purinol; Purixan); pegaspargase (Oncaspar®); prednisone; vincristine sulfate (Oncovin®, Vincasar PFS®, Vincrex®); vincristine sulfate liposome (Marqibo®); hyper-CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone); arsenic trioxide (Trisenox®); idarubicin hydrochloride (Idamycin®); mitoxantrone hydrochloride; thioguanine (Tabloid®); ADE (cytarabine, daunorubicin, and etoposide); alemtuzumab (Lemtrada®, Campath®); chlorambucil (Ambochlorin®, Amboclorin®, Leukeran®, Linfolizin®); ofatumumab (Arzerra®); bendamustine hydrochloride (Treanda®); fludarabine phosphate (Fludara®); obinutuzumab (Gazyva®);Ibrutinib (Imbruvica®); Idelalisib (Zydelig®); Mechlorethamine Hydrochloride (Mustargen®); Rituximab (Rituxan®); Chlorambucil-Prednisone; CVP (Cyclophosphamide, Vincristine, and Prednisone); Bosutinib (Bosulif®); Busulfan (Busulfex®; Myleran®); Omacetaxine Mepesuccinate (Synribo®); Nilotinib (Tasigna®); Intron® A (Recombinant Interferon Alpha-2b); DOT1L inhibitors including EPZ-5676 (Epizyme, Inc.); and inhibitors of bromodomain and extra-terminal motif (BET) proteins (BET inhibitors) including MS417, JQ1, I-BET 762, and I-BET 151 for the treatment of leukemia.;

[0205] The compounds of the present invention are not particularly limited for treating insulin resistance, prediabetes, diabetes (e.g., type 2 diabetes or type 1 diabetes), and diabetes risk, but can be used in combination with one or more of the following other agents or therapies: insulin and insulin analogs, such as Humulin® (EIi Lilly), Lantus® (Sanofi Aventis), Novolin® (Novo Nordisk), and Exubera® (Pfizer); Avandamet® (metformin HCl and rosiglitazone maleate, GSK); Avandaryl® (glimepiride and rosiglitazone maleate, GSK); Metaglip® (glypidide and metformin HCl, Bristol Myers Squibb); Glucovance® (glyburide and metformin HCl, Bristol Myers Squibb); PPAR gamma agonists, such as Avandia® (rosiglitazone maleate, GSK), and Actos® (pioglitazone hydrochloride, Takeda / Eli Lilly); sulfonylureas, such as Amaryl® (glimepiride, Sanofi Aventis), Diabeta® (glyburide, Sanofi Aventis), Micronase® / Glynase® (glyburide, Pfizer), and Glucotrol® / Glucotrol XL® (glypidide, Pfizer); meglitinides, such as Prandin® / NovoNorm® (repaglinide, Novo Nordisk), Starlix (nateglinide, Novartis), and Glufast® (mitiglinide, Takeda); biguanides, such as Glucophase® / Glucophase XR® (metformin HCl, Bristol Myers Squibb), and Glumetza® (metformin HCl, Depomed); thiazolidinedione; amylin analogs; GLP-1 analogs;DPP-IV inhibitors, such as Januvia® (sitagliptin, Merck) and Galvus® (vildagliptin, Novartis); PTB-1B inhibitors; protein kinase inhibitors (including AMP-activated protein kinase inhibitors); glucagon antagonists, glycogen synthase kinase-3 beta inhibitors; glucose-6-phosphatase inhibitors; glycogen phosphorylase inhibitors; sodium glucose cotransporter inhibitors; alpha-glucosidase inhibitors, such as Glycet® (miglitol, Pfizer); statins, fibrates, and Zetia® (ezetimibe); alpha blockers; beta blockers; calcium channel blockers; diuretics; angiotensin-converting enzyme (ACE) inhibitors; dual ACE and neutral endopeptidase (NEP) inhibitors; angiotensin receptor blockers (ARBs); aldosterone synthase inhibitors; aldosterone receptor antagonists; endothelin receptor antagonists; orlistat; phentermine; sibutramine; Acomplia® (rimonabant); thiazolidinediones (e.g., rosiglitazone, pioglitazone); SGLT2 inhibitors (e.g., dapagliflozin, luseogliflozin etabonate, sergliflozin, canagliflozin, and 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy))-benzyl]-benzene); PPAR-gamma agonists (e.g., GI262570) and antagonists; PPAR-gamma / alpha modulators (e.g., KRP297); alpha-glucosidase inhibitors (e.g., acarbose, voglibose); DPPIV inhibitors (e.g., Januvia® (sitagliptin), Galvus® / Zomelis® (vildagliptin), Onglyza® (saxagliptin), Nesina® / Vipidia® (alogliptin), Tradjenta® / Trajenta® (linagliptin)); alpha2-antagonists; glucagon-like protein-1 (GLP-1) receptor agonists and analogs (e.g., exendin-4); amylin;Inhibitors of protein tyrosine phosphatase 1; substances that affect deregulated glucose production in the liver, such as glucose-6-phosphatase, or fructose-1,6-bisphosphatase, inhibitors of glycogen phosphorylase; glucagon receptor antagonists; inhibitors of phosphoenolpyruvate carboxykinase; glycogen synthase kinase and glucokinase activators; lipid-lowering agents, such as HMG-CoA-reductase inhibitors (e.g., simvastatin, atorvastatin); fibrates (e.g., bezafibrate, fenofibrate), nicotinic acid and its derivatives, PPAR-alpha agonists, PPAR-delta agonists; ACAT inhibitors (e.g., avasimibe); cholesterol absorption inhibitors such as ezetimibe; bile acid-binding substances such as cholestyramine; inhibitors of ileal bile acid transport; HDL-raising compounds such as CETP inhibitors and ABC1 regulators; active substances for treating obesity such as sibutramine and tetrahydrolipostatin; SDRI; axokin; leptin; leptin mimetics; antagonists of the cannabinoid 1 receptor; and MCH-1 receptor antagonists; MC4 receptor agonists; NPY5 and NPY2 antagonists; beta3 adrenergic agonists such as SB-418790 and AD-9677; agonists of the 5HT2c receptor; GABA receptor antagonists; Na channel blockers; topiramate; protein kinase C inhibitors; advanced glycation end product inhibitors; and aldose reductase inhibitors.;

[0206] Pharmaceutical formulations, administration, and dosage forms When used as a medicament, the compounds of the present invention can be administered in the form of a pharmaceutical composition which is a combination of the compound of the present invention or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier. These compositions can be prepared by methods known in the pharmaceutical art and can be administered by various routes depending on whether local or systemic treatment is desired and on the area to be treated. Administration can be local (e.g., to the eye membranes and mucous membranes including intranasal, vaginal, and rectal delivery), pulmonary administration (e.g., by nebulizer; inhalation or insufflation of powders or aerosols including intratracheal, intranasal, epidermal, and transdermal), ocular, or parenteral. Methods for intravitreal delivery can include topical administration (eye drops), subconjunctival, periocular or intravitreal injection, or introduction by a balloon catheter or ophthalmic insert surgically placed in the conjunctival sac. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion; or intracranial, e.g., intrathecal or intraventricular administration. Parenteral administration can be in the form of a single bolus dose or, for example, a continuous perfusion pump. Pharmaceutical compositions and formulations for local administration can include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Conventional pharmaceutical carriers, aqueous, powder, or oily bases, thickeners, etc. may be necessary or desirable.

[0207] The present invention also includes a pharmaceutical composition comprising, as an active ingredient, one or more of the above compounds of the present invention in combination with one or more pharmaceutically acceptable carriers. In the manufacture of the compositions of the present invention, the active ingredient is typically admixed with excipients and is diluted by the excipients or enclosed within a carrier in the form of, for example, capsules, sachets, paper, or other containers. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material that acts as a vehicle, carrier, or medium for the active ingredient. That is, the compositions can be in the form of tablets, pills, powders, troches, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (in solid or liquid media), e.g., ointments containing up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injection solutions, and sterile packaged powders.

[0208] The compounds or compositions described herein can be administered to a patient using any amount and route of administration effective to treat or reduce the severity of one or more of the diseases and conditions described herein. The exact amount required will vary from subject to subject depending on the species, age, and general condition of the subject, the severity of the infection, disease, or disorder, the particular agent, its mode of administration, and the like. The compounds provided are preferably formulated in specific unit dosage forms for ease of administration and uniformity of dosage. As used herein, the expression "unit dosage form" refers to physically discrete units suitable for the patient to be treated.

[0209] The therapeutic dosage of the compounds of the present invention can vary, for example, according to the particular use for which the treatment is carried out, the mode of administration of the compound, the health condition of the patient, and the judgment of the attending physician. The proportion or concentration of the compound of the present invention in the pharmaceutical composition can vary depending on many factors including the dosage, chemical properties (e.g., hydrophobicity), and route of administration. For example, the compounds of the present invention can be provided in a physiologically buffered aqueous solution containing from about 0.1 to about 10% w / v of the compound for parenteral administration. Some typical dosage ranges are from about 1 μg / kg to about 1 g / kg body weight per day. In some embodiments, the dosage range is from about 0.01 mg / kg to about 100 mg / kg body weight per day. The dosage is likely to depend on variables such as the type and degree of progression of the disease or disorder, the overall health condition of the specific patient, the relative biological effectiveness of the selected compound, the formulation of the excipient, and its route of administration. The effective amount can be extrapolated from a dose-response curve derived from in vitro or animal model test systems.

Example

[0210] As shown in the following examples, the compounds of the present invention were prepared and isolated according to the following general procedures. The general methods can illustrate the synthesis of specific compounds of the present invention, but it will be understood that the following general methods, as well as other methods known to those skilled in the art, are applicable to all compounds and their respective subclasses and types as described herein.

[0211] The microwave reactions were carried out in a CEM reactor using a Discovery SP system. When NMR data are shown, the spectra were obtained on a Varian-400 (400 MHz). The spectra are reported as ppm from tetramethylsilane downfield, together with the number of protons, multiplicity, and coupling constants shown in parentheses relative to the deuterated solvent in some examples. The compounds were also purified by an ISCO flash chromatography system using standard methods described in the manual.

[0212] The compounds were purified by acidic, basic, or neutral preparative HPLC methods as described in the following HPLC methods A - G.

[0213] Preparative RP-HPLC Method A : RP-HPLC (C-18, Boston Green ODS 150×30 mm×5 μm; eluent gradient: water + 0.1% TFA / acetonitrile = 81:19~51:49). Mobile phase A: water + 0.1% TFA; Mobile phase B: CH3CN; Flow rate: 30 mL / min; Detection: UV 220 nm / 254 nm; Column: Boston Green ODS 150×30 mm×5 μm; Column temperature: 30 °C.

Table 1

[0214] Preparative RP-HPLC Method B : RP-HPLC (C-18, Phenomenex Synergi C18 250×21.2 mm×4 μm; eluent gradient: water + 0.1% TFA / acetonitrile = 75:25~45:55). Mobile phase A: water + 0.1% TFA; Mobile phase B: CH3CN; Flow rate: 25 mL / min; Detection: UV 220 nm / 254 nm; Column: Phenomenex Synergi C18 250×21.2 mm×4 μm; Column temperature: 30 °C.

Table 2

[0215] Preparative RP-HPLC Method C : RP-HPLC (C-18, Phenomenex Synergi C18 250×21.2mm×4μm; Eluent gradient: water + 0.05% HCl / acetonitrile = 82:18~52:48). Mobile phase A: water containing 0.05% HCl; Mobile phase B: CH3CN; Flow rate: 30 mL / min; Detection: UV 220nm / 254nm; Column: Phenomenex Gemini 150×30mm×4μm; Column temperature: 30°C.

Table 3

[0216] Preparative RP-HPLC Method D : RP-HPLC (C-18, Phenomenex Gemini 150×25mm×10m; Eluent gradient: water + 0.05% aqueous ammonia / acetonitrile = 30:70~0:100). Mobile phase A: water containing 0.05% aqueous ammonia; Mobile phase B: CH3CN; Flow rate: 25 mL / min; Detection: UV 220nm / 254nm; Column: Phenomenex Gemini 150×25mm×10m; Column temperature: 30°C.

Table 4

[0217] Preparative RP-HPLC Method E : Mobile phase A: water containing 0.1% TFA; Mobile phase B: acetonitrile containing 0.1% TFA; Flow rate: 25 mL / min; Detection: UV 220nm / 254nm; Column: C-18 Synergi Max-RP 150×30mm×4μm; Column temperature: 30°C.

Table 5

[0218] Neutral Preparative HPLC Method F : Mobile phase A: Water Mobile phase B: CH3CN Flow rate: 120 mL / min Detection: UV 220 nm / 254 nm Column: Phenomenex Synergi Max-RP 250×50 mm×10 um Column temperature: 30 °C

Table 6

[0219] Preparative HPLC Method G : Mobile phase A: Water (10 mM NH4HCO3) Mobile phase B: CH3CN Flow rate: 25 mL / min Detection: UV 220 nm / 254 nm Column: Xtimate C18 150×25 mm×5μm Column temperature: 30 °C

Table 7

[0220] LCMS data was obtained using the following chromatography conditions: LCMS Method A : HPLC system: Waters ACQUITY; Column: Waters ACQUITY CSH (trademark) C18 1.7 μM. Guard column: Waters Assy. Frit. 0.2 μM, 2.1 mm; Column temperature: 40 °C. Mobile phase: A: TFA: Water (1:1000, v:v); Mobile phase B: TFA: ACN (1:1000, v:v); Flow rate: 0.65 mL / min; Injection volume: 2 μL; Collection time: approximately 1.5 min. Gradient program:

Table 8

[0221] Mass spectrometer: Waters SQD; Ionization: Positive electrospray ionization (ESI); Mode scan (100 - 1400 m / z every 0.2 seconds). ES capillary voltage: 3.5 kV; ES cone voltage: 25 V. Source temperature: 120 °C; Desolvation temperature: 500 °C; Desolvation gas flow: Nitrogen set at 650 (L / h). Cone gas flow: Nitrogen set at 50 (L / h).

[0222] LCMS Method B : HPLC system: Waters ACQUITY; Column: Waters ACQUITY CSH™ C18 1.7 μM. Guard column: Waters Assy. Frit. 0.2 μM, 2.1 mm; Column temperature: 40 °C. Mobile phase: A: TFA: water (1:1000, v:v). Mobile phase B: TFA: ACN (1:1000, v:v). Flow rate: 0.65 mL / min; Injection volume: 2 μL; Collection time: approximately 1.5 minutes.

Table 9

[0223] Mass spectrometer: Waters SQD; Ionization: Positive electrospray ionization (ESI); Mode scan (100 - 1400 m / z every 0.2 seconds). ES capillary voltage: 3.5 kV; ES cone voltage: 25 V. Source temperature: 120 °C; Desolvation temperature: 500 °C; Desolvation gas flow: Nitrogen set at 650 (L / h). Cone gas flow: Nitrogen set at 50 (L / h).

[0224] LCMS Method C :

Table 10

[0225] LCMS Method D :

Table 11

[0226] LCMS Method E :

Table 12

[0227] LCMS Method F :

Table 13

[0228] LCMS Method G : HPLC system: Waters ACQUITY; Column: Waters ACQUITY CSH (trademark) C18 1.7 μM; Guard column: Waters Assy. Frit. 0.2 μM, 2.1 mm; Column temperature: 40 °C. Mobile phase: A: TFA: water (1:1000, v:v);; Mobile phase B: TFA: ACN (1:1000, v:v). Flow rate: 1 mL / min; Injection volume: 2 μL; Sampling time: about 115 min.

Table 14

[0229] Mass spectrometer: Waters SQD; Ionization: Positive electrospray ionization (ESI); Mode scan (100 - 1400 m / z every 0.2 s). ES capillary voltage: 3.5 kV; ES cone voltage: 25 v. Source temperature: 120 °C; Desolvation temperature: 500 °C; Desolvation gas flow: Nitrogen set at 650 (L / h). Cone gas flow: Nitrogen set at 50 (L / h).

[0230] The following is the separation method of racemic compounds by supercritical fluid chromatography (SFC).

[0231] Method A Apparatus: Thar SFC80; Column: AD 250 mm × 30 mm, 5 μm; Mobile phase: A: supercritical CO2, B: IPA (0.05% DEA), A:B = 80:20 (at 60 mL / min). Column temperature: 38 °C; Nozzle pressure: 100 bar; Nozzle temperature: 60 °C; Evaporator temperature: 20 °C; Trimmer temperature: 25 °C; Wavelength: 220 nm.

[0232] Method B Apparatus: SFCMG2; Column: OJ 250 mm × 30 mm, 5 μm; Mobile phase: A: supercritical CO2, B: MeOH (0.05% DEA), A:B = 90:10 (at 70 mL / min). Column temperature: 38 °C; Nozzle pressure: 100 bar; Nozzle temperature: 60 °C; Evaporator temperature: 20 °C; Trimmer temperature: 25 °C; Wavelength: 220 nm.

[0233] The following is the SFC analysis (anal.) method used to characterize the final compound.

[0234] SFC analysis method A: Apparatus: Thar SFC80; Column: AD_H 4 mm × 40 mm, 5 μm; Mobile phase: A: supercritical CO2, B: IPA (0.05% DEA), A:B = 80:20 (at 4 mL / min). Run for 3 minutes, Column temperature: 38 °C; Nozzle pressure: 100 bar; Nozzle temperature: 60 °C; Evaporator temperature: 20 °C; Trimmer temperature: 25 °C; Wavelength: 220 nm.

[0235] SFC analysis method B: Apparatus: Thar SFC80; Column: AD_H 4 mm × 40 mm, 5 μm; Mobile phase: A: supercritical CO2, B: IPA (0.05% DEA), A:B = 80:20 (at 2.4 mL / min), Run for 10 minutes, Column temperature: 38 °C; Nozzle pressure: 100 bar; Nozzle temperature: 60 °C; Evaporator temperature: 20 °C; Trimmer temperature: 25 °C; Wavelength: 220 nm.

[0236] SFC analysis method C: Equipment: Thar SFC80; Column: AD_H 4mm×40mm, 5μm; Mobile phase: A: Supercritical CO2, B: IPA (0.05% DEA), A:B = 80:20 (at 2.8 mL / min), run for 13 minutes, Column temperature: 38°C; Nozzle pressure: 100 bar; Nozzle temperature: 60°C; Evaporator temperature: 20°C; Trimmer temperature: 25°C; Wavelength: 220 nm.

[0237] SFC analysis method D: Equipment: Thar SFC80; Column: AD-3, 5mm×40mm, 5μm; Mobile phase: A: Supercritical CO2, B: IPA (0.05% DEA), A:B = 80:20 (at 25 mL / min). Run for 5 minutes, Column temperature: 38°C; Nozzle pressure: 100 bar; Nozzle temperature: 60°C; Evaporator temperature: 20°C; Trimmer temperature: 25°C; Wavelength: 220 nm.

[0238] X-ray Powder Diffraction (XRPD) Method A The Rigaku MiniFlex 600 X-ray diffractometer equipped with a high-speed D / teX detector was used under the following conditions: 40 kV, 15 mA, Cu Kα line (wavelength = 1.54 Å). The 2θ scanning range was 3 - 45°, and the scanning speed was 10° / min.

[0239] X-ray powder diffraction (XRPD) method B

Table 15

[0240] X-ray Powder Diffraction (XRPD) Method C Transmission configuration The XRPD pattern was collected using an incident beam of Cu radiation generated using a long, fine-focus source from Optix with a PANalytical X'Pert PRO MPD diffractometer. An elliptically inclined multilayer mirror was used to focus the CuKα X-rays through the sample onto the detector. Prior to analysis, a silicon sample (NIST SRM 640e) was analyzed to confirm that the observed position of the Si-111 peak matched the NIST-certified position. The sample was placed between films of thickness of 3 μm and analyzed in transmission configuration. A beam stop, short anti-scatter extension, and anti-scatter knife edge were used to minimize the background generated by air. A soller slit for the incident beam and diffracted beam were used to minimize the spread from axial divergence. The diffraction pattern was collected using a scanning position-sensitive detector (X'Celerator) located 240 mm from the sample and Data Collector software v.2.2b.

[0241] Reflection configuration The XRPD pattern was collected using an incident beam of Cu Kα radiation generated using a long, fine-focus source and a nickel filter with a PANalytical X'Pert PRO MPD diffractometer. The diffractometer was configured using the symmetric Bragg-Brentano configuration. Prior to analysis, a silicon sample (NIST SRM 640e) was analyzed to confirm that the observed position of the Si-111 peak matched the NIST-certified position. The sample was prepared as a thin circular layer centered on a silicon zero-background substrate. An anti-scatter slit (SS) was used to minimize the background generated by air. A soller slit for the incident beam and diffracted beam were used to minimize the spread from axial divergence. The diffraction pattern was collected using a scanning position-sensitive detector (X'Celerator) located 240 mm from the sample and Data Collector software v.2.2b.

[0242] Differential Scanning Calorimetry (DSC) DSC measurements were performed using a TA Instruments 2920 differential scanning calorimeter. Temperature calibration was performed using NIST-traceable indium metal.

[0243] Dynamic Vapor Sorption / Desorption (DVS) Water adsorption / desorption data were collected using a VTI SGA-100 vapor sorption analyzer. NaCl and PVP were used as calibration standards. The samples were not dried before analysis. Adsorption and desorption data were collected in nitrogen purge at 10% RH increments in the range of 5% - 95% RH. The equilibrium criterion used for analysis was a weight change of less than 0.0100% in 5 minutes, and the maximum equilibrium time was 3 hours. Data were not corrected for the initial water content of the samples.

[0244] Thermogravimetric Analysis (TGA) TG analysis was performed using a TA Instruments Q5000 IR thermogravimetric analyzer. Temperature calibration was performed using nickel and ALUMEL (trademark). Each sample was prepared in a platinum pan, and the furnace was heated under nitrogen.

[0245] The present invention will be described by the following examples, and the following abbreviations may be used therein:

Table 16

[0246] Intermediate 1 5-(2-Bromo-4-fluorophenoxy)-4-chloropyrimidine

Chemical formula

[0247] Step 1: Ethyl 2-(2-bromo-4-fluorophenoxy)acetate

Chemical formula

[0248] To a solution of 2-bromo-4-fluorophenol (250 g, 1.31 mol) in CH3CN (2 L) were added K2CO3 (270 g, 1.97 mol) and ethyl 2-bromoacetate (219 g, 1.31 mol). The suspension was heated at 90 °C for 1.5 h. The mixture was filtered, and the filtrates were combined to give crude ethyl 2-(2-bromo-4-fluorophenoxy)acetate as a brown oil, which was used directly in the next step.Yield: 312 g; 1 H NMR (CDCl3): δ 7.32 (dd, J = 7.6, 3.2 Hz, 1H), 6.95 - 6.97 (m, 1H), 6.82 (dd, J = 8.8, 4.4 Hz, 1H), 4.66 (s, 2H), 4.27 (q, J = 7.2 Hz, 2H), 1.31 (t, J = 7.2 Hz, 3H). 1 F NMR (CDCl3): δ -120.06 (s, 1F).

[0249] Step 2: 5-(2-Bromo-4-fluorophenoxy)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one

Chemical Structure

[0250] To a solution of ethyl 2-(2-bromo-4-fluorophenoxy)acetate (100 g) in anhydrous THF (2 L), ethyl formate (108 g) and NaH (20 g) were added at 0 °C. The mixture was stirred at 35 - 45 °C for 18 h. The solvent was removed under vacuum, anhydrous EtOH (2 L) and thiourea (25 g, 324.8 mmol) were added, and the mixture was stirred at 90 °C for 16 h. The mixture was concentrated, diluted with water (2 L), and extracted with petroleum ether:ethyl acetate (10:1; 500 mL × 3). When the aqueous layer was acidified to pH = 4 with hydrochloric acid (1 N, 200 mL), a white solid precipitated. The mixture was filtered, and the obtained filter cake was dried to give crude 5-(2-bromo-4-fluorophenoxy)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (62 g) as a white solid, which was used directly in the next step without purification. Yield: 62 g; LCMS method C: Rt = 0.638 min; (M + H) + = 316.9, 318.9 (chlorine isotope).

[0251] Step 3: 5-(2-Bromo-4-fluorophenoxy)pyrimidin-4-ol

Chemical formula

[0252] To a solution of 5-(2-bromo-4-fluorophenoxy)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (62 g) in anhydrous EtOH (1.5 L), Raney nickel (62 g) was added, and the mixture was heated to reflux for 6 h. The solvent was removed under vacuum, and anhydrous EtOH (2 L) was added. The mixture was filtered, and the filtrate stock was concentrated to give crude 5-(2-bromo-4-fluorophenoxy)pyrimidin-4-ol as a gray solid. Yield: 55 g. LCMS method C: Rt = 0.619 min, (M + H) + = 284.9, 287.0 (chlorine isotope).

[0253] Step 4: 5-(2-Bromo-4-fluorophenoxy)-4-chloropyrimidine A solution of 5-(2-bromo-4-fluorophenoxy)pyrimidin-4-ol (55 g) in SOCl2 (500 mL) was added with anhydrous DMF (5 mL). The mixture was heated at 70 °C for 4 h. The mixture was concentrated, dissolved in DCM (500 mL), then poured into saturated NaHCO3 (aqueous solution) (500 mL), and stirred at room temperature for 2 h. The organic layer was separated, dried over Na2SO4, filtered, and concentrated. Next, the residue was purified by an ISCO column of silica gel (from 100% petroleum ether to EtOAc:petroleum ether = 9:1) to obtain 5-(2-bromo-4-fluorophenoxy)-4-chloropyrimidine as a pale yellow solid. Yield: 32 g. LCMS method C: Rt = 0.858 min, (M+H) + = 302.9, 304.9 (chlorine and bromine isotopes); 1 1H NMR (CDCl3): δ 8.77 (s, 1H), 8.07 (s, 1H), 7.45 (dd, J = 7.6 3.2 Hz, 1H), 7.06 - 7.12 (m, 2H). 1 19F NMR (CDCl3): δ -113.64 (s, 1F).

[0254] Intermediates 2 - 10a The following intermediates were prepared according to the procedure described for Intermediate 1.

Table 17-1

Table 17-2

[0255] Intermediate 11 tert-Butyl 7-(5-(2-bromo-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate

Chemical formula

[0256] A solution of 5-(2-bromo-4-fluorophenoxy)-4-chloropyrimidine (Intermediate 1, 4 g, 13.18 mmol), tert-butyl 2,7-diazaspiro[4.4]nonane-2-carboxylate (3.0 g, 13.18 mmol), and K2CO3 (7.3 g, 52.72 mmol) in CH3CN (100 mL) was stirred at 95 °C for 8 h. The solid was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with petroleum ether:ethyl acetate = 10:1 to 3:2) to give tert-butyl 7-(5-(2-bromo-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (Intermediate 11) as a yellow oil. Yield: 9.5 g; HPLC method C: Rt = 0.749 min; (M+H) + = 493.0, 495.1 (bromine isotopes); 1 1H NMR (CD3OD): δ 8.29 (s, 1H), 7.66 (s, 1H), 7.54 (d, J = 2.8 Hz, 1H), 7-16 (d, J = 6.0 Hz, 1H), 6.96 (d, J = 4.8 Hz, 1H), 3.67 - 3.81 (t, 4H), 3.37 (s, 2H), 3.23 - 3.27 (m, 2H), 1.87 - 1.96 (t, 4H), 1.44 (s, 9H). 19 19F NMR (CD3OD): δ -119.01.

[0257] Intermediates 12 - 19 The following intermediates were prepared according to the procedure described for Intermediate 11.

Table 18-1

Table 18-2

Table 18-3

[0258] Intermediate 20 tert-Butyl 6-(5-(2-bromo-4-fluorophenoxy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

Chem.

[0259] To a solution of 5-(2-bromo-4-fluorophenoxy)-4-chloropyrimidine (Intermediate 1, 5.55 g, 18.4 mmol) in CH3CN (80 mL) were added tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (3.62 g, 18.4 mmol) and Na2CO3 (3.89 g, 36.74 mmol). The mixture was stirred at 90 - 95 °C for 16 h. The mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 0:1) to give tert-butyl 6-(5-(2-bromo-4-fluorophenoxy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate as a yellow solid. Yield: 6.5 g; HPLC Method C: Rt = 0.742 min, (M+H) + = 465.0, 467.0 (bromine isotopes).

[0260] Intermediates 20a - 25 The following intermediates were prepared according to the procedure described for Intermediate 20.

Table 19-1

Table 19-2

[0261] Intermediate 26 2-(5-(4-Fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane

Chem.

[0262] Step 1: 7-(5-(4-Fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylic acid tert-butyl

Chem.

[0263] To a suspension of 7-(5-(2-bromo-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylic acid tert-butyl (Intermediate 11, 200 mg, 0.40 mmol), (4-isopropylpyrimidin-5-yl)boronic acid (130 mg, 0.80 mmol), and K3PO4 (170 mg, 0.80 mmol) in dioxane (6 mL) and H2O (2 mL), Esphosparadacycle (14.4 mg, 0.02 mmol) was added under an N2 atmosphere, and the mixture was stirred at 90 °C for 16 h. The reaction mixture was washed with water (80 mL) and extracted with EtOAc (3 × 50 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC on silica gel (petroleum ether:EtOAc = 1:1, R f = 0.25) to give 7-(5-(4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylic acid tert-butyl as a white solid. Yield: 110 mg; HPLC Method C: Rt = 0.759 min; (M+H) + = 535.2. [[ID=CHEM18]]

[0264] Step 2: 2-(5-(4-Fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane A solution of tert-butyl 7-(5-(4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (100 mg, 1.87 mmol) in CH2Cl2 (3 mL) was treated with TFA (1 mL). The mixture was stirred at 20 - 25 °C for 2 h. Next, the reaction mixture was neutralized with NH3-H2O (pH = 8), washed with water (80 mL), and extracted with CH2Cl2 (3 × 50 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give crude 2-(5-(4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)2,7-diazaspiro[4.4]nonane as a yellow solid, which was used in the next step without further purification. Yield: 90 mg; HPLC method C: Rt = 0.575 min; (M + H) + = 435.2.

[0265] Intermediates 27 - 32 The following intermediates were prepared according to the procedure described for Intermediate 26.

Table 20-1

Table 20-2

[0266] Intermediate 33 2-((4-(2,7-Diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropyl-N-methylbenzamide

Chemical formula

[0267] Step 1: tert-Butyl 7-(5-(4-fluoro-2-(methoxycarbonyl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate

Chemical formula

[0268] To a solution of 7-(5-(2-bromo-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylic acid tert-butyl (Intermediate 11, 9.5 g, 19.31 mmol) and Pd(dppf)Cl2 (7.1 g, 9.66 mmol) were added Et3N (13.4 mL) and MeOH (100 mL). The reaction mixture was then stirred at 65 °C under CO (50 psi) for about 16 h. The reaction solution was filtered through celite and concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (eluting with DCM:MeOH = 1:0 to 10:1) to give 7-(5-(4-fluoro-2-(methoxycarbonyl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylic acid tert-butyl as a brown oil. Yield: 9.0 g; LC-MS method E: Rt = 0.914 min; (M+H) + = 473.2。

[0269] Step 2: 2-((4-(7-(tert-butoxycarbonyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluorobenzoic acid

Chemical formula

[0270] A solution of tert-butyl 7-(5-(4-fluoro-2-(methoxycarbonyl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (3.3 g, 6.99 mmol) in MeOH (30 mL), THF (30 mL), and H2O (10 mL) was added with KOH (0.78 g, 13.98 mmol). The mixture was stirred at 13 - 23 °C for 16 h. The mixture was concentrated and adjusted to pH = 3 - 4 with aqueous HCl (3 mol / L). The mixture was extracted with EtOAc (3 × 50 mL), and the combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated to obtain crude 2-((4-(7-(tert-butoxycarbonyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluorobenzoic acid as a brown solid, which was used directly without further purification. Yield: 3.2 g; LCMS method C: Rt = 0.702 min, (M + H) + = 459.0。 1 H NMR (DMSO-d6): δ 8.30 (s, 1 H), 7.39 - 7.69 (m, 3 H), 6.95 - 7.05 (m, 1 H), 3.60 - 3.72 (m, 5 H), 3.17 (s, 3 H), 1.77 - 1.88 (m, 4 H), 1.38 (s, 9 H). 19 F NMR (DMSO-d6): δ -119.13。

[0271] Step 3: tert-butyl 7-(5-(4-fluoro-2-isopropyl(methyl)carbamoyl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate

Chemical Structure

[0272] To a solution of 2-((4-(7-(tert-butoxycarbonyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluorobenzoic acid (2.9 g, 5.45 mmol) and N-methylpropan-2-amine (0.6 g, 8.18 mmol) in DCM (100 mL) were added HATU (3.1 g, 8.18 mmol) and DIPEA (2.1 g, 16.3 mmol). The mixture was stirred at 13 - 21 °C for 16 h. The mixture was concentrated and the residue was purified by neutral preparative HPLC to give tert-butyl 7-(5-(4-fluoro-2-isopropyl(methyl)carbamoyl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate. Yield: 2.1 g; LCMS method E: Rt = 0.731 min, (M + H) + = 514.1. 1 H NMR (DMSO-d6): δ 8.30 - 8.33 (m, 1 H), 7.77 - 7.82 (m, 1 H), 7.19 - 7.29 (m, 2 H), 6.87 - 6.97 (m, 1 H), 4.67 (s, 1 H), 3.56 - 3.78 (m, 6 H), 3.15 - 3.17 (m, 2 H), 2.67 - 2.83 (m, 3 H), 1.79 - 1.84 (m, 4 H), 1.38 (s, 9 H), 1.06 - 1.11 (m, 6 H). 19 F NMR (DMSO-d6): δ -111.36.

[0273] Step 4: 2-((4-(2,7-Diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropyl-N-methylbenzamide A solution of tert-butyl 7-(5-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (1 g, 1.95 mmol) in anhydrous DCM (10 mL) was slowly added with HCl-MeOH (2 mL, 4 mol / L in MeOH) at 0 °C under N2. The reaction mixture was stirred at 17 - 23 °C for 16 h. The mixture was adjusted to pH = 11 - 12 with aqueous NaOH solution (1 mol / L), and then extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain crude 2-((4-(2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropyl-N-methylbenzamide as a brown solid. Yield: 0.8 g (95% crude product). LCMS method C: Rt = 0.508 min, (M + H) + = 414.0。

[0274] Intermediates 35 - 39 The following intermediates were prepared according to the procedure provided for Intermediate 33.

Table 21-1

Table 21-2

[0275] Intermediate 40 2-Oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbaldehyde

Chem.

[0276] To a suspension of 2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrile (10 g, 57.75 mmol) in HCO2H (187 mL) and H2O (63 mL), Ni-Al alloy (6.19 g, 144.38 mmol) was added portionwise. Next, the mixture was stirred at 90 °C for 16 h. The reaction mixture was filtered, the filtrate was washed with EtOH, and concentrated under reduced pressure. The residue was washed with water (150 mL) and filtered. The filter cake was dried under reduced pressure to afford 2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbaldehyde as an off-white solid. Yield: 9.1 g (97.2%). LCMS Method D: Rt = 1.404 min, (M+H) + = 163.0。 1 H NMR (CD3OD): δ 9.87 (s, 1H), 7.65 (dd, J = 8.4, 1.2 Hz, 1H), 7.55 (s, 1H), 7.19 (d, J = 8.0 Hz, 1H).

[0277] Intermediate 41 2-((4-Chloropyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Chem.

[0278] Step 1: Methyl 5-fluoro-2-methoxybenzoate

Chem.

[0279] To a solution of 5-fluoro-2-hydroxybenzoic acid (100 g, 641 mmol) in acetone (1000 mL) were added K2CO3 (190 g, 1380 mmol) and MeI (268.3 g, 1890 mmol). The mixture was stirred at 50 °C for 16 h. The mixture was filtered and concentrated under reduced pressure. The residue was mixed with EtOAc (500 mL) and washed with H2O (3 × 300 mL). The organic layer was then dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether:ethyl acetate = 20:1 to give methyl 5-fluoro-2-methoxybenzoate. Yield: 78 g (66%). 1 1H NMR (CDCl3): δ 7.50 (dd, J = 3.6 Hz, 8.8 Hz, 1H), 7.17 - 7.18 (m, 1H), 6.92 (dd, J = 4.0 Hz, 8.8 Hz 1H), 3.89 (s, 3H), 3.88 (s, 3H).

[0280] Step 2: 5-Fluoro-2-methoxybenzoic acid

Chemical formula

[0281] To a solution of methyl 5-fluoro-2-methoxybenzoate (25 g, 135.9 mmol) in MeOH (250 mL) and H2O (50 mL) was added KOH (25 g, 446.4 mmol). The mixture was stirred at 60 °C for 3 h. The mixture was then adjusted to pH 3 - 4 with 2N HCl solution and concentrated to remove MeOH under reduced pressure. The residue was mixed with EtOAc (200 mL) and washed with H2O (2 × 200 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give crude 5-fluoro-2-methoxybenzoic acid as a white solid, which was used in the next step without further purification. Yield: 23 g.

[0282] Step 3: 5-Fluoro-N,N-diisopropyl-2-methoxybenzamide

Chemical formula

[0283] To a solution of 5-fluoro-2-methoxybenzoic acid (20 g, 117.6 mmol) and diisopropylamine (23.8 g, 235.6 mmol) in anhydrous CH2Cl2 (300 mL), DIEA (22.8 g, 176.7 mmol) and HATU (53.6 g, 141.4 mmol) were added at 0 °C. The mixture was stirred at 25 °C for 16 h. Next, the mixture was washed with H2O (3 × 200 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether:ethyl acetate = 5:1 to give 5-fluoro-N,N-diisopropyl-2-methoxybenzamide as a white solid. Yield: 22 g. LCMS method C: Rt value: 0.785 min, (M + H) + = 254.0.

[0284] Step 4: 5-Fluoro-2-hydroxy-N,N-diisopropylbenzamide

Chemical formula

[0285] To a solution of 5-fluoro-N,N-diisopropyl-2-methoxybenzamide (15 g, 59.3 mmol) in anhydrous CH2Cl2 (250 mL), BBr3 (11 mL, 116.6 mmol) was added dropwise at -70 °C. The mixture was stirred at 5 °C for 16 h. The reaction mixture was quenched slowly with MeOH (30 mL) at -78 °C and adjusted to pH 7 - 8 with saturated NaHCO3 solution. The mixture was extracted with EtOAc (2 × 300 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether:ethyl acetate = 4:1 to give 5-fluoro-2-hydroxy-N,N-diisopropylbenzamide as a white solid. Yield: 11 g. LCMS method C: Rt = 0.744 min; (M + H) + = 240.0.

[0286] Step 5: 5-Fluoro-N,N-diisopropyl-2-(pyrimidin-5-yloxy)benzamide

Chem.

[0287] To a solution of 5-fluoro-2-hydroxy-N,N-diisopropylbenzamide (11.0 g, 46.0 mmol) and 5-bromopyrimidine (21.8 g, 138.0 mmol) in anhydrous DMF (300 mL) was added Cs2CO3 (45.0 g, 138.0 mmol). The mixture was stirred at 130 °C for 16 h. The mixture was added to EtOAc (500 mL) and washed with H2O (3 × 300 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether:ethyl acetate = 3:1 to give 5-fluoro-N,N-diisopropyl-2-(pyrimidin-5-yloxy)benzamide as a white solid. Yield: 14 g (97%). LCMS method C: Rt = 0.731 min; (M + H) + = 317.9。

[0288] Step 6: 5-(2-(Diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-1-oxide

Chem.

[0289] To a solution of 5-fluoro-N,N-diisopropyl-2-(pyrimidin-5-yloxy)benzamide (14 g, 44.2 mmol) in anhydrous CH2Cl2 (400 mL) was added m-CPBA (27 g, 132.7 mmol). The mixture was stirred at 10 °C for 16 h. The reaction mixture was quenched with saturated Na2SO3 solution (200 mL) and washed with NaHCO3 (2 × 200 mL). The organic layer was dried over anhydrous Na2CO3, filtered, and concentrated under reduced pressure to give crude 5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidine 1-oxide as a pale yellow solid, which was used in the next step without further purification. Yield: 16 g (109%). LCMS method C: Rt = 0.705 min, (M + H) + = 333.9.

[0290] Step 7: 2-((4-Chloropyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide To a solution of Et3N (7.3 g, 72.3 mmol) in CHCl3 (30 mL) was added POCl3 (12.5 g, 81.7 mmol) at 0 °C. Next, the mixture was slowly added to a solution of 5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidine-1-oxide (16.0 g, 48.0 mmol) in CHCl3 (270 mL) at 0 °C. The mixture was stirred at 65 °C for 16 h. Next, the mixture was slowly added to saturated NaHCO3 solution (500 mL), and the pH was adjusted to 7 - 8 with saturated NaHCO3 solution. The mixture was extracted with ethyl acetate (2 × 300 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether:ethyl acetate = 5:1 to give 2-((4-chloropyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide (6 g) as a yellow solid. HPLC method C: Rt = 0.735 min, (M + H) + = 351.9. 11H NMR (CDCl3): δ 8.71 (s, 1H), 8.21 (s, 1H), 7.02 - 7.12 (m, 3H), 3.73 - 3.80 (m, 1H), 3.46 - 3.53 (m, 1H), 1.49 (d, J = 6.8 Hz, 3H), 1.34 (d, J = 6.8 Hz, 3H), 1.26 (d, J = 6.4 Hz, 3H), 1.14 (d, J = 6.8 Hz, 3H). 19 19F NMR (CDCl3): δ -114.5。

[0291] Intermediate 41a 2-((4-(2,6-Diazaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Chemical Structure

[0292] The title compound was synthesized from Intermediate 41 and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate by the method described for the preparation of Intermediate 20. LCMS - Method C: 0.620 min, (M + H) + = 413.2。

[0293] Intermediates 41b - 41f The following intermediates were prepared according to the procedures described for Intermediates 41 and 41a.

Table 22

[0294] Intermediates 42 and 42c 1-(2-Hydroxyethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbaldehyde and 2-(5-formyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethyl formate

Chemical Structure

[0295] Step 1: 4-((2-Hydroxyethyl)amino)-3-nitrobenzonitrile

Chem.

[0296] To a solution of 4-fluoro-3-nitrobenzonitrile (15 g, 90.4 mmol) and 2-aminoethanol (11.0 g, 180.7 mmol) in anhydrous DMF (600 mL) was added K2CO3 (37.4 g, 271.2 mmol) under N2, and then the reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was washed with H2O (100 mL) and the mixture was extracted with EtOAc (3 × 500 mL). The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give 4-((2-hydroxyethyl)amino)-3-nitrobenzonitrile. The residue was used in the next step as a yellow solid without further purification. Yield: 17.3 g. LCMS method E: Rt = 1.016 min; (M + H) + = 207.9.

[0297] Step 2: 3-Amino-4-((2-hydroxyethyl)amino)benzonitrile

Chem.

[0298] A solution of 4-((2-hydroxyethyl)amino)-3-nitrobenzonitrile (17.3 g, 83.6 mmol) in EtOH (800 mL) and H2O (400 mL) was added with Fe (23.4 g, 418.0 mmol) and NH4Cl (44.8 g, 836.0 mmol) under N2. The reaction mixture was stirred at 80 °C for 2 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in EtOAc (500 mL), washed with H2O (2 × 100 mL) and brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated to obtain 3-amino-4-((2-hydroxyethyl)amino)benzonitrile. The residue was used in the next step as a reddish-brown solid without further purification. Yield: 11.6 g. LCMS method D: Rt = 0.941 min; (M + H) + = 178.2.

[0299] Step 3: 3-Amino-4-((2-((tert-butyldimethylsilyl)oxy)ethyl)amino)benzonitrile

Chemical Structure

[0300] To a solution of 3-amino-4-((2-hydroxyethyl)amino)benzonitrile (11.6 g, 65.46 mmol) and tert-butyldimethylsilyl chloride (11.84 g, 78.55 mmol) in anhydrous DMF (300 mL) was added imidazole (11.14 g, 163.65 mmol), and then the reaction solution was stirred at 35 °C for 16 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The reaction mixture was added to water (1000 mL) and extracted with EtOAc (3 × 500 mL). The organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain 3-amino-4-((2-((tert-butyldimethylsilyl)oxy)ethyl)amino)benzonitrile as a black oil, which was used in the next step without further purification. Yield: 25 g. LCMS method C: Rt = 0.878 min; (M + H) + = 292.1.

[0301] Step 4: 1-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrile

Chem.

[0302] To a solution of 3-amino-4-((2-((tert-butyldimethylsilyl)oxy)ethyl)amino)benzonitrile (14 g, 48.1 mmol) in anhydrous THF (400 mL) was added BTC (28.5 g, 96.2 mmol) at 0 °C. Next, Et3N (33 mL) was added dropwise to the mixture at 0 °C. After the addition, the reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was poured into saturated aqueous NaHCO3 (500 mL) and extracted with EtOAc (3 × 300 mL). The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluted with petroleum ether:EtOAc = 5:1 to 1:1) to obtain 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrile. Yield: 4.8 g (31%). LCMS method F: Rt = 1.378 min, (M+H) + = 318.3, 1 1H NMR (CDCl3): δ 10.06 (brs, 1 H), 7.31 (d, J = 8.4 Hz, 1 H), 7.16 (s, 1H), 7.11 (d, J = 8.0 Hz, 1 H), 3.94 - 3.96 (m, 2 H), 3.83 - 3.85 (m, 2 H), 0.67 (s, 9 H), -0.198 (s, 6H).

[0303] Step 5: 1-(2-Hydroxyethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbaldehyde and 2-(5-formyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethyl formate

Chem.

[0304] To a solution of 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbonitrile (6.1 g, 19.2 mmol) in HCOOH (120 mL) and HO (40 mL) under N was added a solution of Ni—Al (8.27 g, 96.2 mmol), and the reaction mixture was then stirred at 90° C. for 16 h. The reaction mixture was then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with DCM:MeOH=10:1) to give 1-(2-hydroxyethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbaldehyde as a white solid and 2-(5-formyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethyl formate as a yellow solid.

[0305] Intermediate 42: 2-(5-formyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethyl formate: Yield: 1.7 g (27%). LCMS Method F: Rt=0.858 min; (M+H) + = 235.2, 1 H NMR (DMSO-d6): δ 11.27 (brs, 1 H), 9.87 (s, 1 H), 8.12 (s, 1H), 7.63 (dd, J = 8.0, 1.2 Hz, 1 H), 7.42 (s, 1H), 7.37 (d, J = 8.0 Hz, 1 H), 4.35-4.38 (m, 2H), 4.12-4.14 (m, 2H).

[0306] Intermediate 42c: 1-(2-hydroxyethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbaldehyde: Yield: 1.5 g (27%). LCMS Method F: Rt=0.788 min; (M+H) + = 207.2, 11H NMR (DMSO-d6): δ 11.20 (brs, 1 H), 9.86 (s, 1 H), 7.60 (d, J = 8.0 Hz, 1 H), 7.40 (s, 1H), 7.31 (d, J = 8.0 Hz, 1 H), 4.86 (s, 1 H), 3.85-3.86 (m, 2 H), 3.63-3.65 (m, 2 H).

[0307] Intermediate 42a 1-(2-Methoxyethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbaldehyde

Chem.

[0308] The title product was prepared starting from 2-methoxyethan-1-amine according to the procedure provided for Intermediate 41. LCMS Method F: Rt = 0.828 min; (M+H) + = 221.2.

[0309] Intermediate 42b 1-Ethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbaldehyde

Chem.

[0310] The title product was prepared starting from ethylamine according to the procedure provided for Intermediate 41. LCMS Method F: Rt = 0.868 min; (M+H) + = 191.2.

[0311] Intermediate 43 2-((4-Chloropyrimidin-5-yl)oxy)-5-fluoro-N-isopropyl-N-methylbenzamide

Chem.

[0312] Project 1: 5-(2-Bromo-4-fluorophenoxy)pyrimidine

Chem.

[0313] To a solution of 2-bromo-4-fluorophenol (6 g, 31.41 mmol) and 5-bromopyrimidine (5.7 g, 36.12 mmol) in anhydrous DMF (60 mL), Cs2CO3 (30.7 g, 94.23 mmol) was added under N2. The reaction mixture was stirred at 130 °C for 16 h. Next, the reaction mixture was filtered through celite and diluted with H2O (60 mL). The mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (3 × 100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 5-(2-bromo-4-fluorophenoxy)pyrimidine as a brown oil, which was used directly in the next step. Yield: 6.5 g. LCMS method F: Rt = 0.969 min, (M + H) + = 269.1。

[0314] Project 2: 5-Fluoro-N-isopropyl-N-methyl-2-(pyrimidin-5-yloxy)benzamide

Chem.

[0315] A solution of 5-(2-bromo-4-fluorophenoxy)pyrimidine (5.5 g, crude, 20.45 mmol) and N-methylpropan-2-amine (12 g, 163.60 mmol) in anhydrous DMF (60 mL) was added with Pd(dppf)Cl2 (3 g, 4.09 mmol) and Et3N (14 mL, 102.25 mmol, d = 0.726 g / mL) under a CO atmosphere. The reaction mixture was stirred at 80 °C for 20 h at 50 psi. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (eluted with petroleum ether:EtOAc = 10:1 to 1:1) to give 5-fluoro-N-isopropyl-N-methyl-2-(pyrimidin-5-yloxy)benzamide as a brown oil. Yield: 3.5 g. LCMS method E: Rt = 0.700 min; (M+H) + = 290.1.

[0316] Step 3: 5-(4-Fluoro-2-(isopropyl(methyl)carbamoyl)phenoxy)pyrimidin-1-oxide [Chemical formula]

[0317] To a solution of 5-fluoro-N-isopropyl-N-methyl-2-(pyrimidin-5-yloxy)benzamide (1.8 g, 6.22 mmol) in anhydrous CH2Cl2 (80 mL) was added m-CPBA (2.6 g, 15.55 mmol) under N2. The reaction mixture was stirred at 11 - 20 °C for 30 h. The reaction mixture was quenched with saturated NaHSO3 solution (100 mL) and extracted with CH2Cl2 (3 × 100 mL). The combined organic layers were washed with saturated NaHCO3 solution (3 × 100 mL), brine (3 × 100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 5-(4-fluoro-2(isopropyl(methyl)carbamoyl)phenoxy)pyrimidin-1-oxide as a yellow solid, which was used directly in the next step. Yield: 1.6 g; LCMS method F: Rt = 0.886 min; (M+H) + = 306.1.

[0318] Step 4: 2-((4-Chloropyrimidin-5-yl)oxy)-5-fluoro-N-isopropyl-N-methylbenzamide

Chem.

[0319] To a solution of Et3N (1.1 mL, 7.86 mmol, d = 0.726 g / mL) and POCl3 (1.2 g, 7.86 mmol) in CHCl3 (5 mL), 5-(4-Fluoro-2-(isopropyl(methyl)carbamoyl)phenoxy)pyrimidine-1-oxide (1.6 g, 5.24 mmol) in CHCl3 (15 mL) was slowly added under N2. The reaction mixture was stirred at 65 °C for 16 h. Then the reaction mixture was quenched with saturated NaHCO3 solution (100 mL) and extracted with CH2Cl2 (3 × 80 mL). The combined organic layers were washed with brine (3 × 80 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (petroleum ether:EtOAc = 20:1~3:1) to afford 2-((4-Chloropyrimidin-5-yl)oxy)-5-fluoro-N-isopropyl-N-methylbenzamide as a yellow solid. Yield: 470 mg. LCMS method E: Rt = 0.982 min; (M+H) + = 324.2。

[0320] Intermediate 43a 5-(2-(Benzyloxy)-4-fluorophenoxy)-4-chloropyrimidine

Chem.

[0321] The title product was synthesized starting from 2-(benzyloxy)-4-fluorophenol according to the procedure described for Intermediate 43. LCMS method B: Rt = 2.13 min; (M+H) + = 313.3。 11H NMR (CDCl3, 400 MHz): δ 8.66 (s, 1H), 8.03 (s, 1H), 7.32 - 7.27 (m, 3H), 7.19 - 7.15 (m, 3H), 6.84 - 6.81 (m, 1H), 6.76 - 6.71 (m, 1H), 5.02 (s, 2H).

[0322] Intermediate 43b tert-Butyl 7-(5-(4-fluoro-2-hydroxyphenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate

Chem.

[0323] Step 1: tert-Butyl 7-(5-(2-(benzyloxy)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate

Chem.

[0324] To a solution of 5-(2-(benzyloxy)-4-fluorophenoxy)-4-chloropyrimidine (0.80 mmol) and tert-butyl 2,7-diazaspiro[4.4]nonane-2-carboxylate (218 mg, 0.96 mmol) in iPrOH (2 mL) was added Hunig's base (285 μL, 1.60 mmol). The reaction mixture was heated in a microwave reactor at 120 °C for 90 min. After cooling to room temperature, the mixture was diluted with H2O (10 mL) and extracted with EtOAc (3 × 15 mL). The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by silica gel flash chromatography eluting with 3% MeOH / DCM to give 170 mg of tert-butyl 7-(5-(2-(benzyloxy)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate as an orange oil. LCMS Method B: Rt = 1.71 min; (M+H)+ = 521.7.

[0325] Process 2: 7-(5-(4-Fluoro-2-hydroxyphenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylic acid tert-butyl To a solution of tert-butyl 7-(5-(2-(benzyloxy)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (160 mg, 0.3 mmol) in MeOH (5 mL) was added palladium-on-carbon (5% on dry basis, 33 mg, 30 μmol). The mixture was stirred at room temperature for 3 h under a hydrogen balloon atmosphere and filtered through a Celite pad. The filtrate was then concentrated under reduced pressure. The crude product was used directly in the next step reaction without further purification. LCMS Method B: Rt = 1.56 min; (M+H) + = 431.

[0326] Intermediate 44 N-(2-(5-Formyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethyl)acetamide [Chemical formula]

[0327] Process 1: N-(2-((4-Cyano-2-nitrophenyl)amino)ethyl)acetamide [Chemical formula]

[0328] A solution of 4-fluoro-3-nitrobenzonitrile (200 mg, 1.2 mmol) and N-(2-aminoethyl)acetamide (245 mg, 2.4 mmol) in anhydrous DMF (10 mL) was added with K2CO3 (496 mg, 3.6 mmol) under N2, and then the reaction mixture was stirred at 14 - 20 °C for 4 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Next, the residue was extracted with H2O (10 mL) and EtOAc (3 × 20 mL). The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to obtain N-(2-((4-cyano-2-nitrophenyl)amino)ethyl)acetamide. The residue was used in the next step as a yellow solid without further purification. Yield: 250 mg. LCMS method D: Rt = 1.256 min, (M + H) + = 249.1.

[0329] Step 2: N-(2-((2-Amino-4-cyanophenyl)amino)ethyl)acetamide [Chemical formula]

[0330] To a solution of N-(2-((4-cyano-2-nitrophenyl)amino)ethyl)acetamide (250 mg, 1.0 mmol) in EtOH (10 mL) and H2O (5 mL) were added Fe (280 mg, 5.0 mmol) and NH4Cl (530 mg, 10 mmol) under N2. The reaction mixture was stirred at 80 °C for 2 h. Then the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was extracted with H2O (10 mL) and EtOAc (20 mL). The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to obtain N-(2-((2-amino-4-cyanophenyl)amino)ethyl)acetamide. The residue was used in the next step as a brown solid without further purification. Yield: 200 mg. LCMS method F: Rt = 0.992 min, (M + H) + = 219.1.

[0331] Process 3: N-(2-(5-Cyano-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethyl)acetamide

Chemical formula

[0332] To a solution of N-(2-((2-Amino-4-cyanophenyl)amino)ethyl)acetamide (10 mg, 0.046 mmol) in anhydrous THF (4 mL) was added Et3N (0.5 mL), and then a solution of BTC (27 mg, 0.092 mmol) in anhydrous THF (2 mL) was added dropwise to this mixture at 0 °C. After the addition, the reaction mixture was stirred at 3 - 14 °C for 12 hours. The reaction mixture was extracted with H2O (5 mL) and EtOAc (20 mL × 3). The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluted with CH2Cl2:MeOH = 1:0 - 10:1) to obtain N-(2-(5-Cyano-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethyl)acetamide as a brown oil. Yield: 20 mg. LCMS method F: Rt = 1.175 min; (M+H) + = 245.2。

[0333] Process 4: N-(2-(5-Formyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethyl)acetamide A solution of N-(2-(5-cyano-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethyl)acetamide (20 mg, 0.082 mmol) in HCOOH (3 mL) and H2O (1 mL) was added with Ni-Al (35 mg, 0.41 mmol), and then the reaction mixture was stirred at 90 °C for 12 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain N-(2-(5-formyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethyl)acetamide (15 mg, purity 92%, 75%). The residue was used in the next step as a brown solid without further purification. Yield: 15 mg. LCMS method F: Rt = retention time value: 0.773 min; (M + H) + = 248.1.

[0334] Intermediate 44a 1-(2-(dimethylamino)ethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbaldehyde

Chemical Structure

[0335] The title product was synthesized starting from N1,N1-dimethylethane-1,2-diamine and 4-fluoro-3-nitrobenzonitrile according to the procedure described for Intermediate 44. LCMS method F: Rt = 0.773 min; (M + H) + = 233.1.

[0336] Intermediate 45 3,3-dimethyl-2-oxoindoline-6-carbaldehyde

Chemical Structure

[0337] A solution of 6-bromo-3,3-dimethylindolin-2-one (502 mg, 2.09 mmol) in DMF (10 mL) under a N2 atmosphere was added with Pd(OAc)2 (14 mg, 0.063 mmol), N-formyl saccharin (662 mg, 3.14 mmol), dppb (39 mg, 0.094 mmol), Na2CO3 (315 mg, 3.16 mmol), and Et3SiH (316 mg, 2.72 mmol). The resulting mixture was heated at 80 °C for 16 h. The reaction mixture was diluted with EtOAc, washed with H2O and brine, dried over anhydrous Na2SO4, and filtered. Then the filtrate was concentrated to dryness. The residue was purified by flash chromatography to obtain 70 mg of 3,3-dimethyl-2-oxoindoline-6-carbaldehyde. LCMS method B: Rt = 1.63 min; (M + H) + = 190.

[0338] Intermediate 46 6-Formyl-3-methyl-2-oxoindoline-3-carbonitrile [Chemical formula]

[0339] Step 1: Methyl 4-(2-cyano-1-ethoxy-1-oxopropan-2-yl)-3-nitrobenzoate [Chemical formula]

[0340] A 60% suspension of sodium hydride (2.0 g, 50 mmol) in anhydrous DMF (50 mL) at 0 °C was added dropwise with ethyl 2-cyanoacetate (5.33 mL, 50 mmol), and the reaction mixture was stirred at 0 °C for an additional 30 minutes. Methyl 4-fluoro-3-nitrobenzoate (7.97 g, 40 mmol) was added to the resulting gray suspension at 0 °C. The resulting dark red mixture was stirred at 0 °C for 30 minutes and then warmed to room temperature over 2 hours. The reaction mixture was cooled to 0 °C, MeI (7.8 mL) was added, followed by KOtBu (8.4 g, 75 mmol). After the addition, the mixture was stirred at room temperature for 2 days and then quenched with an aqueous NH4Cl solution. The resulting mixture was then extracted twice with EtOAc. The organic layers were combined, washed successively with H2O and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography to give methyl 4-(2-cyano-1-ethoxy-1-oxopropan-2-yl)-3-nitrobenzoate. Yield 6.04 g. LCMS method B: Rt = 1.63 minutes.

[0341] Step 2: Methyl 3-cyano-3-methyl-2-oxoindoline-6-carboxylate

Chemical formula

[0342] To a solution of methyl 4-(2-cyano-1-ethoxy-1-oxopropan-2-yl)-3-nitrobenzoate (6.039 g, 19.72 mmol) in EtOH (60 mL) were added saturated aqueous NH4Cl (15 mL) and iron powder (5.803 g, 98.61 mmol). The mixture was heated to reflux overnight. The mixture was then cooled to room temperature, filtered through a short pad of celite, and then washed with EtOAc. The filtrate was washed with H2O, brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography to give methyl 3-cyano-3-methyl-2-oxoindoline-6-carboxylate. Yield 4.404 g. LCMS method B: Rt = 1.07 minutes; (M+H) + = 231.

[0343] Step 3: 6-(Hydroxymethyl)-3-methyl-2-oxoindoline-3-carbonitrile [Chemical formula]

[0344] To a solution of methyl 3-cyano-3-methyl-2-oxoindoline-6-carboxylate (2.101 g, 9.12 mmol) in anhydrous THF (40 mL) under N2 atmosphere was added a solution of LiBH4 (9.1 mL, 18.2 mmol), followed by the addition of MeOH (0.2 mL). The mixture was heated to reflux for 2 hours and then quenched with an aqueous NH4Cl solution. Next, the mixture was extracted twice with EtOAc. The combined organic layers were washed successively with H2O and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography to obtain 6-(hydroxymethyl)-3-methyl-2-oxoindoline-3-carbonitrile. Yield: 1.42 g. LCMS Method B: Rt = 0.79 min; (M+H) + = 203.1

[0345] Step 4: 6-Formyl-3-methyl-2-oxoindoline-3-carbonitrile To a solution of 6-(hydroxymethyl)-3-methyl-2-oxoindoline-3-carbonitrile (0.597 g, 2.95 mmol) in DCM was added activated MnO2 (2.57 g, 29.56 mmol). The mixture was stirred at room temperature overnight and then filtered through a short pad of celite. The filtrate was concentrated to remove the solvent. The residue was purified by flash chromatography to obtain 6-formyl-3-methyl-2-oxoindoline-3-carbonitrile. Yield: 0.347 g. LCMS Method B: Rt = 1.25 min, (M+H) + = 201.1

[0346] Intermediate 47 N-((1r,4r)-4-Formylcyclohexyl)methanesulfonamide [Chemical formula]

[0347] Step 1: Methyl (1r,4r)-4-(methylsulfonamido)cyclohexane-1-carboxylate

Chem.

[0348] A mixture of methyl (1r,4r)-4-aminocyclohexane-1-carboxylate hydrochloride (50 g, 0.259 mol) and Et3N (130.8 g, 1.295 mol) in anhydrous CH2Cl2 (2000 mL) was stirred at room temperature for 20 minutes. MsCl (29.8 g, 0.259 mol) was added dropwise at 0 °C under N2, and the mixture was stirred at 0 °C for 2 hours. The DCM reaction mixture was washed with H2O (3 × 800 mL) and brine (800 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The mixture was purified by silica gel column chromatography eluting with petroleum ether:EtOAc = 2:1 to 1:1 (25 mL of CH2Cl2 was added to 1 L of petroleum ether / ethyl acetate as the eluent) to give methyl (1r,4r)-4-(methylsulfonamido)cyclohexane-1-carboxylate (58 g, 89.5%) as a white solid. 1 1H NMR (CDCl3): δ 4.45 (d, J = 7.6 Hz, 1H), 3.69 (s, 3H), 3.29 - 3.23 (m, 1H), 2.98 (s, 3H), 2.24 - 2.13 (m, 1H), 2.11 - 2.09 (m, 2H), 2.05 - 2.02 (m, 2H), 1.55 - 1.51 (m, 2H), 1.29 - 1.26 (m, 2H).

[0349] Step 2: N-((1r,4r)-4-formylcyclohexyl)methanesulfonamide

Chem.

[0350] Methyl (1r,4r)-4-(methylsulfonamido)cyclohexane-1-carboxylate (20 g, 85.11 mmol) in anhydrous toluene (500 mL) was stirred at 40 °C for 30 minutes under N2. The resulting solution was cooled to -70 °C (internal temperature). A solution of DIBAL-H (1 M in toluene, 180 mL, 180 mmol) was added dropwise under N2 within 110 minutes (keeping the internal temperature below -70 °C). After the addition, the mixture was stirred vigorously at -70 °C for 4 hours. Next, MeOH (30 mL) was carefully added dropwise over 30 minutes (keeping the internal temperature below -70 °C). After stirring for 10 minutes, saturated Rochelle salt solution (600 mL) was added at -70 °C and the mixture was warmed to room temperature. EtOAc (300 mL) was added and the mixture was stirred at room temperature for 16 hours. The mixture was separated and the aqueous layer was extracted with EtOAc (3 × 400 mL). The combined organic layers were washed with brine (3 × 500 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain crude N-((1r,4r)-4-formylcyclohexyl)methanesulfonamide (19 g), which was used in the next step without further purification. 1 1H NMR (CDCl3): δ 9.65 (s, 0.035H), 9.62 (s, 1H), 4.40 - 4.39 (m, 1H), 3.28 - 3.25 (m, 1H), 2.98 (s, 3H), 2.18 - 2.03 (m, 5H), 1.38 - 1.28 (m, 4H).

[0351] Step 3: Sodium (R)-hydroxy((1r,4R)-4-(methylsulfonamido)cyclohexyl)methanesulfonate

Chemical formula

[0352] A solution of crude N-((1r,4r)-4-formylcyclohexyl)methanesulfonamide (19 g) in THF (200 mL) was added dropwise with a NaHSO3 solution (4 M, 110 mL) at 45 °C over 10 minutes. After stirring at 45 °C for 30 minutes, the mixture was cooled to room temperature and further stirred for 1 hour. The resulting white precipitate was filtered, and the filter cake was washed with THF (3 × 50 mL) and dried under high vacuum to obtain sodium (R)-hydroxy((1r,4R)-4-(methylsulfonamido)cyclohexyl)methanesulfonate (16.5 g, 55% in Steps 2 - 3) as a white solid, which was used in the next step without further purification. 1 1H NMR (DMSO-d6): δ 9.90 (s, 0.17H), 6.91 (d, J = 7.2 Hz, 1H), 4.98 (d, J = 5.2 Hz, 1H), 3.65 (t, J = 4.4 Hz, 1H), 2.97 - 2.95 (m, 1H), 2.89 (d, J = 6.8 Hz, 3H), 2.06 - 2.03 (m, 1H), 1.86 - 1.81 (m, 3H), 1.61 (brs, 1H), 1.23 - 1.06 (m, 4H).

[0353] Step 4: N-((1r,4r)-4-formylcyclohexyl)methanesulfonamide To a mixture of sodium (R)-hydroxy((1r,4R)-4-(methylsulfonamido)cyclohexyl)methanesulfonate (16.5 g, 53.4 mmol) in CH2Cl2 (160 mL) was added an aqueous Na2CO3 solution (1 M, 160 mL). The mixture was stirred at room temperature for 30 minutes. The mixture was separated, and the aqueous layer was extracted with CH2Cl2 (3 × 80 mL). The combined organic layers were washed with brine (300 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain crude N-((1r,4r)-4-formylcyclohexyl)methanesulfonamide (7.5 g, 69%) as a white solid, which was used in the next step without further purification. 11H NMR (CDCl3): δ 9.66 (s, 0.021H), 9.62 (s, 1H), 4.38 (brs, 1H), 3.30 - 3.25 (m, 1H), 2.98 (s, 3H), 2.18 - 2.14 (m, 3H), 2.05 - 2.01 (m, 2H), 1.42 - 1.30 (m, 4H).

[0354] Intermediate 48 Methyl 2 - ((4 - chloropyrimidin - 5 - yl)oxy)-5 - fluorobenzoate

Chem.

[0355] Step 1: Ethyl 2-(2 - bromo - 4 - fluorophenoxy)acetate

Chem.

[0356] To a solution of 2 - bromo - 4 - fluorophenol (250 g, 1.31 mol) in MeCN (2 L) were added K2CO3 (270 g, 1.97 mol) and ethyl 2 - bromoacetate (219 g, 1.31 mol). The suspension was heated at 90 °C for 1.5 h. The mixture was filtered and the filtrate was concentrated to give crude ethyl 2-(2 - bromo - 4 - fluorophenoxy)acetate as a brown oil, which was used directly in the next step (312 g); 1 1H NMR (CDCl3): δ 7.32 (dd, J = 7.6, 3.2 Hz, 1 H), 6.95 - 6.97 (m, 1 H), 6.82 (dd, J = 8.8, 4.4 Hz, 1 H), 4.66 (s, 2 H), 4.27 (q, J = 7.2 Hz, 2 H), 1.31 (t, J = 7.2 Hz, 3 H); 1 19F NMR (CDCl3): δ -120.06 (s, 1F).

[0357] Step 2: 5-(2-Bromo-4-fluorophenoxy)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one

Chem.

[0358] Ethyl formate (108 g) and NaH (20 g) were added to a solution of ethyl 2-(2-bromo-4-fluorophenoxy)acetate (100 g) in anhydrous THF (2 L) at 0 °C. The mixture was stirred at 35 - 45 °C for 18 h. The solvent was removed under vacuum, anhydrous EtOH (2 L) and thiourea (25 g, 324.8 mmol) were added, and the mixture was stirred at 90 °C for 16 h. The mixture was concentrated, diluted with water (2 L), and extracted with petroleum ether:ethyl acetate (10:1; 500 mL × 3). When the aqueous layer was acidified to pH = 4 with hydrochloric acid (1 N, 200 mL), a white solid precipitated. The mixture was filtered, and the obtained filter cake was dried to give crude 5-(2-bromo-4-fluorophenoxy)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (62 g) as a white solid, which was used directly in the next step without purification. LCMS method C: Rt = 0.638 min; (M + H) + = 316.9, 318.9 (chlorine isotope).

[0359] Step 3: 5-(2-Bromo-4-fluorophenoxy)pyrimidin-4-ol

Chem.

[0360] Raney nickel (62 g) was added to a solution of 5-(2-bromo-4-fluorophenoxy)-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (62 g) in anhydrous EtOH (1.5 L), and the mixture was heated to reflux for 6 h. The solvent was removed under vacuum, and anhydrous EtOH (2 L) was added. The mixture was filtered, and the filtrate was concentrated to give crude 5-(2-bromo-4-fluorophenoxy)pyrimidin-4-ol as a gray solid (55 g); LCMS method C: Rt = 0.62 min, (M + H) +=284.9, 287.0 (bromine isotope).

[0361] Step 4: Methyl 5-fluoro-2-((4-hydroxypyrimidin-5-yl)oxy)benzoate [Chemical formula]

[0362] To a solution of 5-(2-bromo-4-fluorophenoxy)pyrimidin-4-ol (60 g, 0.17 mol) in DMF (100 mL) and MeOH (150 mL) were added TEA (25.5 g, 0.252 mol) and Pd(dppf)Cl2 (12.4 g, 0.017 mol). The resulting reaction mixture was stirred at 80 °C for 24 h under 50 PSI of CO. The mixture was then concentrated, diluted with H2O (300 mL), and extracted with DCM / MeOH (10:1) (200 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated to give the crude product, which was washed with ethyl acetate (100 mL). The filter cake was dried to obtain crude methyl 5-fluoro-2-((4-hydroxypyrimidin-5-yl)oxy)benzoate as a brown solid (20 g, 45%); LCMS method C: Rt = 0.56 min; (M+H) + =264.9.

[0363] Step 5: Methyl 2-((4-chloropyrimidin-5-yl)oxy)-5-fluorobenzoate To a solution of methyl 5-fluoro-2-((4-hydroxypyrimidin-5-yl)oxy)benzoate (11 g, 42 mmol) in SOCl2 (5 mL) was added DMF (0.5 mL). The resulting mixture was heated at 70 °C for 2 h. The mixture was concentrated to give a residue, which was dissolved in DCM (100 mL) and H2O (100 mL). The mixture was neutralized with saturated NaHCO3 (50 mL). The separated organic layer was dried over Na2SO4, filtered, concentrated, and the residue was purified by chromatography column (petroleum ether:ethyl acetate = 5:1 to 1:1) to give methyl 2-((4-chloropyrimidin-5-yl)oxy)-5-fluorobenzoate as a brown solid (8.3 g, 57%). LCMS method C: Rt = 0.74 min; (M+H) + = 283.5.

[0364] Intermediate 49 5-Fluoro-2-(pyrimidin-5-yloxy)benzoic acid

Chemical formula

[0365] Step 1: 5-(2-Bromo-4-fluorophenoxy)pyrimidine

Chemical formula

[0366] Into a 100 L jacketed reactor were charged 2-bromo-4-fluorophenol (11.00 kg, 57.59 mol), 5-bromopyrimidine (9.43 kg, 59.32 mol), cesium carbonate (24.39 kg, 74.87 mol), and DMA (66.00 L). The mixture was heated to 115 - 125 °C over 2.5 h. Next, the batch was stirred at 120 °C for 4 days. Then, the internal temperature of the batch was adjusted to 20 - 30 °C. Once the batch was cooled, it was partitioned between deionized water (132.00 L) and MTBE (44.00 L) in a 250 L Schott reactor. The reactor contents were stirred at room temperature for 30 min. After this time, stirring was stopped and phase separation was allowed to occur. The upper organic layer was removed and placed in a separate container. A total of 4 MTBE extractions were performed. The MTBE extracts were combined and washed with 2 N sodium hydroxide (22.00 L), then 0.5 M citric acid solution (11.00 L), and finally 5 wt% sodium bicarbonate solution (11.00 L). The MTBE solution was concentrated using a rotary evaporator (25 in Hg vacuum, 40 °C water bath). The residue was passed through a wiped film evaporator (WFE) system to remove volatile substances (MTBE) and a portion of the remaining 5-bromopyrimidine. The conditions for WFE distillation were as follows: first pass - vacuum 10 - 15 in Hg, wiper speed 600 rpm, jacket temperature 150 - 160 °C, addition rate 4 mL / min; second pass - vacuum 0.7 Torr, wiper speed 600 rpm, jacket temperature 160 - 170 °C, addition rate 4 mL / min. The product 5-(2-bromo-4-fluorophenoxy)-pyrimidine was isolated in 45% yield (7.15 kg) with 95.3% (AUC) HPLC purity.

[0367] Step 2: Methyl 5-fluoro-2-(pyrimidin-5-yloxy)benzoate [Chemical formula]

[0368] An 80 L stainless steel reactor with a jacket was charged with palladium catalyst (Pd(dppf)Cl2 DCM complex) (1.00 kg, 1.22 mol), 5-(2-bromo-4-fluorophenoxy)pyrimidine (8.54 kg, 31.59 mol), TEA (6.38 kg, 63.18 mol), and methanol (42.50 L). The reactor was purged with nitrogen (3 times at a maximum nitrogen pressure of 50 psig) and then purged with carbon monoxide gas (3 times at a maximum carbon monoxide of 50 psig). The internal temperature of the reactor was adjusted to 65 - 75 °C over 75 minutes. Once at temperature, the internal pressure of the vessel was adjusted to 50 psig with carbon monoxide gas. The reactor contents were stirred at a specific temperature and pressure for at least 34 hours. After this time, the reaction mixture was cooled to 15 - 25 °C and purged 3 times with nitrogen at a pressure of 50 psig to obtain a methanol solution containing methyl 5-fluoro-2-(pyrimidin-5-yloxy)benzoate. The batch was filtered over a Celite™ pad to remove the palladium catalyst.

[0369] Step 3: 5-Fluoro-2-(pyrimidin-5-yloxy)benzoic acid A methanolic solution containing methyl 5-fluoro-2-(pyrimidin-5-yloxy)benzoate of Project 2 was placed in a 100 L glass reactor with a jacket and diluted with water (17.00 L). Then, a 50 wt% aqueous sodium hydroxide solution (10.11 kg, 126.36 mol) was added while maintaining the batch internal temperature at 35 - 45 °C. After the addition was complete, the temperature was adjusted to 35 - 45 °C and the batch was stirred for at least 14 hours. The reaction volume was reduced from 87 to 33 liters by vacuum distillation (a vacuum of 27 inches Hg was achieved; the final batch temperature was 32.4 °C). Next, the batch was diluted with water (42.5 L), cooled to 20 - 30 °C, and filtered through a Celite(trademark) pad to remove the catalyst. The aqueous layer was extracted twice with MTBE (17 L). While maintaining the internal batch temperature at 10 - 20 °C, the batch was adjusted to pH = 2 using 6 M hydrochloric acid (about 17 L). After the addition of the acid was complete, the batch was cooled to 0 - 10 °C and filtered through a polypropylene cloth using a filter / dryer. The filter cake was washed with water (17.00 L) and dried under a nitrogen stream at 40 - 45 °C for several days until the moisture content reached 0.3 wt% by KF analysis. The product was isolated in a 102% yield (7.57 kg) with a HPLC purity of 97.5% (AUC) and a purity of 94 wt% by NMR analysis.

[0370] Intermediate 50 ((1r,4r)-4-(Ethylsulfonamido)cyclohexyl)methyl 4-methylbenzenesulfonate

Chemical Structure

[0371] Step 1: Methyl (1r,4r)-4-(ethylsulfonamido)cyclohexane-1-carboxylate

Chemical Structure

[0372] A solution of methyl (1r,4r)-4-aminocyclohexane-1-carboxylate hydrochloride (120 g, 0.62 mol) and Et3N (346 mL, 2.48 mol) in anhydrous DCM (2.5 L) was stirred at room temperature for 30 minutes. Ethanesulfonyl chloride (80.6 g, 0.63 mol) was added dropwise to the reaction mixture at 0 - 5 °C over 30 minutes. After addition, the mixture was stirred at 0 °C for 3 hours. The mixture was quenched with water (250 mL) at 0 °C. After partitioning, the organic layer was washed with H2O (600 mL, 5 volumes), 1N HCl (2×600 mL, 2×5 volumes), H2O (600 mL, 5 volumes), and brine (600 mL, 5 volumes), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give crude methyl (1r,4r)-4-(ethylsulfonamido)cyclohexane-1-carboxylate (117.6 g, 76%) as a pale yellow solid, which was used in the next step without further purification. 1 1H NMR (CDCl3 400 MHz): δ 4.36 (d, J = 8.0 Hz, 1 H), 3.67 (s, 3 H), 3.29 - 3.22 (m, 1 H), 3.04 (q, J = 7.6 Hz, 2 H), 2.25 - 2.21 (m, 1 H), 2.15 - 2.09 (m, 2 H), 2.08 - 2.01 (m, 2 H), 1.58 - 1.51 (m, 2 H), 1.39 - 1.25 (m, 5 H).

[0373] Step 2: N-((1r,4r)-4-(hydroxymethyl)cyclohexyl)ethanesulfonamide

Chemical formula

[0374] To a solution of methyl (1r,4r)-4-(ethylsulfonamido)cyclohexane-1-carboxylate (100 g, 402 mmol) in anhydrous THF (1 L) was added LiAlH4 (403 mL, 403 mmol, 1 M in THF) dropwise over about 1 hour at 0 - 5 °C under N2. The mixture was then stirred at 0 °C for 2 hours under N2. Next, additional LiAlH4 (40 mL, 40 mmol, 1 M in THF) was added to the reaction mixture. The mixture was stirred at 0 °C for 1 hour under N2. The mixture was slowly quenched with 20% NaCl solution (20 mL) at 0 °C and diluted with THF (500 mL, 5 volumes). The mixture was warmed to 15 °C and stirred for 15 minutes. The mixture was filtered and washed with THF (2 × 200 mL). The filter cake was suspended in THF (1 L, 10 volumes) for ½ hour. The suspension was filtered and washed with THF (2 × 200 mL). The suspension and filtration of the filter cake were repeated twice in THF (1 L, 10 volumes) and then washed with THF (2 × 200 mL). The combined filtrates were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give crude N-((1r,4r)-4-(hydroxymethyl)cyclohexyl)ethanesulfonamide (72 g, 81%) as a white solid, which was used in the next step without further purification; 1 1H NMR (CDCl3 400 MHz): δ 4.23 (d, J = 8.0 Hz, 1 H), 3.46 (t, J = 6.4 Hz, 2 H), 3.25 - 3.18 (m, 1 H), 3.04 (q, J = 7.6 Hz, 2 H), 2.11 - 2.07 (m, 2H), 1.88 - 1.84 (m, 2 H), 1.46 - 1.35 (m, 4 H), 1.29 - 1.24 (m, 2 H), 1.09 - 1.00 (m, 2 H). [[ID= (m, 2 H), 1.09 - 1.00 (m, 2 H).

[0375] Step 3: ((1r,4r)-4-(ethylsulfonamido)cyclohexyl)methyl 4-methylbenzenesulfonate To a solution of crude N-((1r,4r)-4-(hydroxymethyl)cyclohexyl)ethanesulfonamide (30 g, 136 mmol) in anhydrous DCM (300 mL) were added TsCl (25.84 g, 136 mmol), DMAP (1.66 g, 13.6 mmol), and Et3N (41.2 g, 408 mmol). The mixture was stirred at 10 °C for 6 h under N2. Next, the mixture was quenched with H2O (200 mL). After partitioning, the organic layer was washed with H2O (2 × 150 mL) and brine (150 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate = 1 / 0 to 2 / 1 to give ((1r,4r)-4-(ethylsulfonamido)cyclohexyl)methyl 4-methylbenzenesulfonate (37 g, 73%) as a white solid; 1 1H NMR (CDCl3 400 MHz): δ 7.78 (d, J = 8.4 Hz, 2 H), 7.35 (d, J = 8.8 Hz, 2 H), 4.23 (d, J = 7.6 Hz, 1 H), 3.81 (d, J = 6.4 Hz, 2 H), 3.19 - 3.14 (m, 1 H), 3.01 (q, J = 7.6 Hz, 2 H), 2.46 (s, 3 H), 2.09 - 2.03 (m, 2 H), 1.79 - 1.74 (m, 2 H), 1.66 - 1.56 (m, 1 H), 1.35 (t, J = 7.6 Hz, 3 H), 1.28 - 1.18 (m, 2 H), 1.09 - 1.01 (m, 2 H).

[0376] Example 1 5-Fluoro-N,N-diisopropyl-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide (racemic mixture) [Chemical Structure]

[0377] Project 1: tert-Butyl 7-(5-(4-fluoro-2-(methoxycarbonyl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate

Chem.

[0378] tert-Butyl 7-(meso-(2-bromo-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (Intermediate 11, 900 mg, 1.82 mmol) and Pd(dppf)Cl2 (134 mg, 0.18 mmol) were added to Et3N (3 mL) and MeOH (20 mL). The reaction mixture was then stirred at 65 °C under CO (50 psi) for about 16 h. The reaction mixture was filtered through a Celite pad and concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (eluting with dichloromethane:methanol = 1:0 to 0:1) to give tert-Butyl 7-(5-(4-fluoro-2-(methoxycarbonyl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate as a pale yellow oil. Yield: 850 mg. LCMS Method C: Rt = 0.739 min; (M+H) + = 473.2。

[0379] Project 2: 2-((4-(7-(tert-Butoxycarbonyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluorobenzoic acid

Chem.

[0380] To a mixture of tert-butyl 7-(5-(4-fluoro-2-(methoxycarbonyl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (850 mg, 1.79 mmol) and NaOH (143 mg, 3.58 mmol), MeOH (10 mL) and H2O (2 mL) were added under N2. The reaction mixture was stirred at 21 - 27 °C for 12 h. The solvent was removed under reduced pressure to obtain a residue. Next, 1N HCl was added to adjust the solution to pH 5 - 6, and EtOAc (10 mL) was added. The organic layer was concentrated under reduced pressure to obtain 2-((4-(7-(tert-butoxycarbonyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluorobenzoic acid. Yield: 700 mg (85%). LCMS method C: Rt = 0.705 min; (M + H) + = 459.2

[0381] Step 3: tert-Butyl 7-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate [Chemical formula]

[0382] A solution of 2-((4-(7-(tert-butoxycarbonyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluorobenzoic acid (800 mg, 1.746 mmol) in anhydrous CH2Cl2 (15 mL) was added with HATU (553 mg, 1.455 mmol) and DIEA (677 mg, 5.238 mmol) under N2, and the reaction mixture was stirred at 9 - 20 °C for 30 minutes. Next, diisopropylamine (265 mg, 2.619 mmol) was added to the solution, and the reaction mixture was stirred at 9 - 20 °C for 12 hours. Then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluted with CH2Cl2:MeOH = 1:0 - 10:1) to give tert-butyl 7-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate as a brown oil. Yield: 900 mg. LCMS method F: Rt = 1.238 min; (M + H) + = 542.4.

[0383] Step 4: 2-((4-(2,7-Diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide [Chemical formula]

[0384] To a solution of tert-butyl 7-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (900 mg, 1.67 mmol) in anhydrous CH2Cl2 (25 mL) was added TFA (5 mL) under N2. The reaction mixture was stirred at 10 - 22 °C for 2 h. Next, the solvent was removed under reduced pressure. The resulting residue was adjusted to pH 9 - 10 using 10% NaOH. The mixture was then extracted with CH2Cl2 (20 mL × 3). The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 2-((4-(2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide. The residue was used in the next step as a brown oil without further purification. Yield: 730 mg. LCMS method F: Rt = 0.888 min; (M + H) + = 442.4.

[0385] Step 5: 5-Fluoro-N,N-diisopropyl-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide 2-((4-(2,7-Diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide (730 mg, 1.654 mmol), 2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbaldehyde (Intermediate 40, 536 mg, 3.308 mmol), and 4 Å molecular sieves (100 mg) were combined in anhydrous MeOH (20 mL). The reaction mixture was then stirred at 60 °C under N2 for 30 minutes. Next, NaBH3CN (513 mg, 8.270 mmol) was added to the solution, and the reaction mixture was stirred at 60 °C for 4 hours. The reaction mixture was then filtered and concentrated under reduced pressure. The resulting residue was diluted with MeOH (15 mL), and the mixture was purified by preparative RP-HPLC method C (HCl) to give the compound 5-fluoro-N,N-diisopropyl-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide as a white solid. Yield: 540 mg (55%). LCMS method C: Rt = 0.931; (M+H) + = 588.5. 1 1H NMR (CD3OD): δ 8.30 - 8.38 (m, 1 H), 7.62 - 7.84 (m, 1 H), 6.86 - 7.15 (m, 6 H), 4.22 - 4.30 (m, 3 H), 3.20 - 4.03 (m, 9 H), 1.87 - 2.04 (m, 5 H), 0.81 - 1.30 (m, 11 H). 19 19F NMR (CD3OD): δ -117.14.

[0386] Examples 1A and 1B 5-Fluoro-N,N-diisopropyl-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide (Isomers 1 and 2)

Chemical Structure

[0387] The racemic compound of Example 1 was separated by SFC method A to obtain two isomers. Isomer 1 (Example 1A): LCMS method C: Rt = 0.931; (M+H) + = 588.5. 1 H NMR (CD3OD): δ 8.54 - 8.61 (m, 1 H), 7.86 - 8.09 (m, 1 H), 7.20 - 7.31 (m, 5 H), 7.15 (d, J = 36.4 Hz, 1 H), 4.41 - 4.51 (m, 3 H), 3.40 - 4.02 (m, 9 H), 2.15 - 2.25 (m, 4 H), 1.06 - 1.48 (m, 12 H). 19 F NMR (CD3OD): δ -117.11. SFC analysis method A: t R = 0.569 min, ee = 100%.

[0388] Isomer 2 (Example 1B): LCMS method C: Rt = 0.930; (M+H) + = 588.5. 1 H NMR (CD3OD): δ 8.58 - 8.65 (m, 1 H), 7.90 - 8.14 (m, 1 H), 7.25 - 7.35 (m, 5 H), 7.18 (d, J = 44.8 Hz, 1 H), 4.45 - 4.54 (m, 3 H), 3.43 - 4.06 (m, 9 H), 2.18 - 2.30 (m, 4 H), 1.10 - 1.52 (m, 12 H). 19 F NMR (CD3OD 400 MHz): δ -117.10. SFC analysis method A: t:t R = 0.809 min, ee = 98.87%.

[0389] Example 2 N-Ethyl-5-fluoro-N-isopropyl-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide (racemic mixture)

Chemical formula

[0390] The title product was synthesized by the method described in Example 1. In Step 3, N-isopropyl-N-ethylamine was used. LCMS Method B: Rt = 1.164; (M+H) + = 574.1.

[0391] Examples 2A and 2B N-Ethyl-5-fluoro-N-isopropyl-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2,azaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide (Isomers 1-2)

Chemical formula

[0392] The racemic compound of Example 2 was separated by SFC Method A to obtain two isomers. Isomer 1 (Example 2A): Yield: 92.5 mg. LCMS Method E: Rt = 1.132 min; (M+H) + = 574.3. 1 1H NMR (CD3OD): δ 8.20-8.29 (m, 1 H), 7.72-7.80 (m, 1 H), 6.85-7.16 (m, 6 H), 4.35-4.41 (m, 1 H), 3.45-3.89 (m, 8H), 3.12-3.23 (m, 1H), 2.50-2.71 (m, 4 H), 1.76-1.96 (m, 4 H), 1.05-1.27 (m, 8 H). 19 19F NMR (CD3OD): δ -120.380. SFC Analysis Method A: t R = 0.722 min, ee = 100%.

[0393] Isomer 2 (Example 2B): Yield: 115.8 mg. LCMS Method E: Rt = 1.121 min; (M+H) + = 574.3. 11H NMR (CD3OD): δ 8.21 - 8.29 (m, 1 H), 7.71 - 7.80 (m, 1 H), 6.85 - 7.16 (m, 6 H), 4.35 - 4.42 (m, 1 H), 3.45 - 3.90 (m, 8H), 3.15 - 3.23 (m, 1H), 2.48 - 2.71 (m, 4 H), 1.76 - 1.96 (m, 4 H), 1.05 - 1.27 (m, 8 H). 19 19F NMR (CD3OD): δ -120.390. SFC analysis method A: t R = 1.455 min, ee = 99.65%.

[0394] Examples 3A and 3B 5-Fluoro-2-((4-(7-((1-(2-hydroxyethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4,4]nonan-2-yl)pyrimidin-5-yl)oxy)-N,N-diisopropylbenzamide (isomers 1 - 2)

Chemical formula

[0395] To a solution of 2-((4-(2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide (70 mg, 0.16 mmol) and 1-(2-hydroxyethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbaldehyde (intermediate 42c, 33 mg, 0.16 mmol) in anhydrous MeOH (3 mL), NaBH3CN (50 mg, 0.80 mmol) was added under N2. The reaction mixture was stirred at 55 °C for 16 h. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was purified by silica gel chromatography (CH2Cl2:MeOH = 10:1) and further purified by preparative SFC method B and RP-HPLC method E to obtain the compound as two isomers.

[0396] Isomer 1 (Example 3A): White solid. LCMS method E: Rt = 0.736 min; (M + H)+ = 632.4. 1 1H NMR (CD3OD): δ 8.28 (s, 1H), 7.80 (d, J = 2.4 Hz, 1H), 6.89 - 7.15 (m, 5H), 6.89 - 6.90 (m, 1H), 3.99 (t, J = 5.6 Hz, 2H), 3.55 - 3.85 (m, 10H), 2.52 - 2.72 (m, 4H), 1.84 - 1.96 (m, 4H), 1.54 (dd, J = 2.4, 6.8 Hz, 3H), 1.43 (t, J = 4.8 Hz, 3H), 1.19 (d, J = 3.2 Hz, 3H), 1.32 (t, J = 4.8 Hz, 3H). 19 19F NMR (CD3OD): δ -120.25 - 120.33. SFC analysis method B: t R = 7.26 min, ee = 100%.

[0397] Isomer 2 (Example 3B): White solid. LCMS method E: Rt = 0.738 min; (M + H) + = 632.4. 1 1H NMR (CD3OD): δ 8.28 (s, 1H), 7.80 (d, J = 2.4 Hz, 1H), 6.89 - 7.15 (m, 5H), 6.89 - 6.90 (m, 1H), 3.99 (t, J = 5.6 Hz, 2H), 3.55 - 3.85 (m, 10H), 2.52 - 2.72 (m, 4H), 1.84 - 1.96 (m, 4H), 1.54 (dd, J = 2.4, 6.8 Hz, 3H), 1.43 (t, J = 4.8 Hz, 3H), 1.19 (d, J = 3.2 Hz, 3H), 1.32 (t, J = 4.8 Hz, 3H). 19 19F NMR (CD3OD): δ -120.27 - 120.35. SFC analysis method B: t R = 7.92 min, ee = 97.04%.

[0398] Example 4 N-Ethyl-5-fluoro-2-((4-(7-((1-(2-hydroxyethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-N-isopropylbenzamide

Chem.

[0399] To a solution of 2-((4-(2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide (prepared as an intermediate during the synthesis of Example 2, 100 mg, 0.23 mmol) in anhydrous MeOH (10 mL) was added 1-(2-hydroxyethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbaldehyde (Intermediate 42c, 72 mg, 0.35 mmol), and the mixture was stirred under N2 for 5 minutes. Next, NaBH3CN (71 mg, 1.15 mmol) was added, and the mixture was stirred at 65 °C for 2 hours. The reaction mixture was concentrated under reduced pressure together with an additional 20 mg of 2-((4-(2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-N-ethyl-5-fluoro-N-isopropylbenzamide to obtain a residue, which was purified by silica gel column chromatography (eluting with dichloromethane:methanol = 20:1 to 10:1) to give N-ethyl-5-fluoro-2-((4-(7-((1-(2-hydroxyethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-N-isopropylbenzamide as a yellow oil. Yield: 70 mg. LCMS Method C: Rt = 0.583 min; (M+H) + = 618.1。

[0400] Example 4A and 4B N-Ethyl-5-fluoro-2-((4-(7-((1-(2-hydroxyethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-N-isopropylbenzamide (Isomers 1 - 2)

Chemical Structure

[0401] 70 mg of N-Ethyl-5-fluoro-2-((4-(7-((1-(2-hydroxyethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-N-isopropylbenzamide (Example 4) was separated by SFC Method A to obtain Isomers 1 and 2 as white solids.

[0402] Isomer 1 (Example 4A): Yield: 8.70 mg. Rt = 1.14 min; (M+H) + = 618.3. 1 1H NMR (CD3OD): δ 8.27 - 8.29 (m, 1 H), 7.78 - 7.82 (m, 1 H), 6.89 - 7.18 (m, 6 H), 3.33 - 4.01 (m, 13 H), 2.48 - 2.75 (m, 4 H), 1.75 - 1.96 (m, 4 H), 1.05 - 1.26 (m, 9 H). 19 19F NMR (CD3OD): δ -120.390. SFC Analysis Method C: t R = 1.870 min, ee = 98.60%.

[0403] Isomer 2 (Example 4B): Yield: 9.2 mg. LCMS Method E: Rt = Rt value: 1.140 min; (M+H) + = 618.3. 11H NMR (CD3OD): δ 8.25 - 8.31 (m, 1 H), 7.76 - 7.25 (m, 1 H), 6.85 - 7.20 (m, 6 H), 3.48 - 4.00 (m, 13 H), 2.48 - 2.75 (m, 4 H), 1.75 - 1.96 (m, 4 H), 1.05 - 1.33 (m, 9 H). 19 19F NMR (CD3OD): δ -120.398. SFC analysis method C: t R = 2.922 minutes, ee = 99.43%.

[0404] Example 5 5-Fluoro-N-(2-hydroxyethyl)-N-isopropyl-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide

Chemical formula

[0405] Step 1: tert-Butyl 7-(5-(2-((2-(tert-butyldimethylsilyl)oxy)ethyl)(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate

Chemical formula

[0406] A solution of 2-((4-(7-(tert-butoxycarbonyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluorobenzoic acid (Intermediate 33, Step 2, 50 mg, 0.1092 mmol) in anhydrous DMF (3 mL) was added with N-(2-((tert-butyldimethylsilyl)oxy)ethyl)propan-2-amine (36 mg, 0.1637 mmol), HATU (83 mg, 0.2183 mmol), and DIEA (28 mg, 0.2183 mmol), and the mixture was stirred at 16 °C for 6 hours under N2. Next, the mixture was diluted with EtOAc (20 mL) and washed with brine (3 × 20 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC using EtOAc to obtain tert-butyl 7-(5-(2-((2-((tert-butyldimethylsilyl)oxy)ethyl)(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate as a yellow oil. Yield: 50 mg. LCMS Method C: Rt = 0.851 min, (M + H) + = 658.1.

[0407] Step 2: 2-((4-(2,7-Diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-(2-hydroxyethyl)-N-isopropylbenzamide

Chem.

[0408] A solution of tert-butyl 7-(5-(2-((2-((tert-butyldimethylsilyl)oxy)ethyl)(isopropyl)carbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (50 mg, 0.0761 mmol) in CH2Cl2 (4 mL) was added with TFA (1 mL), and the mixture was stirred at 16 °C for 3 h. Then the mixture was concentrated under reduced pressure. The residue was adjusted to pH = 8 - 9 with saturated NaHCO3 solution and diluted with water (15 mL). The aqueous layer was extracted with CH2Cl2:iPrOH (3:1, 3×20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain crude 2-((4-(2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-(2-hydroxyethyl)-N-isopropylbenzamide as a yellow oil, which was used directly in the next step without further purification. Yield: 34 mg.

[0409] Step 3: 5-Fluoro-N-(2-hydroxyethyl)-N-isopropyl-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide A solution of 2-((4-(2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-(2-hydroxyethyl)-N-isopropylbenzamide (34 mg, 0.0761 mmol) in anhydrous MeOH (3 mL) was added with 2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbaldehyde (Intermediate 40, 25 mg, 0.1522 mmol) and NaBH3CN (24 mg, 0.3805 mmol). The mixture was stirred at 60 °C for 16 h under N2. LCMS indicated the completion of the reaction. The mixture was concentrated under reduced pressure and directly purified by RP-HPLC method D to give 5-fluoro-N-(2-hydroxyethyl)-N-isopropyl-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide as a pale yellow solid. Yield: 10.00 mg. LCMS method C: Rt = 0.560 min, (M+H) + = 590.2. 1 H NMR (CDCl3): δ 10.35-10.15 (m, 0.5H), 9.75-9.60 (m, 0.5H), 9.01-8.77 (m, 1H), 8.36 (s, 1H), 7.81-7.70 (m, 1H), 7.35-7.25 (m, 0.5H), 7.18-7.08 (m, 0.5H), 7.05-6.90 (m, 2H), 6.89-6.75 (m, 2H), 6.65-6.50 (m, 1H), 4.05-3.25 (m, 12H), 2.97-2.25 (m, 4H), 2.12-1.85 (m, 4H), 1.30-1.07 (m, 6H). 19 F NMR (CDCl3): δ -119.3。

[0410] Example 6A 5-Fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide [Chemistry]

[0411] Process 1: tert-Butyl 2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate [Chemistry]

[0412] i A mixture of 2-((4-chloropyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide (Intermediate 41, 1.8 g, 5.13 mmol), tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate (1.35 g, 5.13 mmol), and DIEA (1.32 g, 10.26 mmol) in PrOH (20 mL) was stirred at 70 °C for 16 h. After concentration, the mixture was directly purified by silica gel column chromatography eluting with petroleum ether:ethyl acetate = 3:7 to give tert-butyl 2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate as a yellow oil. Yield: 2.9 g. LCMS Method E: Rt = 0.767 min; (M+H) + = 542.2.

[0413] Process 2: 2-((4-(2,7-Diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide [Chemistry]

[0414] A solution of tert-butyl 2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (2.9 g, 5.35 mmol) in anhydrous CH2Cl2 (30 mL) was added with TFA (10 mL), and the mixture was stirred at 25 °C for 2 h. Next, the mixture was concentrated under reduced pressure, and 30% aqueous NaOH solution was added to the residue to adjust the pH to 11 - 12. Then, the aqueous layer was extracted with CH2Cl2 / i PrOH (4 / 1, 3 × 30 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain crude 2-((4-(2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide as a yellow solid, which was used in the next step without further purification. Yield: 2.3 g. LCMS method C: Rt = 0.584 min, (M + H) + = 442.1.

[0415] Step 3: tert-Butyl ((1r,4r)-4-((2-(5-(2-((diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)cyclohexyl)carbamate (Example 99A)

Chemical Structure

[0416] A solution of 2-((4-(2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide (2.3 g, 5.20 mmol) in anhydrous MeOH (50 mL) was adjusted to pH 6 - 7 with AcOH. Next, tert-butyl ((1r,4r)-4-formylcyclohexyl)carbamate (1.3 g, 5.72 mmol) was added. After stirring at 25 °C for 5 minutes, NaBH3CN (656 mg, 10.41 mmol) was added and the mixture was stirred at 70 °C for 1 hour. Then the mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL) and washed with H2O (2 × 30 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether:ethyl acetate = 3:7 to give tert-butyl ((1r,4r)-4-((2-(5-(2-((diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)cyclohexyl)carbamate as a white solid. Yield: 3.0 g. LCMS method C: Rt = 0.929 min; (M + H) + = 653.3.

[0417] Step 4: 2-((4-(7-(((1r,4r)-4-aminocyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Chemical Structure

[0418] A solution of tert-butyl ((1r,4r)-4-((2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)cyclohexyl)carbamate (3 g, 4.60 mmol) in anhydrous ethyl CH2Cl2 (30 mL) was treated with TFA (10 mL), and the mixture was stirred at 25 °C for 2 h. The mixture was then concentrated under reduced pressure to give crude 2-((4-(7-(((1r,4r)-4-aminocyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide as a pale yellow oil, which was used in the next step without further purification. Yield: 4.0 g. LCMS method C: Rt = 0.513 min; (M+H) + = 553.2.

[0419] Step 5: (5-Fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide)

Chemical formula

[0420] A solution of 2-((4-(7-(((1r,4r)-4-aminocyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide (3.6 g, crude, ca. 4.14 mmol) and Et3N (2.47 g, 24.0 mmol) in anhydrous CH2Cl2 (50 mL) was added MsCl (844 mg, 7.34 mmol) at 0 °C under N2, and the mixture was stirred at 0 °C for 2 h. Next, the mixture was washed with H2O (3 × 50 mL) and brine (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2:CH3OH = 19:1 to give 5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide as a white solid, which was further purified by RP-HPLC method D to give 5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide as a white solid. Yield: 1.59 g. LCMS method C: Rt = 0.565 min; (M+H) + = 631.1. 11H NMR (CDCl3): δ 8.27 (s, 1H), 8.78 (s, 1H), 7.17 - 7.15 (m, 2H), 7.03 - 6.99 (m, 1H), 4.06 - 4.03 (m, 2H), 3.96 - 3.89 (m, 2H), 3.87 - 3.84 (m, 1H), 3.66 - 3.63 (m, 1H), 3.34 - 3.32 (m, 1H), 3.20 - 3.15 (m, 1H), 2.95 (s, 3H), 2.55 - 2.51 (m, 3H), 2.33 - 2.30 (m, 2H), 2.06 - 2.04 (m, 2H), 1.89 - 1.87 (m, 6H), 1.56 (d, J = 6.8 Hz, 4H), 1.48 (d, J = 6.8 Hz, 3H), 1.33 - 1.30 (m, 2H), 1.20 (d, J = 6.8 Hz, 3H), 1.13 (d, J = 6.4 Hz, 3H), 1.08 - 1.07 (m, 2H). 19 19F NMR (CDCl3): δ -119.7。

[0421] Examples 6A - 6B Alternative synthesis of 5 - fluoro - N,N - diisopropyl - 2 - ((4 - (7 - (((1r,4r) - 4 - (methylsulfonamido)cyclohexyl)methyl) - 2,7 - diazaspiro[3.5]nonan - 2 - yl)pyrimidin - 5 - yl)oxy)benzamide (Example 6A) and 5 - fluoro - N,N - diisopropyl - 2 - ((4 - (7 - (((1s,4s) - 4 - (methylsulfonamido)cyclohexyl)methyl) - 2,7 - diazaspiro[3.5]nonan - 2 - yl)pyrimidin - 5 - yl)oxy)benzamide (Example 6B).

Chemical Structure

[0422] A solution of 2-((4-(2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide (Example 6A, Step 2, 11 g, 24.9 mmol) in anhydrous CH2Cl2 (170 mL) was added to Intermediate 47 (7.5 g, 36.6 mmol). The mixture was stirred at room temperature for 15 minutes, and NaBH(OAc)3 (7.2 g, 33.9 mmol) was added portionwise over 5 minutes. The mixture was stirred at room temperature for an additional 2 hours. The mixture was washed with H2O (3 × 100 mL) and brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH2Cl2 / CH3OH = 24 / 1 to 10 / 1 to afford the title compound as a free base having a trans:cis ratio of 97:3. LC-MS Method D t R = 0.555 min, MS (m / z 631.3 [M + H] + ). The trans and cis isomers were separated by SFC Method A.

[0423] Trans isomer (Example 6A): LC-MS Method E: t R = 3.881 min, m / z 631.3 [M + H] + . Isomer SFC t during 10 minutes of chromatography R = 4.430 min (column: OD-3; method name: OD-3_EtOH / diethylamine_5_40_25 mL, trans = 100%). 11H NMR (CD3OD): δ 8.22 (s, 1H), 7.73 (s, 1H), 7.23 - 7.10 (m, 2H), 7.01 - 6.95 (m, 1H), 4.08 - 3.80 (m, 5H), 3.68 - 3.56 (m, 1H), 3.20 - 3.07 (m, 1H), 2.92 (s, 3H), 2.48 - 2.25 (m, 4H), 2.13 (d, J = 6.4 Hz, 2H), 2.06 - 1.96 (m, 2H), 1.91 - 1.76 (m, 6H), 1.53 (d, J = 6.8 Hz, 3H), 1.51 - 1.45 (m, 1H), 1.45 (d, J = 6.8 Hz, 3H), 1.35 - 1.24 (m, 2H), 1.17 (d, J = 6.8 Hz, 3H), 1.09 (d, J = 6.4 Hz, 3H), 1.06 - 0.98 (m, 2H). 19 19F NMR (CDCl3): δ -119.711.

[0424] Cis isomer (Example 6B): LC-MS method D: t R = 0.582 min / z 631.1 [M+H] + Retention time of the isomer in 10-minute chromatography SFC t R = 4.461 min (column: OD-3; method name: OD-3_EtOH / diethylamine_5_40_25 mL, trans / cis = 2.1% / 97.9%). 1 1H NMR (CDCl3): δ 8.36 (s, 1H), 7.75 (s, 1H), 7.05 - 6.96 (m, 2H), 6.80 - 6.71 (m, 1H), 4.40 - 4.30 (m, 1H), 4.05 - 3.75 (m, 5H), 3.70 - 3.60 (m, 1H), 3.55 - 3.45 (m, 1H), 2.96 (s, 3H), 2.45 - 2.09 (m, 6H), 1.85 - 1.65 (m, 10H), 1.60 - 1.45 (m, 7H), 1.44 - 1.19 (m, 2H), 1.13 (d, J = 6.8 Hz, 3H), 1.09 (d, J = 6.8 Hz, 3H). 1919F NMR (CDCl3): δ -118.583。

[0425] Example 7 5-((7-(5-(2-(Amino(cyclopentyl)methyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzimidazol-2-one

Chem.

[0426] Step 1: tert-Butyl 7-(5-(2-(1-((tert-butylsulfinyl)amino)ethyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate

Chem.

[0427] A solution of tert-butyl 7-(5-(2-bromo-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (Intermediate 11, 407 mg, 0.83 mmol) and (E)-N-(cyclopentylmethylene)-2-methylpropan-2-sulfinamide (249 mg, 1.24 mmol) in anhydrous THF (6 mL) was added dropwise with a 1.6 M BuLi solution in hexane (0.78 mL, 1.24 mmol) at -78 °C under a N2 atmosphere. After the addition, the mixture was stirred for an additional 30 minutes and then quenched with an aqueous NH4Cl solution. The reaction mixture was extracted twice with EtOAc, the combined organic phases were washed with H2O, dried over anhydrous Na2SO4, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography using DCM / MeOH as the eluent to give 461 mg of the desired product tert-butyl 7-(5-(2-(1-((tert-butylsulfinyl)amino)ethyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate. LCMS Method B: Rt = 1.32 min, (M+H) + = 616.3.

[0428] Step 2: N-((2-((4-(2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluorophenyl)(dicyclopentyl)methyl)-2-methylpropan-2-sulfinamide [Chemical formula]

[0429] A solution of tert-butyl 7-(5-(2-(1-((tert-butylsulfinyl)amino)ethyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (61 mg, 0.099 mmol) in DCM (6 mL) was treated with TFA (0.3 mL). The mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with EtOAc, washed successively with aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, filtered, and the solvent was evaporated under reduced pressure to give 37 mg of the crude product, which was used in the next step without further purification.

[0430] Step 3: N-(Cyclopentyl(5-fluoro-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2,7-diazaspiro(4.4)nonan-2-yl)pyrimidin-5-yl)oxy)phenyl)methyl)-2-methylpropane-2-sulfinamide

Chemical formula

[0431] To a solution of N-((2-((4-(2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluorophenyl)(cyclopentyl)methyl)-2-methylpropane-2-sulfinamide (37 mg, 0.072 mmol) in MeOH (2 mL) were added 2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbaldehyde (Intermediate 40, 14 mg, 0.086 mmol) and NaBH3CN (9 mg, 0.14 mmol). The suspension was stirred at room temperature for 24 h. The solvent was removed under reduced pressure. The residue was used in the next step without further purification.

[0432] Step 4: 5-((7-(5-(2-(Amino(cyclopentyl)methyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one The above crude product was dissolved in MeOH (1 mL) and 4 M HCl / dioxane (3 mL). After the solution was stirred at room temperature for 30 minutes, the solvent was removed under reduced pressure. The residue was purified by RP-HPLC method A to obtain 5-((7-(5-(2-(amino(cyclopentyl)methyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one. LCMS method A: Rt = 0.15 min, (M+H) + = 558.3. 1 H NMR (CD3OD) δ: 8.57 (s, 1H), 7.83 (m, 1H), 7.41 (m, 1H), 7.26 - 7.17 (m, 4H), 7.09 (d, J = 7.6 Hz, 1H), 4.42 (m, 2H), 4.07 (m, 4H), 3.64 - 3.34 (m,4H), 2.48 (m, 1H), 2.22 - 2.03 (m, 5 H), 1.78 - 1.48 (m, 6H), 1.39 (d, J = 6.4 Hz, 1H).

[0433] Example 8 5-((7-(5-(2-(cyclopentyl(dimethylamino)methyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

Chemical Structure

[0434] A solution of 5-((7-(5-(2-(Amino(cyclopentyl)methyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzimidazol-2-one tri-TFA salt (Example 7, 8.7 mg, 0.01 mmol) in DCM (2 mL) was treated with TEA (1 drop), paraformaldehyde (4 mL), and then NaBH3(OAc)3 (9 mg, 0.04 mmol). The mixture was stirred at room temperature overnight and then the solvent was removed under reduced pressure. The residue was purified by RP-HPLC Method A to give the title compound. LCMS Method A: Rt = 0.53 min, (M+H) + = 586.3. 1 1H NMR (CD3OD) δ: 8.57 (s, 1H), 7.83 (m, 1H), 7.61 (m, 1H), 7.36 (m, 1H), 7.26 (m, 1H), 7.21 (s, 1H), 7.18 (d, J = 8.0 Hz, 1H), 7.09 (d, J = 8.0 Hz, 1H), 4.43 (m, 2H), 4.14 (m, 2H), 3.62 - 3.45 (m, 3H), 2.84 (s, 6H), 2.20 - 2.06 (m, 5H), 1.76 (m, 2H), 1.62 - 1.47 (m, 4H), 0.99 (m, 1H).

[0435] Example 9 N-(Cyclopentyl(5-fluoro-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)phenyl)methyl)acetamide [Chemical Structure Diagram]

[0436] The title product was synthesized by acylating the compound of Example 7 with acetic anhydride in pyridine. The final product was purified by RP-HPLC Method A. LCMS Method A: Rt = 0.53 min, (M+H) + = 600.3.

[0437] Example 10 6 - ((7 - (5 - (4 - Fluoro - 2 - (1 - hydroxy - 2 - methylpropyl)phenoxy)pyrimidin - 4 - yl)-2,7 - diazaspiro[4.4]nonan - 2 - yl)methyl)-3,3 - dimethylindolin - 2 - one [Chemical Formula]

[0438] Step 1: 1 - (2 - ((4 - (2,7 - diazaspiro[4.4]nonan - 2 - yl)pyrimidin - 5 - yl)oxy)-5 - fluorophenyl)-2 - methylpropan - 1 - ol [Chemical Formula]

[0439] To a solution of tert - butyl 7 - (5 - (2 - bromo - 4 - fluorophenoxy)pyrimidin - 4 - yl)-2,7 - diazaspiro[4.4]nonane - 2 - carboxylate (Intermediate 11, 526 mg, 1.065 mmol) and N - methoxy - N - methylisobutyramide (268 mg, 2.04 mmol) in anhydrous THF (6 mL) at - 78 °C under a N2 atmosphere, 1.6 M BuLi (0.7 mL, 1.067 mmol) was added dropwise. After the addition, the reaction mixture was stirred for an additional 10 minutes and then quenched with an aqueous NH4Cl solution. The resulting mixture was extracted with EtOAc, washed with H2O and brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated to dryness. The residue was purified by flash chromatography to give 249 mg of tert - butyl 7 - (5 - (4 - fluoro - 2 - isobutyrylphenoxy)pyrimidin - 4 - yl)-2,7 - diazaspiro[4.4]nonane - 2 - carboxylate (Intermediate 41b). LCMS Method B: t R : 1.76 min, (M + H) + = 485.3.

[0440] To a cold solution of intermediate 41b (83 mg, 0.17 mmol) in THF / MeOH (2 / 0.5 mL) at 0 °C was added NaBH4 (20 mg, 0.53 mmol). The mixture was stirred for an additional 20 minutes and quenched with acetone. The solvent was removed to give the crude product. Next, the crude product was dissolved in MeOH (1 mL), 4M HCl / dioxane (0.5 mL) was added, and the mixture was stirred for 30 minutes. The solvent was removed under reduced pressure to give the crude product as the bis-HCl salt.

[0441] Step 2: 6 - ((7-(5-(4-Fluoro-2-(1-hydroxy-2-methylpropyl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-3,3-dimethylindolin-2-one The crude product from Step 1 was dissolved in DCM (1 mL) containing TEA (0.1 mL). Next, the solvent was removed under reduced pressure. The resulting residue was dissolved in DCM (2 mL). To this solution were added intermediate 45 (32 mg, 0.17 mmol) and NaBH(OAc)3 (72 mg, 0.34 mmol), and the mixture was stirred for 30 minutes. The solvent was removed, and the residue was purified by preparative HPLC Method A to give the title compound as the TFA salt. LCMS Method A: Rt = 0.75 min, (M + H) + = 560.3. 1 H NMR (CD3OD) δ: 8.53 (s, 1H), 7.58 (s, 1H), 7.36 - 7.10 (m, 6H), 4.53 - 3.78 (m, 11H), 2.22 (m, 4H), 1.96 (m, 1H), 1.34 (s, 6H), 1.00 (d, J = 6.8 Hz, 3H), 0.84 (d, J = 6.8 Hz, 3H).

[0442] Example 11 6 - ((7-(5-(4-Fluoro-2-isobutyrylphenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-3-methyl-2-oxoindolin-2-yl)3-carbonitrile

Chemical Structure

[0443] The title compound was synthesized from 7-(5-(4-fluoro-2-isobutyrylphenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylic acid tert-butyl (Intermediate 41b) by the method described for Steps 2 and 3 during the synthesis of Example 10. In Step 3, 6-formyl-3-methyl-2-oxoindoline-3-carbonitrile was used. LCMS Method A: Rt = 0.57 min, (M+H) + = 569.3.

[0444] Example 12 5-Fluoro-2-((4-(6-(3-(4-fluorophenyl)propanoyl)-2,6-diazaspiro[3.4]octan-2-yl)pyrimidin-5-yl)oxy)-N,N-diisopropylbenzamide

Chemical Structure

[0445] To a solution of Intermediate 41b (10 mg, 0.02 mmol), 3-(4-fluorophenyl)propanoic acid (10 mg, 0.06 mmol), and iPr2NEt (0.02 mL, 0.11 mmol) in DMF (2 mL) was added HATU (12 mg, 0.03 mmol) at room temperature, and the reaction mixture was stirred at room temperature for 1 hour. EtOAc (5 mL) and H2O (2 mL) were added for workup. The EtOAc layer was dried over Na2SO4 and evaporated. The crude residue was purified by ISCO flash column chromatography (eluting with 10% MeOH in DCM) to afford 5-fluoro-2-((4-(6-(3-(4-fluorophenyl)propanoyl)-2,6-diazaspiro[3.4]octan-2-yl)pyrimidin-5-yl)oxy)-N,N-diisopropylbenzamide as the free base. LCMS Method G: t R = 6.728 min, MS (ESI) m / z 578.56 [M+H] + . 11H NMR (CD3OD): δ 8.45 (s, 1H), 7.72 (s, 1H), 7.25 - 7.17 (m, 5H), 6.93 (t, J = 8.4 Hz, 2H), 4.65 - 4.20 (m, 4H), 3.77 - 3.72 (m, 1H), 3.60 - 3.56 (m, 3H), 3.44 - 3.40 (m, 2H), 2.85 (t, J = 7.6 Hz, 2H), 2.55 (t, J = 7.6 Hz, 2H), 2.16 - 2.10 (m, 2H), 1.46 (d, J = 6.4 Hz, 3H), 1.37 )d, J = 6.4 Hz, 3H), 1.15 (d, J = 6.4 Hz, 3H), 1.03 (d, J = 6.4 Hz, 3H).

[0446] Example 13 5 - ((7 - (5 - (4 - Fluoro - 2 - (1 - isopropyl - 1H - pyrazol - 5 - yl)phenoxy)pyrimidin - 4 - yl) - 3 - oxo - 2,7 - diazaspiro[4.4]nonan - 2 - yl)methyl) - 1H - benzimidazol - 2(3H) - one [Chemical Structure]

[0447] Step 1: 2,7 - Diazaspiro[4.4]nonan - 3 - one [Chemical Structure]

[0448] To a solution of tert - butyl 8 - oxo - 2,7 - diazaspiro[4.4]nonane - 2 - carboxylate (1 g, 4.2 mmol) in anhydrous CH2Cl2 (5 mL) was added HCl - dioxane (5 mL), and the mixture was stirred at 16 °C - 34 °C for 1 hour. The mixture was concentrated to obtain 2,7 - diazaspiro[4.4]nonan - 3 - one (HCl salt, crude product) as a white solid, which was used directly in the next step. Yield: 900 mg (HCl salt).

[0449] Process 2: 7-(5-(2-Bromo-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-3-one

Chem.

[0450] To a solution of 2,7-diazaspiro[4.4]nonan-3-one (900 mg, 4.1 mmol, HCl salt, crude) in CH3CN (20 mL) were added 5-(2-bromo-4-fluorophenoxy)-4-chloropyrimidine (Intermediate 1, 1.3 g, 4.05 mmol) and K2CO3 (1.1 g, 8.1 mmol). The mixture was stirred at 85 °C for 24 h. The mixture was filtered and the filtrate was concentrated and purified by silica gel ISCO column chromatography (100% DCM ~ 5% MeOH in DCM) to give 7-(5-(2-bromo-4-fluorophenoxy)pyrimidin-4-yl)yl)-2,7-diazaspiro[4.4]nonan-3-one as a colorless oil. Yield: 1.2 g (73%). LCMS Method C: Rt = 0.659 min. (M + H) + = 407.0, 409.0 (bromo isotopes).

[0451] Process 3: 7-(5-(4-Fluoro-2-(1-isopropyl-1H-pyrazol-5-yl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-3-one

Chem.

[0452] A solution of 7-(5-(2-bromo-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-3-one (850 mg, 2.09 mmol) in dioxane:H2O (15 mL, 1:1) was added with (1-isopropyl-1H-pyrazol-5-yl)boronic acid (385 mg, 2.51 mmol), Sphos Pallacycle-gen 2 (75 mg, 0.105 mmol) and K3PO4 (1.34 g, 6.27 mmol). The mixture was heated at 115 °C for 30 minutes by microwave. Next, the mixture was concentrated, diluted with EtOAc (30 mL), and washed with brine (50 mL × 2). The organic layer was concentrated, and the residue was purified by silica gel ISCO column chromatography (100% DCM~10% MeOH in DCM) to obtain a brown solid. This solid was purified by basic preparative RP-HPLC method D to obtain 7-(5-(4-fluoro-2-(1-isopropyl-1H-pyrazol-5-yl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-3-one as a white solid. Yield: 350 mg. LCMS method C: Rt = 0.629 min; (M+H) + = 437.2. 1 H NMR (CDCl3): δ 8.40 (s, 1H), 7.82 (s, 1H), 7.57 (s, 1H), 7.05 - 7.15 (m, 2H), 6.81 (dd, J = 9.2 4.4 Hz, 1H), 6.17 (d, J = 2.0 Hz, 1H), 5.74 (s, 1H), 4.30 - 4.41 (m, 1H), 3.80 - 3.85 (m, 1H), 3.71 (d, J = 11.2 Hz, 1H), 3.50 - 3.65 (m, 2H), 3.30 - 3.43 (m, 2H), 2.15 - 2.25 (m, 1H), 2.00 - 2.10 (m, 2H), 1.75 - 1.85 (m, 1H), 143 (d, J = 6.8 Hz, 3H), 1.47 (d, J = 6.8 Hz, 3H). 19 F NMR (CDCl3): δ -119.08。

[0453] Step 4: 7-(5-(4-Fluoro-2-(1-isopropyl-1H-pyrazol-5-yl)phenoxy)pyrimidin-4-yl)-2-(4-fluoro-3-nitrobenzyl)-2,7-diazaspiro[4.4]nonan-3-one [Chemical Structure]

[0454] To a solution of 7-(5-(4-fluoro-2-(1-isopropyl-1H-pyrazol-5-yl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-3-one (50 mg, 0.11 mmol) in anhydrous THF (3 mL) were added NaH (7 mg, 0.17 mmol) and n-Bu4I (4 mg, 0.01 mmol). Next, 4-(bromomethyl)-1-fluoro-2-nitrobenzene (33 mg, 0.14 mmol, dissolved in 1 mL of THF) was added dropwise to the mixture, and the mixture was stirred at 0 °C for 30 minutes. Then the mixture was stirred at 16 - 25 °C for 2 hours. The mixture was quenched with saturated NH4Cl (5 mL, aqueous solution) and extracted with EtOAc (5 mL × 2). The combined organic layers were dried over Na2SO4 and concentrated. The resulting residue was purified by acidic preparative RP-HPLC method A to give 7-(5-(4-fluoro-2-(1-isopropyl-1H-pyrazol-5-yl)phenoxy)pyrimidin-4-yl)-2-(4-fluoro-3-nitrobenzyl)-2,7-diazaspiro[4.4]nonan-3-one as the TFA salt as a white solid. Yield: 21 mg (32%); LCMS method C: Rt = 0.740 min; (M+H)+ = 589.9. 11H NMR (MeOD): δ 8.54 (s, 1H), 8.03 (d, J = 6.8 Hz, 1H), 7.94 (s, 1H), 7.60 - 7.70 (m, 1H), 7.56 (s, 1H), 7.46 (t, J = 9.2 Hz, 1H), 7.35 - 7.40 (m, 2H), 7.31 (d, J = 8.8 Hz, 1H), 6.30 (s, 1H), 4.57 (s, 2H), 4.35 - 4.45 (m, 1H), 4.05 - 4.15 (m, 1H), 4.00 - 4.05 (m, 1H), 3.85 - 3.95 (m, 1H), 3.65 - 3.80 (m, 1H), 3.35 - 3.50 (m, 2H), 2.00 - 2.25 (m, 4H), 1.30 - 1.45 (m, 6H). 19 19F NMR (MeOD): δ -77.21, -117.66, -122.07。

[0455] Step 5: 2-(4-Amino-3-nitrobenzyl)-7-(5-(4-fluoro-2-(1-isopropyl-1H-pyrazol-5-yl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-3-one

Chem.

[0456] A solution of 7-(5-(4-fluoro-2-(1-isopropyl-1H-pyrazol-5-yl)phenoxy)pyrimidin-4-yl)-2-(4-fluoro-3-nitrobenzyl)-2,7-diazaspiro[4.4]nonan-3-one (80 mg, 0.14 mmol) in NH3-MeOH (5 mL) was heated in an autoclave at 70 °C for 36 h. The mixture was then concentrated and purified by preparative TLC on silica gel (DCM:MeOH = 10:1) to give 2-(4-amino-3-nitrobenzyl)-7-(5-(4-fluoro-2-(1-isopropyl-1H-pyrazol-5-yl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-3-one as a yellow solid. Yield: 65 mg (80%). LCMS Method C: Rt = 0.713 min; (M+H) + = 587.2. 1 H NMR (MeOD): δ 8.29 (s, 1H), 7.96 (s, 1H), 7.83 (s, 1H), 7.51 (s, 1H), 7.22 - 7.30 (m, 2H), 7.19 (dd, J = 8.0 2.8 Hz, 1H), 6.96 - 6.99 (m, 2H), 6.19 (s, 1H), 4.38 - 4.43 (m, 3H), 3.65 - 3.73 (m, 1H), 3.59 - 3.71 (m, 2H), 3.51 (d, J = 12.0 Hz, 1H), 3.35 (s, 1H), 3.27 - 3.29 (m, 1H), 2.11 - 2.16 (m, 1H), 1.84 - 2.06 (m, 3H), 1.33 - 1.44 (m, 6H). 19 F NMR (MeOD): δ -120.79。

[0457] Step 6: 2-(3,4-Diaminobenzyl)-7-(5-(4-fluoro-2-(1-isopropyl-1H-pyrazol-5-yl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-3-one

Chemical Structure

[0458] A solution of 2-(4-amino-3-nitrobenzyl)-7-(5-(4-fluoro-2-(1-isopropyl-1H-pyrazol-5-yl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-3-one (50 mg, 0.85 mmol) in anhydrous EtOH (10 mL) was added with Raney Ni (10 mg, wet), and stirred at 17 - 26 °C under H2 (15 psi) for 18 h. The mixture was filtered and the filtrate was concentrated. The residue was purified by preparative TLC on silica gel (DCM:MeOH = 10:1) to give 2-(3,4-diaminobenzyl)-7-(5-(4-fluoro-2-(1-isopropyl-1H-pyrazol-5-yl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-3-one as a white solid. Yield: 20 mg (42%); LCMS method C: Rt = 0.624 min. (M+H) + = 557.3

[0459] Step 7: 5-((7-(5-(4-Fluoro-2-(1-isopropyl-1H-pyrazol-5-yl)phenoxy)pyrimidin-4-yl)-3-oxo-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one To a solution of 2-(3,4-diaminobenzyl)-7-(5-(4-fluoro-2-(1-isopropyl-1H-pyrazol-5-yl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-3-one (13 mg, 0.023 mmol) in anhydrous THF (5 mL) were added Et3N (10 μL) and bis(trichloromethyl) carbonate (7 mg, 0.023 mmol), and the resulting mixture was stirred at 18 - 26 °C for 16 h. TLC (DCM:MeOH = 10:1, R f= 0.7) showed a new spot, and 2-(3,4-diaminobenzyl)-7-(5-(4-fluoro-2-(1-isopropyl-1H-pyrazol-5-yl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-3-one was not completely consumed. The mixture was poured into water (5 mL) and extracted with EA (10 mL × 2). The combined organic layers were washed with brine (30 mL × 2), dried over Na2SO4, concentrated, and purified by basic preparative RP-HPLC method D to obtain 5-((7-(5-(4-fluoro-2-(1-isopropyl-1H-pyrazol-5-yl)phenoxy)pyrimidin-4-yl)-3-oxo-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one as a white solid. Yield: 2.9 mg (22%). LCMS method C: Rt = 1.596 min, (M + H) + = 583.2. 1 H NMR (MeOD): δ 8.30 (s, 1H), 7.83 (s, 1H), 7.48 (s, 1H), 7.25 - 7.35 (m, 1H), 7.21 (d, J = 8.4 Hz, 1H), 7.00 - 7.05 (m, 1H), 6.95 - 7.00 (m, 3H), 6.16 (s, 1H), 4.35 - 4.55 (m, 3H), 3.80 - 3.90 (m, 1H), 3.55 - 3.70 (m, 2H), 3.45 - 3.55 (m, 1H), 3.20 - 3.30 (m, 2H), 1.85 - 2.20 (m, 4H), 1.35 - 1.45 (m, 6H). 19 F NMR (MeOD): δ -120.78。

[0460] Examples 14A - 14B N-(4-Fluoro-2-(5-isopropyl-3-methylisoxazol-4-yl)phenyl)-4-(6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-amine (Example 14A) and 4-(5-fluoro-2-((4-(6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)phenyl)-5-isopropyl-3-methylisoxazole (Example 14B)

Chemical Structure

[0461] Step 1: 5-Isopropyl-3-methylisoxazole and 3-Isopropyl-5-methylisoxazole

Chemical Structure

[0462] A suspension of 5-methylhexane-2,4-dione (300 mg, 2.34 mmol) and hydroxylamine HCl (194 mg, 2.82 mmol) in EtOH was heated at 130 °C in a microwave for 3 minutes. The EtOH was evaporated, and the crude product was partitioned between Et2O (5 mL) and water (3 mL). The Et2O layer was dried using MgSO4 and then evaporated to give the crude product as a 4:1 mixture of isoxazole positional isomers. The major isomer was designated as 5-isopropyl-3-methylisoxazole and the minor isomer as 3-isopropyl-5-methylisoxazole. This crude mixture was used directly in the next step without further purification. LCMS Method A: t R = 1.485; [M+H]+ = 126.28

[0463] Step 2: 4-Bromo-5-isopropyl-3-methylisoxazole and 4-Bromo-3-isopropyl-5-methylisoxazole

Chemical Structure

[0464] To a solution of crude 5-isopropyl-3-methylisoxazole (4:1 crude mixture from step 1, 2.34 mmol) in DMF (3 mL) was added N-bromosuccinimide (625 mg, 3.51 mmol) at room temperature, and the reaction mixture was stirred at room temperature for 15 h. Next, EtOAc (10 mL) and H2O (10 mL) were added for workup. The EtOAc layer was separated and washed with saturated aqueous Na2S2O5 followed by brine. The EtOAc layer was then dried over Na2SO4 and evaporated. The crude product was purified by ISCO flash column chromatography (eluting with 20% EtOAc in hexanes) to give 200 mg (42% over 2 steps) of the product as a 4:1 mixture of positional isomers. The major isomer was 4-bromo-5-isopropyl-3-methylisoxazole and the minor isomer was 4-bromo-3-isopropyl-5-methylisoxazole. LCMS method A: t R = 1.787; [M]+ = 204.25 and 206.26. 1 H NMR (CDCl3): major isoxazole positional isomer (4-bromo-5-isopropyl-3-methylisoxazole) δ 3.21 - 3.14 (m, 1H), 2.26 (s, 3H), 1.32 (d, J = 7.2 Hz, 6H).

[0465] Step 3: 5-Isopropyl-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole and 3-isopropyl-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole

Chem.

[0466] A mixture of 4-bromo-5-isopropyl-3-methylisoxazole (a 4:1 mixture of positional isomers from Step 2, 100 mg, 0.49 mmol), pinacolborane (0.11 mL, 0.78 mmol), PdCl2(MeCN)2 (3 mg, 2 mol%), Esphos ligand (10 mg, 5 mol%), and Et3N (0.24 mL, 1.72 mmol) in dioxane (2 mL) was heated at 100 °C for 1 h under a N2 blanket in a sealed vial. The reaction mixture was cooled to room temperature, filtered through a plug of celite, and the solvent was evaporated. The crude residue was purified using ISCO flash column chromatography (eluting with 20% EtOAc in hexane) to give 100 mg of 5-isopropyl-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole and 3-isopropyl-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole as a 4:1 mixture of positional isomers, which was used in the next step without further purification.

[0467] Step 4: tert-Butyl 6-(5-bromopyrimidin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

Chemical Structure

[0468] A suspension of 5-bromo-4-chloropyrimidine (1.67 g, 8.65 mmol), tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate hemisuccinate (2 g, 4.12 mmol), and iPr2NEt (1.80 mL, 10.3 mmol) in iPrOH (10 mL) was heated to reflux for 15 h. For workup, saturated aqueous NH4Cl (10 mL) and EtOAc (20 mL) were added to the reaction mixture. The EtOAc layer was separated, and the aqueous layer was extracted again with EtOAc. The combined EtOAc layers were washed with water and then brine and dried over Na2SO4. Evaporation of EtOAc gave tert-butyl 6-(5-bromopyrimidin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate as an off-white foamy solid (2 g, 70%), which was almost pure by LCMS analysis and used directly in the next step without further purification. LCMS method A: t R = 1.330 min; [M+H] + = 355.41 and 357.

[0469] Step 5: tert-Butyl 6-(5-((2-chloro-4-fluorophenyl)amino)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate [Chemical Structure]

[0470] A mixture of tert-butyl 6-(5-bromopyrimidin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (100 mg, 0.28 mmol), 2-chloro-4-fluoroaniline (39 mg, 0.27 mmol), Pd2(dba)3 (5 mg, 0.005 mmol), XPhos (11 mg, 0.023 mmol), and NaOtBu (60 mg, 0.63 mmol) in toluene (2 mL) was heated in a CEM microwave at 160 °C for 30 minutes. After cooling, the reaction mixture was diluted with 5 mL of EtOAc and filtered through a plug of celite. The solvent was evaporated to give a crude solid, which was triturated with hexane overnight. The solid material was filtered to give 92 mg (79%) of tert-butyl 6-(5-((2-chloro-4-fluorophenyl)amino)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate, which was nearly pure by LCMS analysis and was used directly in the next step without further purification. LCMS method A: t R = 1.411; [M+H] + = 420.54 and 422.55.

[0471] Step 6: tert-Butyl 6-(5-((4-fluoro-2-(5-isopropyl-3-methylisoxazol-4-yl)phenyl)amino)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate and tert-Butyl 6-(5-((4-fluoro-2-(3-isopropyl-5-methylisoxazol-4-yl)phenyl)amino)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

Chem.

[0472] tert-Butyl 6-(5-((2-chloro-4-fluorophenyl)amino)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (35 mg, 0.083 mmol), and 5-isopropyl-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole and 3-isopropyl-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole as a 4:1 mixture of isomers (step 3, 21 mg, 0.083 mmol) in dioxane / H2O (1 mL / 0.40 mL) were heated in a CEM microwave at 120 °C for 15 min with a mixture of K3PO4 (53 mg, 0.25 mmol), and Esphos - Paradaxycle (CAS#: 1375325-64-6, 3 mg, 0.004 mmol). After cooling, the reaction mixture was filtered through celite and the solvent was evaporated. Purification by ISCO flash column chromatography (eluting with 100% EtOAc) gave tert-butyl 6-(5-((4-fluoro-2-(5-isopropyl-3-methylisoxazol-4-yl)phenyl)amino)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate as the major isoxazole isomer (4:1 mixture) from the isomer mixture of the starting material. The isomer mixture of this product was used directly in the next step without further purification. LCMS method A: t R = 1.367; [M+H] + = 509.70.

[0473] Step 7: N-(4-Fluoro-2-(5-isopropyl-3-methylisoxazol-4-yl)phenyl)-4-(2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-amine and N-(4-Fluoro-2-(3-isopropyl-5-methylisoxazol-4-yl)phenyl)-4-(2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-amine

Chemical Structure

[0474] A solution of tert-butyl 6-(5-((4-fluoro-2-(5-isopropyl-3-methylisoxazol-4-yl)phenyl)amino)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate and tert-butyl 6-(5-((4-fluoro-2-(3-isopropyl-5-methylisoxazol-4-yl)phenyl)amino)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (a 4:1 mixture of isoxazole positional isomers from Step 6, 40 mg, 0.079 mmol) in DCM (3 mL) was treated with TFA (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 h and then the solvent was removed. DCM (2 mL) and Et3N (0.05 mL) were added to form the free base amine from the TFA salt. The solvent was evaporated and dried under high vacuum to afford N-(4-fluoro-2-(5-isopropyl-3-methylisoxazol-4-yl)phenyl)-4-(2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-amine and N-(4-fluoro-2-(3-isopropyl-5-methylisoxazol-4-yl)phenyl)-4-(2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-amine as the free base (a 4:1 mixture of isoxazole positional isomers). This material was used directly in the next step without further purification.

[0475] Step 8: N-(4-Fluoro-2-(5-isopropyl-3-methylisoxazol-4-yl)phenyl)-4-(6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-amine and N-(4-Fluoro-2-(3-isopropyl-5-methylisoxazol-4-yl)phenyl)-4-(6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-amine A solution of crude N-(4-fluoro-2-(5-isopropyl-3-methylisoxazol-4-yl)phenyl)-4-(2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-amine and N-(4-fluoro-2-(3-isopropyl-5-methylisoxazol-4-yl)phenyl)-4-(6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-amine (a 4:1 mixture of isoxazole positional isomers from Step 7, 0.079 mmol) and tetrahydro-2H-pyran-4-carbaldehyde (27 mg, 0.24 mmol) in dichloroethane (2 mL, containing 1% AcOH) was treated with NaBH(OAc)3 (50 mg, 0.24 mmol) at room temperature. The reaction mixture was stirred for 30 minutes and completion was confirmed by LCMS analysis. After evaporation of the solvent, purification was performed using HPLC Method A to afford the TFA salts of N-(4-fluoro-2-(5-isopropyl-3-methylisoxazol-4-yl)phenyl)-4-(6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-amine and N-(4-fluoro-2-(3-isopropyl-5-methylisoxazol-4-yl)phenyl)-4-(6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-amine as a 4:1 mixture of isoxazole positional isomers (15 mg). LCMS Method B: t R = 1.124; [M+H] + = 507.70。

[0476] Example 14A : Major isoxazole positional isomer LCMS Method B: t R = 1.013; [M+H] + = 507.70 11H NMR (CD3OD). δ 8.55 (broad singlet, 1H), 7.79 (broad singlet, 1H), 7.17 - 7.12 (multiplet, 1H), 7.00 (doublet, J = 3.2, 8.8 Hz, 1H), 6.83 (doublet, J = 5.2, 9.2 Hz, 1H), 4.60 - 4.35 (multiplet, 8H), 3.93 (doublet, J = 4.0, 11.6 Hz, 2H), 3.40 (triplet, J = 11.6 Hz, 2H), 3.11 (doublet, J = 7.2 Hz, 2H), 3.07 - 3.00 (multiplet, 1H), 2.17 (singlet, 3H), 1.93 - 1.87 (multiplet, 1H), 1.60 (doublet, J = 11.6 Hz, 2H), 1.37 - 1.20 (multiplet, 1H), 1.27 (doublet, J = 6.4 Hz, 3H), 1.26 (doublet, J = 6.4 Hz, 3H), 1.21 - 1.16 (multiplet, 1H).

[0477] Example 14B : Minor isoxazole positional isomer LCMS method B t R = 1.124; [M + H] + = 507.70.

[0478] Example 15 N-(5-Fluoro-2'-isopropyl-[1,1'-biphenyl]-2-yl)-4-(6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-amine

Chemical Structure

[0479] The title product was synthesized by the methods described in Examples 14A - 14B. In step 3, 2-isopropylphenylboronic acid was used. LCMS method G: Rt = 4.88 min; M + H + = 502.85. 11H NMR (d4-MeOH) δ 8.45 (s, 1H), 7.72, (s, 1H), 7.47 (d, 1H), 7.42 (m, 1H), 7.28 (m, 1H), 7.20 (d, 1H), 7.07 (m, 1H), 6.92 (m, 1H), 6.81 (m, 1H), 4.32 - 4.56 (m, 8H), 3.94 (m, 2H), 3.39 (m, 2H), 3.11 (d, 2H), 2.82 (m, 2H), 1.86 (m, 1H), 1.59 (d, 2H), 1.33 (m, 2H), 1.20 (d, 3H), 1.13 (d, 3H) ppm。

[0480] Example 16 5-Fluoro-2-((4-(2-(2-hydroxy-2-methylpropyl)-2,7-diazaspiro[3.5]nonan-7-yl)pyrimidin-5-yl)amino)-N,N-diisopropylbenzamide

Chem.

[0481] Step 1: 2-((4-(2-(tert-Butoxycarbonyl)-2,7-diazaspiro[3.5]nonan-7-yl)pyrimidin-5-yl)amino)-5-fluorobenzoic acid

Chem.

[0482] To a round-bottom flask were added tert-butyl 7-(5-iodopyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (Example 71, Step 1, 500 mg, 1 equivalent), 2-amino-5-fluorobenzoic acid (216 mg, 1.2 equivalents), Pd2(dba)3 (21 mg, 0.02 equivalent), Xantphos (54 mg, 0.08 equivalent), and Cs2CO3 (1.33 g, 3.5 equivalents). To this solid mixture was added dioxane (8 mL, 0.15 M with respect to tert-butyl 7-(5-iodopyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate). The heterogeneous solution was purged with a nitrogen stream for 1 minute. The flask was capped and the reaction mixture was heated at 100 °C overnight. Next, Cs2CO3 was filtered off, the filtrate was diluted with EtOAc, and 0.5 M HCl was added. The resulting white solid was filtered and dried under vacuum. Yield: 400 mg.

[0483] Step 2: tert-Butyl 7-(5-((2-(diisopropylcarbamoyl)-4-fluorophenyl)amino)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate [Chemical formula]

[0484] To a round-bottom flask were added 2-((4-(2-(tert-butoxycarbonyl)-2,7-diazaspiro[3.5]nonan-7-yl)pyrimidin-5-yl)amino)-5-fluorobenzoic acid (500 mg) and HOBt (184 mg). To this solid mixture were added DMF (3.65 mL), diisopropylamine (1 mL), and diisopropylethylamine (209 μL), followed by BOP reagent (532 mg, 1.1 eq), and the mixture was stirred overnight. Next, the mixture was partitioned between EtOAc and water. The phases were separated, and the aqueous phase was back-extracted twice with EtOAc. The combined organic phases were dried over magnesium sulfate and concentrated. The crude material was purified by flash chromatography (40 g of SiO2, using MeOH / DCM as the eluent) to give tert-butyl 7-(5-((2-(diisopropylcarbamoyl)-4-fluorophenyl)amino)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (300 mg).

[0485] Step 3: 5-Fluoro-2-((4-(2-(2-hydroxy-2-methylpropyl)-2,7-diazaspiro[3.5]nonan-7-yl)pyrimidin-5-yl)amino)-N,N-diisopropylbenzamide tert-Butyl 7-(5-((2-(diisopropylcarbamoyl)-4-fluorophenyl)amino)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (300 mg), DCM (5 mL), and TFA (5 mL) were added to a round-bottom flask, and the reaction mixture was stirred at room temperature for 30 minutes. Next, the volatile substances were removed under vacuum. The crude residue was co-evaporated twice with DCM to obtain 2-((4-(2,7-diazaspiro[3.5]nonan-7-yl)pyrimidin-5-yl)amino)-5-fluoro-N,N-diisopropylbenzamide bis-TFA salt. To the round-bottom flask were added the bis-TFA salt (20 mg), 2,2-dimethyloxirane (11 mg), triethylamine (21 μL), and THF:ethanol (2 mL, 1:1 ratio). The flask was capped, and the mixture was heated at 65 °C overnight. When the reaction was complete, the volatile substances were removed under vacuum. The crude material was purified by RP-HPLC method A to obtain 5-fluoro-2-((4-(2-(2-hydroxy-2-methylpropyl)-2,7-diazaspiro[3.5]nonan-7-yl)pyrimidin-5-yl)amino)-N,N-diisopropylbenzamide (3.7 mg). LCMS method G Rt = 3.65 min; (M+H) + = 513.61. 1 H NMR (d4-MeOH) 8.52 (s, 1H), 7.87 (s, 1H), 7.07 - 7.15 (m, 2H), 6.93 (m, 1H), 4.23 (d, 2H), 4.04 (d, 2H), 3.82 - 3.89 (m, 6H), 1.93 - 1.99 (m, 4H), 1.26 - 1.34 (m, 18H).

[0486] Example 17 5-((7-(5-(2-(dimethylphosphoryl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one

Chemical Structure

[0487] Process 1: tert-Butyl 7-(5-(2-(dimethylphosphoryl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate

Chem.

[0488] To a mixture of tert-butyl 7-(5-(2-bromo-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (Intermediate 11, 200 mg, 0.41 mmol), (CH3)2PO (35 mg, 0.45 mmol), and K3PO4 (104 mg, 0.49 mmol) in anhydrous DMF (3 mL) were added Pd(OAc)2 (1.0 mg, 0.004 mmol) and Xantphos (4.0 mg, 0.006 mmol), and the reaction mixture was stirred under microwave at 150 °C for 30 minutes. The reaction mixture was filtered through a Celite pad and concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography (eluting with dichloromethane:methanol = 1:0 to 10:1) to give tert-butyl 7-(5-(2-(dimethylphosphoryl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate as a pale yellow oil. Yield: 120 mg. LCMS method E: Rt = 0.836 min, (M+H) + = 491.2.

[0489] Processes 2 - 3: 5-((7-(5-(2-(dimethylphosphoryl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one Processes 2 - 3 were carried out according to the procedures of Steps 4 - 5 in Example 1. LCMS method E: Rt = 1.344 min; (M+H) + = 537.2. 11H NMR (CD3OD): δ 8.34 (s, 1 H), 7.89 (s, 1 H), 7.61 (m, 1 H), 7.22 - 7.60 (m, 1 H), 6.96 - 7.00 (m, 3 H), 6.73 - 6.77 (m, 1 H), 3.59 (s, 6 H), 2.43 - 2.67 (m, 4 H), 1.90 (d, J = 14 Hz, 8 H), 1.78 (t, J = 6.4 Hz, 2 H). 19 19F NMR (CD3OD): δ -120.92。

[0490] Example 18 2-(5-(4-Fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)-N-(4-fluorobenzyl)-5-oxa-2-azaspiro[3.4]octan-7-amine

Chemical Structure

[0491] Step 1: 5-Oxa-2-azaspiro[3.4]octan-7-one trifluoroacetate

Chemical Structure

[0492] To a solution of tert-butyl 7-oxo-5-oxa-2-azaspiro[3.4]octane-2-carboxylate (300 mg, 1.32 mmol) in DCM (3 mL) was added TFA (1 mL) at room temperature, and the reaction mixture was stirred at room temperature for 1 hour. The solvent was removed to obtain 5-oxa-2-azaspiro[3.4]octan-7-one TFA salt, which was used directly in the next step without further purification. LCMS Method A: t R = 0.269 min; [M + H] + = 128.28。

[0493] Step 2: 2-(5-(2-Bromo-4-fluorophenoxy)pyrimidin-4-yl)-5-oxa-2-azaspiro[3.4]octan-7-one

Chem.

[0494] A mixture of 5-oxa-2-azaspiro[3.4]octan-7-one TFA salt (168 mg, 1.32 mmol), 5-(2-bromo-4-fluorophenoxy)-4-chloropyrimidine (Intermediate 1, 481 mg, 1.58 mmol), and iPr2NEt (0.92 mL, 5.28 mmol) in iPrOH (3 mL) was heated at 100 °C for 12 h. Purification was performed using ISCO flash column chromatography (eluting with 10% MeOH in DCM) to afford 406 mg of 2-(5-(2-bromo-4-fluorophenoxy)pyrimidin-4-yl)-5-oxa-2-azaspiro[3.4]octan-7-one. LCMS Method A: t R = 0.961 min; [M+H] + = 394.35 and 396.37.

[0495] Step 3: 2-(5-(4-Fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)-5-oxa-2-azaspiro[3.4]octan-7-one

Chem.

[0496] A mixture of 2-(5-(2-bromo-4-fluorophenoxy)pyrimidin-4-yl)-5-oxa-2-azaspiro[3.4]octan-7-one (147 mg, 0.37 mmol), (4-isopropylpyrimidin-5-yl)boronic acid (93 mg, 0.56 mmol), PdCl2(PPh3)2 (26 mg, 0.037 mmol), and K3PO4 (237 mg, 1.12 mmol) in dioxane (2.5 mL) and water (0.25 mL) was heated in a CEM microwave at 120 °C for 2 h. The mixture was filtered through celite and the solvent was evaporated. Purification was performed using ISCO flash column chromatography (eluting with 10% MeOH in DCM) to give 151 mg of 2-(5-(4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)-5-oxa-2-azaspiro[3.4]octan-7-one. LCMS method A: t R = 0.926 min; [M+H] + = 436.48.

[0497] Step 4: 2-(5-(4-Fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)-N-(4-fluorobenzyl)-5-oxa-2-azaspiro[3.4]octan-7-amine To a solution of 2-(5-(4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)-5-oxa-2-azaspiro[3.4]octan-7-one (14 mg, 0.03 mmol) and (4-fluorophenyl)methanamine (0.006 mL, 0.047 mmol) in MeOH (2 mL) was added NaBH3CN (8 mg, 0.12 mmol) and the reaction mixture was stirred at 50 °C for 6 h. The solvent was evaporated and purification was performed using Gilson HPLC to give 4.6 mg of 2-(5-(4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)-N-(4-fluorobenzyl)-5-oxa-2-azaspiro[3.4]octan-7-amine TFA salt. LCMS method A: t R = 0.572 min; [M+H] + = 545.60. 11H NMR (CD3OD): δ 9.10 (s, 1H), 8.57 (s, 1H), 8.21 (s, 1H), 7.69 (s, 1H), 7.38 - 7.34 (m, 2H), 7.30 - 7.22 (m, 2H), 7.10 - 7.03 (m, 3H), 4.19 (bs, 1H), 4.14 - 4.03 (m, 3H), 3.91 (dd, J = 6.0, 9.0 Hz, 1H), 3.75 (d, J = 6.4 Hz, 2H), 3.71 - 3.66 (m, 1H), 3.46 - 3.41 (m, 1H), 3.08 - 3.01 (m, 1H), 2.35 - 2.30 (m, 1H), 2.08 - 2.02 (m, 1H), 1.19 (d, J = 6.8 Hz, 6H).

[0498] Example 19 4 - ((((2 - (5 - ((5 - Fluoro - 2'-isopropyl - [1,1'-biphenyl] - 2 - yl)oxy)pyrimidin - 4 - yl)-5 - oxa - 2 - azaspiro[3.4]octan - 7 - yl)amino)methyl)benzonitrile

Chem.

[0499] The title compound was synthesized according to the method described in Example 18. In Step 3, 2 - isopropylphenylboronic acid was used. In Step 4, 4 - cyanobenzaldehyde was used. LCMS Method A: Rt = 1.125 min; (M + H) + = 550.68. 11H NMR (CD3OD): δ 8.12 (s, 1H), 7.70 (d, J = 7.6 Hz, 2H), 7.55 (d, J = 7.6 Hz, 2H), 7.38 - 7.32 (m, 2H), 7.21 - 7.05 (m, 5H), 4.19 - 4.09 (m, 2H), 4.03 - 3.97 (m, 2H), 3.92 - 3.87 (m, 1H), 3.87 - 3.82 (m, 2H), 3.67 (dd, J = 4.8, 9.0 Hz, 1H), 3.40 (bs, 1H), 2.84 - 2.78 (m, 1H), 2.29 - 2.22 (m, 1H), 2.05 - 2.01 (m, 2H), 1.11 - 1.08 (m, 6H).

[0500] Example 20 7-(5-(4-Fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)-N-(4-fluorobenzyl)-1-oxa-7-azaspiro[4.4]nonan-3-amine

Chemical Structure

[0501] Starting from tert-butyl 3-oxo-1-oxa-7-azaspiro[4.4]nonane-7-carboxylate, the title compound was synthesized according to the method described in Example 18. LCMS Method A: t R = 0.585; [M+H] + = 559.61. 1 1H NMR (CD3OD): δ 9.10 (s, 1H), 8.57 (s, 1H), 8.21 (s, 1H), 7.78 (s, 1H), 7.41 - 7.35 (m, 2H), 7.28 - 7.20 (m, 2H), 7.09 - 6.95 (m, 3H), 4.42 (bs, 1H), 3.97 - 3.47 (m, 8H), 3.12 - 3.05 (m, 1H), 2.27 - 2.23 (m, 1H), 2.18 - 2.10 (m, 1H), 1.99 - 1.81 (m, 2H), 1.24 - 1.19 (m, 6H).

[0502] Example 21 5-Fluoro-N-isopropyl-N-methyl-2-((4-(7-(((1r,4r)-4-(methylcarbamoyl)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide [Chemical formula]

[0503] Step 1: Methyl (1r,4r)-4-((2-(5-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)cyclohexane-1-carboxylate [Chemical formula]

[0504] The title compound was synthesized by reductive amination between 2-((4-(2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropyl-N-methylbenzamide (0.18 mmol) and methyl (1r,4r)-4-formylcyclohexane-1-carboxylate (100 μL) according to the method described in Step 4 of Example 18. LCMS Method B: Rt = 0.73 min, (M+H) + = 568.5

[0505] Step 2: (1r,4r)-4-((2-(5-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)cyclohexane-1-carboxylic acid [Chemical formula]

[0506] A solution of methyl (1r,4r)-4-((2-(5-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)cyclohexane-1-carboxylate (30 mg, 0.053 mmol) in MeOH (1 mL) was added with 2N LiOH solution (0.2 mL). The solution was stirred at room temperature overnight, the solvent was removed until dry, and the residue was used in the next step without purification. LCMS method B: Rt = 0.63 min, (M+H) + = 554.6.

[0507] Step 3: 5-Fluoro-N-isopropyl-N-methyl-2-((4-(7-(((1r,4r)-4-(methylcarbamoyl)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide To a solution of the crude product from Step 2 in DMF (0.5 mL) were added MeNH2HCl (15 mg) and Et3N (200 μL), followed by HATU (20 mg), and the resulting solution was stirred at room temperature for 30 min. The product was purified by preparative RP-HPLC method A to give 5-fluoro-N-isopropyl-N-methyl-2-((4-(7-(((1r,4r)-4-(methylcarbamoyl)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide as the TFA salt (7 mg); LCMS method B: Rt = 0.60 min, (M+H) + = 567.6; 1 1H NMR (MeOH-d4): δ 8.38, 8.37 (s, 1 H), 7.73, 7.61 (br.s, 1 H), 7.24 - 7.12 (m, 3 H), 4.65 (m, 1 H), 4.52 - 3.96 (m, 4 H), 3.45 (m, 2 H), 2.88 (m, 4 H), 2.82, 2.68 (two s, 3 H), 2.58 (s, 3 H), 2.16 (m, 2 H), 2.08 - 1.88 (m, 3 H), 1.74 (m, 5 H), 1.41 (m, 2 H), 1.12 - 0.92 (m, 8 H).

[0508] Examples 22A and 22B 2-((4-(7-Amino-7-(4-cyanobenzyl)-2-azaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide (Isomers 1 - 2) [Chemical Formula]

[0509] Step 1: tert-Butyl 7-(4-bromobenzyl)-7-((tert-butylsulfinyl)amino)-2-azaspiro[4.4]nonane-2-carboxylate [Chemical Formula]

[0510] To a solution of tert-butyl 7-((tert-butylsulfinyl)imino)-2-azaspiro[4.4]nonane-2-carboxylate (Examples 250A - 250B, Step 1, 0.73 g, 2.13 mmol) in THF (15 mL) at 0 °C was added 4-bromobenzylmagnesium bromide (0.25 M in Et2O, 20 mL), and the solution was warmed to room temperature. After 2 hours, another 20 mL of the Grignard reagent was added, and the mixture was stirred for an additional 2 hours. The reaction was quenched with NH4Cl, and the organic layer was separated. The aqueous layer was extracted with EtOAc (2 × 5 mL), and the combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography to give tert-butyl 7-(4-bromobenzyl)-7-((tert-butylsulfinyl)amino)-2-azaspiro[4,4]nonane-2-carboxylate (174.4 mg, 16%). LCMS Method B: Rt = 2.22 min; (M + H) + = 513.6

[0511] Step 2: tert-Butyl 7-((tert-butylsulfinyl)amino)-7-(4-cyanobenzyl)-2-azaspiro[4.4]nonane-2-carboxylate [Chemistry]

[0512] To a solution of tert-butyl 7-(4-bromobenzyl)-7-((tert-butylsulfinyl)amino)-2-azaspiro[4.4]nonane-2-carboxylate (88.4 mg, 0.17 mmol) in anhydrous DMF (0.5 mL) were added Zn(CN)2 (20 mg, 0.17 mmol) and Pd(PPh3)4 (20 mg, 0.02 mmol). The resulting solution was degassed and heated overnight at 110 °C under N2 in an oil bath. The reaction mixture was cooled, diluted with EtOAc, washed with 1N HCl (5 mL), brine, and dried over Na2SO4. After removal of the solvent, the residue was purified by silica gel column (0 - 9% MeOH / DCM) to give tert-butyl 7-((tert-butylsulfinyl)amino)-7-(4-cyanobenzyl)-2-azaspiro[4.4]nonane-2-carboxylate (56 mg, 72%). LCMS Method B: Rt = 1.67 min; (M+H) + = 460.6.

[0513] Step 3: 4-((7-Amino-2-azaspiro[4.4]nonan-7-yl)methyl)benzonitrile [Chemistry]

[0514] To a solution of tert-butyl 7-((tert-butylsulfinyl)amino)-7-(4-cyanobenzyl)-2-azaspiro[4.4]nonane-2-carboxylate (56 mg, 0.12 mmol) in DCM (2 mL) was added TFA (50 μL), and the resulting solution was stirred overnight at room temperature to give 4-((7-amino-2-azaspiro[4.4]nonan-7-yl)methyl)benzonitrile. The solvent was removed, and the resulting residue was used in the next step without purification. LCMS Method B: Rt = 0.32 min; (M+H) + = 256.6.

[0515] Step 4: 2-((4-(7-Amino-7-(4-cyanobenzyl)-2-azaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide (Isomers 1 - 2) To a solution of the crude product from Step 3 in isopropanol (0.5 mL) was added 2-((4-chloropyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide (Intermediate 41, 30 mg) and Et3N (200 μL), and the resulting solution was heated in a CEM microwave reactor at 110 °C for 1 hour. The reaction solution was cooled to room temperature and purified by preparative RP-HPLC Method A to give the following: Isomer 1 as the TFA salt (1.22 mg); LCMS Method B: Rt = 0.83 min; (M + H) + = 571.4. 1 H NMR (MeOH-d4): δ 8.49 (s, 1 H), 7.92 (s, 1 H), 7.70 (m, 2H), 7.47 (d, J = 6.8 Hz, 2 H), 7.19 (m, 2 H), 7.07 (br, 1 H), 4.04 - 3.66 (m, 4 H), 3.61 (m, 2 H), 3.26 (m, 1 H), 3.08 (s, 2 H), 2.28 - 1.76 (m, 8 H), 1.49 (m, 3 H), 1.40 (m, 3 H), 1.17 (d, J = 7.6 Hz, 3 H), 1.10 (m, 3 H); and Isomer 2 as the TFA salt (1.36 mg); LCMS Method B: Rt = 0.89 min; (M + H) + = 571.4. 11H NMR (MeOH-d4): δ 8.36 (s, 1 H), 7.86 (br, 1 H), 7.57 (d, J = 8 Hz, 2H), 7.32 (d, J =7.6 Hz, 2 H), 7.04 (d, J = 7.6 Hz, 2 H), 6.96 (br, 1 H), 3.80-3.48 (m, 5 H), 3.18 (m, 1 H), 2.94 (s, 2 H), 2.05 (m, 2 H), 1.86-1.58 (m, 4 H), 1.49 (m, 2 H), 1.34 (d, J = 6.8 Hz, 3 H), 1.24 (d, J = 6. 4 Hz, 3 H), 1.02 (d, J = 6.8 Hz, 3 H), 0.94 (d, J = 6.8 Hz, 3 H).

[0516] Examples 23A to 23C 5-Fluoro-2-((4-(7-hydroxy-8-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2-azaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-N,N-diisopropylbenzamide (Isomers 1 to 3) [Chemical formula]

[0517] Step 1: tert-Butyl 7-oxo-8-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methylene)-2-azaspiro[4.4]nonane-2-carboxylate [Chemical formula]

[0518] To a solution of tert-butyl 7-oxo-2-azaspiro[4.4]nonane-2-carboxylate (0.28 g, 1.17 mmol) and 2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbaldehyde (Intermediate 40, 0.23 g, 1.29 mmol) in DMSO (3 mL) were added L-proline (40 mg), 3-ethyl-1-methyl-1H-imidazol-3-ium 2,2,2-trifluoroacetate ([EMIm][CF3COO]) (79 mg, 0.35 mmol) and H2O (0.32 g). The resulting mixture was heated at 80 °C for 4 days, cooled to room temperature, diluted with H2O (5 mL), and extracted with EtOAc (4 × 5 mL). The combined organic layers were concentrated and the residue was purified by silica gel column (0 - 4% MeOH / DCM) to give tert-butyl 7-oxo-8-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methylene)-2-azaspiro[4.4]nonane-2-carboxylate (ca. 190 mg, ca. 42%, aldehyde starting material still present). LCMS Method B: Rt = 1.16 min; (M - 55) + = 328.3; 1 H NMR (MeOH-d4): δ 9.62 (br 1 H), 9.46 (br, 1 H), 7.40 (s, 1 H), 7.18 (d, J = 6.8 Hz, 1 H), 7.03 (d, J = 6.8 Hz, 1 H), 5.24 (s, 1 H), 3.40 (m, 2 H), 3.28, 3.20 (two s, 2 H), 2.88 (s, 2 H), 2.40 (s, 2 H), 1.80 (m, 2 H), 1.4, 1.40 (two s, 9 H).

[0519] Step 2: tert-Butyl 7-hydroxy-8-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2-azaspiro[4.4]nonane-2-carboxylate and tert-butyl 7-oxo-8-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2-azaspiro[4.4]nonane-2-carboxylate

Chem.

[0520] To a solution of tert-butyl 7-oxo-8-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methylene)-2-azaspiro[4.4]nonane-2-carboxylate (130 mg) in MeOH (10 mL) was added Pd-C (10 mg), and the solution was stirred overnight at room temperature with an H2 balloon. LC-MS showed a mixture of tert-butyl 7-hydroxy-8-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2-azaspiro[4.4]nonane-2-carboxylate and tert-butyl 7-oxo-8-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2-azaspiro[4.4]nonane-2-carboxylate. The reaction mixture was filtered through a Celite pad and the solvent was removed under vacuum. The residue was purified by silica gel column (3 - 7% MeOH / DCM) to afford tert-butyl 7-oxo-8-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2-azaspiro[4.4]nonane-2-carboxylate (ca. 50 mg); LCMS method B: Rt = 1.17 min; (M - 55) + = 330.3; and tert-butyl 7-hydroxy-8-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2-azaspiro[4.4]nonane-2-carboxylate (ca. 80 mg) was obtained; LCMS method B: Rt = 1.17 min; (M - 55) + = 332.3。

[0521] Step 3: 5-((8-Hydroxy-2-azaspiro[4.4]nonan-7-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

Chem.

[0522] To a solution of tert-butyl 7-hydroxy-8-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2-azaspiro[4.4]nonane-2-carboxylate (20 mg, 0.052 mmol) in DCM (0.5 mL) was added TFA (0.2 mL), and the solution was stirred at room temperature for 30 minutes. Next, the solvent was removed to dryness to obtain the TFA salt of 5-((8-hydroxy-2-azaspiro[4.4]nonan-7-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one, which was used in the next step without purification. LCMS method B: Rt = 0.47 min; (M + H) + = 288.3.

[0523] Step 4: 5-Fluoro-2-((4-(7-hydroxy-8-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2-azaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-N,N-diisopropylbenzamide (isomers 1 - 3) To a solution of the crude product from Step 3 in isopropanol (0.3 mL) were added 2-((4-chloropyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide (Intermediate 41, 20 mg) and Et3N (150 μL), and the resulting solution was heated in a CEM microwave reactor at 110 °C for 1 hour. LC-MS showed three products with t R = 0.88, 0.90, and 0.95 min in a ratio of 1:1:5. The products were isolated by preparative RP-HPLC method A to give the following: Isomer 1 (1.4 mg) as the TFA salt, LCMS method B: Rt = 0.88 min; (M + H) + = 603.5. 11H NMR (MeOH-d4): δ 8.37 (s, 1 H), 7.68, 7.54 (two br, 1 H), 7.10 (m, 3 H), 6.84 - 6.72 (m, 3 H), 4.08 - 3.94 (m, 2 H), 3.94 - 3.50 (m, 5 H), 3.00 - 2.74 (m, 1 H), 2.52 - 2.26 (m, 1 H), 2.14 - 1.78 (m, 5 H), 1.68 - 1.30 (m, 6 H), 1.24 - 1.02 (m, 6 H), 1.02 - 0.82 (m, 2 H); Isomer 2 (0.82 mg) as the TFA salt, LCMS method B: Rt = 0.90 min; (M + H) + = 603.5. 1 1H NMR (MeOH-d4): δ 8.33 (s, 1 H), 7.62, 7.50 (two br, 1 H), 7.10 (m, 3 H), 6.84 - 6.70 (m, 3 H), 3.98 - 3.54 (m, 6 H), 3.52 - 3.34 (m, 1 H), 3.02 - 2.92 (m, 1 H), 2.78, 2.48 (two br, 1 H), 2.28 (m, 1 H), 2.08 - 1.92 (m, 2 H), 1.90 - 1.72 (m, 2 H), 1.68 - 1.46 (m, 2 H), 1.34 (m, 3 H), 1.28 - 0.84 (m, 7 H); and Isomer 3 (5 mg) as the TFA salt, LCMS method B: Rt = 0.95 min; (M + H) + = 603.5. 11H NMR (MeOH-d4): δ 8.35 (s, 1 H), 7.68 - 7.50 (m, 1 H), 7.22 - 7.04 (m, 3 H), 6.77 (m, 3 H), 4.08 - 3.90 (m, 2 H), 3.90 - 3.56 (m, 4 H), 3.56 - 3.32 (m, 1 H), 2.76 (m, 1 H), 2.45 (m, 1 H), 2.11 (m, 1 H), 1.88 - 1.58 (m, 4 H), 1.55 - 1.24 (m, 6 H), 1.22 - 0.98 (m, 6 H), 0.92 (br, 1 H), 0.84 (br, 1 H).

[0524] Examples 24A - 24B 2 - ((4 - (7 - Amino - 8 - ((2 - oxo - 2,3 - dihydro - 1H - benzimidazol - 5 - yl)methyl)-2 - azaspiro[4.4]nonan - 2 - yl)pyrimidin - 5 - yl)oxy)-5 - fluoro - N,N - diisopropylbenzamide (Isomers 1 - 2)

Chemical Structure

[0525] Step 1: tert - Butyl 7 - ((tert - butylsulfinyl)imino)-8 - ((2 - oxo - 2,3 - dihydro - 1H - benzimidazol - 5 - yl)methyl)-2 - azaspiro[4.4]nonane - 2 - carboxylate

Chemical Structure

[0526] The title product was synthesized as a mixture of multiple diastereoisomers starting from tert-butyl 7-oxo-8-((2-oxo)-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2-azaspiro[4.4]nonane-2-carboxylate (see Examples 23A - 23C, Step 2) according to the procedures described in Step 1 of Examples 23A - 23C and subsequently in Step 1 of Examples 250A - 250B. The title product was used in the next step without purification. LCMS Method B: Rt = 1.29 - 1.32 minutes, multiple peaks; (M + H) + = 489.4.

[0527] Step 2: tert-Butyl 7-((tert-butylsulfinyl)amino)-8-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2-azaspiro[4.4]nonane-2-carboxylate

Chemical Structure

[0528] To a solution of the residue from Step 1 in THF (5 mL) was added NaBH4 (10 mg, 0.26 mmol) and 1 drop of water. The resulting solution was stirred at room temperature for 2 hours. The reaction mixture was quenched with ice water and extracted with EtOAc. The combined organic layers were concentrated under vacuum and the residue was purified by preparative RFHPLC Method A to give two fractions of diastereoisomers: Fraction 1 (5.8 mg, TFA salt): LC-MS Method B: Rt = 1.26 minutes, (M + H) + = 491.4; Fraction 2 (18.8 mg, TFA salt): LC-MS Method B: Rt = 1.32 minutes, (M + H) + = 491.4.

[0529] Step 3: 2-Methyl-N-(8-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2-azaspiro[4.4]nonan-7-yl)propan-2-sulfinamide

Chemical Structure

[0530] To a solution of tert-butyl 7-((tert-butylsulfinyl)amino)-8-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2-azaspiro[4.4]nonane-2-carboxylate (18.8 mg, 0.038 mmol, fraction 2, step 2) in DCM (3 mL) was added TFA (50 μL), and the resulting solution was stirred at room temperature overnight. Next, Et3N was added to the solution to neutralize the acid. The solvent was removed and the residue was used in the next step without purification.

[0531] Step 4: 2-((4-(7-((tert-Butylsulfinyl)amino)-8-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2-azaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Chemical formula

[0532] To a solution of the crude product from step 3 in isopropanol (0.3 mL) were added 2-((4-chloropyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide (intermediate 41, 20 mg) and Et3N (100 μL), and the resulting solution was heated in a CEM microwave reactor at 110 °C for 1 hour. The solvent was removed to obtain the crude product, which was used in the next step without purification. LCMS method B: Rt = 1.06 min, (M+H) + = 706.6.

[0533] Step 5: 2-((4-(7-Amino-8-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2-azaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide (isomer 1-2) To the crude product from Step 4 in MeOH (2 mL) was added 6N HCl (2 mL), and the resulting solution was stirred at room temperature overnight. LC-MS showed two products with retention times of t r = 0.65 and 0.67 min in a ratio of 1:6. The products were isolated by preparative RP-HPLC Method A to obtain two isomers:

[0534] Isomer 1 as the TFA salt (0.67 mg). LCMS Method B: Rt = 0.65 min, (M+H) + = 602.5; 1 1H NMR (MeOH-d4): δ 8.33, 8.31 (two s, 1 H), 7.78, 7.71 (two br, 1 H), 7.06 (m, 2 H), 6.96 (m, 1 H), 6.82 (m, 1 H), 6.76 (m, 2 H), 3.78 - 3.62 (m, 3 H), 3.56 - 3.40 (m, 2 H), 3.38 - 3.28 (m, 1 H), 3.08 - 2.82 (m, 1 H), 2.58 - 2.12 (m, 2 H), 1.92 - 1.54 (m, 4 H), 1.36 (m, 6 H), 1.22 (m, 1 H), 1.06 (m, 6 H), 1.02 - 0.88 (m, 2 H). Isomer 2 as the TFA salt (4.24 mg). LCMS Method B: Rt = 0.69 min, (M+H) + = 602.5. 1 1H NMR (MeOH-d4): δ 8.34 (s, 1 H), 7.80 (br, 1 H), 7.09 (m, 2 H), 6.99 (m, 1 H), 6.82 (m, 1 H), 6.76 (m, 2 H), 3.84 - 3.62 (m, 3 H), 3.58 - 3.42 (m, 2 H), 3.36 - 3.26 (m, 1 H), 3.08 - 2.98 (m, 1 H), 2.45 - 2.12 (m, 2 H), 1.88 - 1.54 (m, 4 H), 1.37 (m, 6 H), 1.22 (m, 1 H), 1.05 (m, 6 H), 0.95 (m, 2 H).

[0535] Example 25 2-((4-(7-Amino-8-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2-azaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide (Isomer 3) [Chemical Structure]

[0536] Using fraction 1 (5.8 mg) prepared in step 2 of Examples 24A - 24B, the title compound was synthesized according to the procedure of Examples 24A - 24B. LCMS method B: Rt = 0.69 min, (M + H) + = 602.5.

[0537] Examples 26A - 26B 5-Fluoro-2-((4-(8-(4-fluorobenzyl)-7-(2-hydroxyethyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-N,N-diisopropylbenzamide (Isomers 1 - 2) [Chemical Structure]

[0538] Step 1: tert-Butyl 7-benzyl-3-oxo-2,7-diazaspiro[4.4]nonane-2-carboxylate [Chemical Structure]

[0539] To a solution of 7-benzyl-2,7-diazaspiro[4.4]nonan-3-one (500 mg, 2.17 mmol) in DCM (15 mL) was added Boc2O (1.04 g, 4.8 mmol), followed by the addition of DMAP (662 mg, 5.4 mmol) portionwise at room temperature. The mixture was stirred at room temperature for 2 days. The reaction was quenched by the addition of H2O (20 mL), and the aqueous phase was extracted with EtOAc (30 mL). The combined organic layers were dried over Na2SO4, and the solvent was evaporated to give a crude product, which was purified by silica gel flash chromatography eluting with 70% EtOAc / hexane to afford 400 mg of tert-butyl 7-benzyl-3-oxo-2,7-diazaspiro[4.4]nonane-2-carboxylate as a colorless oil (yield 56%). LCMS method A: t R = 0.73 min, [M+H] + = 331.4.

[0540] Step 2: ((1-Benzyl-3-(3-(4-fluorophenyl)-2-oxopropyl)pyrrolidin-3-yl)methyl)carbamic acid tert-butyl

Chemical formula

[0541] To a solution of tert-butyl 7-benzyl-3-oxo-2,7-diazaspiro[4.4]nonane-2-carboxylate (280 mg, 0.85 mmol) in anhydrous THF (2 mL) at 0 °C was slowly added 0.25 M (4-fluorobenzyl)magnesium chloride in Et2O (5.0 mL, 1.25 mmol) under N2. The mixture was stirred at 0 °C for 1 h and then quenched by the addition of H2O (10 mL). The mixture was then extracted with EtOAc (2 × 30 mL). The organic layer was washed with brine, dried over Na2SO4, and the solvent was evaporated to give a crude product, which was purified by silica gel flash chromatography eluting with 30% EtOAc / hexane to afford 240 mg of ((1-benzyl-3-(3-(4-fluorophenyl)-2-oxopropyl)pyrrolidin-3-yl)methyl)carbamic acid tert-butyl as a colorless oil (yield 65%). LCMS method A: tR = 1.10 min, [M+H] + = 441.4

[0542] Step 3: tert-Butyl 7-benzyl-3-(4-fluorobenzyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate

Chem.

[0543] To a solution of tert-butyl ((1-benzyl-3-(3-(4-fluorophenyl)-2-oxopropyl)pyrrolidin-3-yl)methyl)carbamate (240 mg, 0.55 mmol) in DCM (3 mL) was added TFA (0.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 h and then concentrated under reduced pressure.

[0544] The resulting crude product was dissolved in DCM (3 mL), neutralized with TEA, and then NaCNBH3 (39 mg, 0.6 mmol) was added. The mixture was stirred at room temperature for 1 h. Boc2O (135 mg, 0.65 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 4 h. The mixture was diluted with H2O (20 mL) and extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography eluting with 20% EtOAc / hexane to afford 184 mg of tert-butyl 7-benzyl-3-(4-fluorobenzyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate as a colorless oil (80% yield). LCMS Method A: t R = 1.17 min, [M+H] + = 425.5

[0545] Step 4: tert-Butyl 3-(4-fluorobenzyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate

Chem.

[0546] To a solution of tert-butyl 7-benzyl-3-(4-fluorobenzyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (184 mg, 0.43 mmol) in MeOH (5 mL) was added Pd(OH)₂ supported on activated carbon (5% based on dry weight, 123 mg, 43 μmol). The mixture was stirred at room temperature under a hydrogen balloon for 40 hours and filtered through a Celite pad. The residue was concentrated under reduced pressure. The crude product was used directly in the next step reaction without further purification. LCMS method A: t R = 1.01 min, [M+H] + = 335.5.

[0547] Step 5: tert-Butyl 7-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-3-(4-fluorobenzyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate

Chemical Structure

[0548] A solution of tert-butyl 3-(4-fluorobenzyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (94 mg, 0.28 mmol) and 2-((4-chloropyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide (Intermediate 41, 100 mg, 0.31 mmol) in iPrOH (2 mL) was heated in a microwave reactor at 120 °C for 2 hours. After cooling to room temperature, the mixture was diluted with H₂O (10 mL) and extracted with EtOAc (3 × 15 mL). The organic layer was washed with brine, dried over Na₂SO₄, and concentrated. The crude product was purified by silica gel flash chromatography eluting with 70% EtOAc / hexane to give 127 mg of tert-butyl 7-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-3-(4-fluorobenzyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate as a colorless oil (yield 70%). LCMS method A: t R = 1.48 min, [M+H] + = 650.4.

[0549] Step 6: 5-Fluoro-2-((4-(8-(4-fluorobenzyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-N,N-diisopropylbenzamide

Chem.

[0550] To a solution of tert-butyl 7-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-3-(4-fluorobenzyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate (100 mg, 0.15 mmol) in DCM (2 mL) was added TFA (0.4 mL) at room temperature. The reaction mixture was stirred for 1 h and neutralized with aqueous NaHCO3. The mixture was then extracted with DCM (4 × 15 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography eluting with 10% MeOH / DCM to afford 65 mg of 5-fluoro-2-((4-(8-(4-fluorobenzyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-N,N-diisopropylbenzamide as a colorless oil (80% yield). LCMS Method A: t R = 0.92 min, [M + H] + = 550.5.

[0551] Step 6: 2-((4-(7-(2-((tert-butyldimethylsilyl)oxy)ethyl)-8-(4-fluorobenzyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide

Chem.

[0552] A solution of 5-fluoro-2-((4-(8-(4-fluorobenzyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-N,N-diisopropylbenzamide (10 mg, 18 μmol) and (2-bromoethoxy)(tert-butyl)dimethylsilane (7 mg, 27 μmol) in DMF (0.5 mL) was added with K2CO3 (7 mg, 45 μmol) at room temperature. The reaction mixture was stirred at 50 °C for 4 hours and extracted with EtOAc (4 × 5 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was used directly in the reaction of the next step without further purification. LCMS method A: t R = 1.34 min, [M+H] + = 708.5.

[0553] Step 7: 5-Fluoro-2-((4-(8-(4-fluorobenzyl)-7-(2-hydroxyethyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-N,N-diisopropylbenzamide (Isomers 1-2) To a solution of crude 2-((4-(7-(2-((tert-butyldimethylsilyl)oxy)ethyl)-8-(4-fluorobenzyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide in THF (0.5 mL) was added TBAF (1 M, 0.1 mL, 0.1 μmol) in THF solution at room temperature. The reaction mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. The crude product was purified by Gilson-HPLC to obtain the title product as a mixture of two racemic compounds.

[0554] Isomer 1: LCMS method A: t R = 0.93 min, [M+H] + = 594.3. 11H NMR (CD3OD): δ 8.58 (s, 1H), 8.00 (s, 1H), 7.33 - 7.25 (m, 5H), 7.27 - 7.09 (m, 2H), 3.97 - 3.88 (m, 8H), 3.68 - 3.61 (m, 2H), 3.48 - 3.41 (m, 2H), 3.26 - 3.21 (m, 1H), 3.15 - 3.05 (m, 1H), 2.90 - 2.85 (m, 1H), 2.15 - 2.04 (m, 4H), 1.55 - 1.52 (m, 3H), 1.39 - 1.37 (m, 3H), 1.23 - 1.21 (m, 3H), 1.11 - 1.07 (m, 3H). 19 19F NMR (CD3OD): δ -76.90, -77.38, -117.20。 Isomer 2: LCMS method A: t R = 0.92 min, [M+H] + = 594.3. 1 1H NMR (CD3OD): δ 8.56 (s, 1H), 8.00 (s, 1H), 7.33 - 7.31 (m, 2H), 7.28 - 7.25 (m, 1H), 7.24 - 7.20 (m, 2H), 7.10 - 7.08 (m, 2H), 3.90 - 3.81 (m, 8H), 3.62 - 3.53 (m, 2H), 3.48 - 3.41 (m, 2H), 3.24 - 3.13 (m, 2H), 2.90 - 2.81 (m, 1H), 2.16 - 2.10 (m, 2H), 1.94 - 1.91 (m, 2H), 1.53 - 1.51 (m, 3H), 1.29 - 1.27 (m, 3H), 1.21 - 1.19 (m, 3H), 1.11 - 1.07 (m, 3H).

[0555] Example 27 6 - ((7 - (5 - (2 - chloro - 4 - fluorophenoxy)pyrimidin - 4 - yl)-2 - azaspiro[4.4]nonan - 2 - yl)methyl)-1 - methyl - 1H - benzimidazol - 2(3H)-one

Chemical Structure

[0556] Step 1: tert-Butyl 7-(((trifluoromethyl)sulfonyl)oxy)-2-azaspiro[4.4]non-7-ene-2-carboxylate

Chem.

[0557] A solution of LiHMDS (4 mL, 4 mmol, 1 M in THF) in THF (10 mL, anhydrous) was added dropwise with tert-butyl 7-oxo-2-azaspiro[4.4]nonane-2-carboxylate (500 mg, 2 mmol) in THF (4 mL, anhydrous) at -78 °C, and the mixture was stirred under N₂ at -78 °C for 1 h. PhNTf₂ (1.1 g, 3 mmol) in THF (6 mL, anhydrous) was added, and the reaction solution was warmed to 12 - 21 °C and stirred under N₂ for 16 h. The resulting mixture was quenched with saturated aqueous NH₄Cl (30 mL) and extracted with EtOAc (3 × 30 mL). The organic layer was washed with brine (30 mL), dried over Na₂SO₄, filtered, and concentrated to obtain a crude residue. The residue was purified by flash chromatography (SiO₂, 1% - 50% EtOAc / petroleum ether) to obtain tert-butyl 7-(((trifluoromethyl)sulfonyl)oxy)-2-azaspiro[4.4]non-7-ene-2-carboxylate (impurity) as a colorless oil. Yield: 950 mg. 1 ¹H NMR (MeOD-d₄): δ 5.69 (s, 1 H), 3.38 - 3.50 (m, 2 H), 3.20 - 3.30 (m, 2 H), 2.65 - 2.80 (m, 2 H), 1.90 - 2.10 (m, 3 H), 1.77 - 1.85 (m, 1 H), 1.46 (s, 9 H).

[0558] Step 2: tert-Butyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-azaspiro[4.4]non-7-ene-2-carboxylate

Chem.

[0559] To a solution of tert-butyl 7-(((trifluoromethyl)sulfonyl)oxy)-2-azaspiro[4.4]non-7-ene-2-carboxylate (950 mg, 2 mmol, 55% purity) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (760 mg, 3 mmol) in dioxane (10 mL, anhydrous) were added Pd(dppf)Cl2 (73 mg, 0.11 mmol) and KOAc (390 mg, 4 mmol) under N2. The resulting mixture was stirred at 80 °C for 16 h under N2. The resulting mixture was concentrated to give a crude residue. The residue was purified by flash chromatography (SiO2, 1% - 100% EtOAc in petroleum ether) to give tert-butyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-azaspiro[4.4]non-7-ene-2-carboxylate (impure crude) as a colorless oil. Yield: 800 mg. 1 1H NMR (MeOD-d4): δ 6.27 (s, 1 H), 3.38 - 3.50 (m, 2 H), 3.15 - 3.30 (m, 2 H), 2.40 - 2.60 (m, 2 H), 1.65 - 1.90 (m, 2 H), 1.40 - 1.50 (m, 9 H), 1.26 (s, 12 H), 0.80 - 0.95 (m, 2 H).

[0560] Step 3: tert-Butyl 7-(5-(2-chloro-4-fluorophenoxy)pyrimidin-4-yl)-2-azaspiro[4.4]non-7-ene-2-carboxylate

Chemical formula

[0561] A solution of 4-chloro-5-(2-chloro-4-fluorophenoxy)pyrimidine (Intermediate 10A, 50 mg, 0.2 mmol), tert-butyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-azaspiro[4.4]non-7-ene-2-carboxylate (140 mg, 0.4 mmol, 50% purity) in dioxane (2.5 mL) and H2O (0.5 mL) was added with Pd(dppf)Cl2 (15 mg, 0.02 mmol) and Na2CO3 (42 mg, 0.4 mmol) under N2. The resulting mixture was stirred at 80 °C for 16 h under N2. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (3 × 20 mL). The organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated to obtain a residue. The residue was purified by preparative TLC (EtOAc:petroleum ether = 2:1) to obtain tert-butyl 7-(5-(2-chloro-4-fluorophenoxy)pyrimidin-4-yl)-2-azaspiro[4.4]non-7-ene-2-carboxylate as a yellow oil. Yield: 50 mg. LCMS Method C: Rt = 0.914 min; (M+H) + = 446.0, 448.0 (chlorine isotope).

[0562] Step 4: tert-Butyl 7-(5-(2-chloro-4-fluorophenoxy)pyrimidin-4-yl)-2-azaspiro[4.4]nonane-2-carboxylate [Chemical formula]

[0563] A solution of tert-butyl 7-(5-(2-chloro-4-fluorophenoxy)pyrimidin-4-yl)-2-azaspiro[4.4]non-7-ene-2-carboxylate (50 mg, 0.11 mmol) in MeOH (5 mL, anhydrous) and THF (5 mL, anhydrous) was added with PtO2 (5 mg, 10%). The resulting mixture was stirred at 25 °C for about 16 h under H2 (20 psi). The mixture was filtered, the filtrate was concentrated, and purified by preparative TLC on silica gel (EtOAc:petroleum ether = 1:5) to obtain tert-butyl 7-(5-(2-chloro-4-fluorophenoxy)pyrimidin-4-yl)-2-azaspiro[4.4]nonane as a yellow oil. Yield: 30 mg (61%). LCMS method C: Rt = 0.923 min, (M+H) + = 448.0, 450.0 (chlorine isotope).

[0564] Step 5: 7-(5-(2-Chloro-4-fluorophenoxy)pyrimidin-4-yl)-2-azaspiro[4.4]nonane

Chemical Structure

[0565] A solution of tert-butyl 7-(5-(2-chloro-4-fluorophenoxy)pyrimidin-4-yl)-2-azaspiro[4.4]nonane-2-carboxylate (30 mg, 0.07 mmol) in TFA-CH2Cl2 (3 mL, V:V = 1:4) was stirred at 10 - 21 °C for about 3 h. Then the mixture was concentrated. The resulting mixture was adjusted to pH 8 with saturated aqueous NaHCO3 and extracted with CH2Cl2 (2 × 20 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated to obtain 7-(5-(2-chloro-4-fluorophenoxy)pyrimidin-4-yl)-2-azaspiro[4.4]nonane as a yellow oil, which was used directly in the next step without further purification. Yield: 30 mg. LCMS method C: Rt = 0.642 min; (M+H) + = 348.0, 350.0 (chlorine isotope).

[0566] Step 6: 6-((7-(5-(2-chloro-4-fluorophenoxy)pyrimidin-4-yl)-2-azaspiro[4.4]nonan-2-yl)methyl)-1-methyl-1H-benzo[d]imidazol-2(3H)-one To a solution of 7-(5-(2-chloro-4-fluorophenoxy)pyrimidin-4-yl)-2-azaspiro[4.4]nonane (30 mg, 0.07 mmol, crude) and 1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carbaldehyde (12 mg, 0.07 mmol) in MeOH (3 mL, anhydrous) was added NaBHCN (22 mg, 0.35 mmol). The resulting mixture was stirred at 10–21 °C for approximately 16 h. The mixture was concentrated and purified by acidic preparative RP-HPLC Method A to give 6-((7-(5-(2-chloro-4-fluorophenoxy)pyrimidin-4-yl)-2-azaspiro[4.4]nonan-2-yl)methyl)-1-methyl-1H-benzo[d]imidazol-2(3H)-one (TFA salt) as a white solid. Yield: 15 mg. LCMS Method E: Rt=0.902 min; (M+H) + =508.3, 510.3 (chlorine isotopes). 1 H NMR (MeOD-d4): δ 8.70-8.85 (m, 1 H), 7.99 (d, J = 5.2 Hz, 1 H), 7.35-7.50 (m, 1 H), 7.10-7.35 (m, 5 H), 4.35-4.50 (m, 2 H), 3.80-3.95 (m, 1 H), 3.35-3.70 (m, 6 H), 3.20-3.30 (m, 1 H), 1.75-2.40 (m, 8 H). 19 F NMR (MeOD-d4): δ -77.02, -116.39.

[0567] Example 28 5-((7-(3-(4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyridin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one [ka]

[0568] Step 1: 4-Fluoro-2-(4-isopropylpyrimidin-5-yl)phenol [Chemical formula]

[0569] To a solution of 2-bromo-4-fluorophenol (650 mg, 3.40 mmol) in dioxane (15 mL) and H2O (3 mL) were added (4-isopropylpyrimidin-5-yl)boronic acid (622 mg, 3.74 mmol), Pd(dppf)Cl2 (125 mg, 0.17 mmol), and Na2CO3 (720 mg, 6.55 mmol). The resulting mixture was degassed with N2 and stirred in an oil bath at 90 °C under N2 for about 20 h. The reaction mixture was concentrated under reduced pressure to remove dioxane, and the resulting residue was diluted with EtOAc (20 mL). The suspension was filtered through a short pad of silica gel. The filtrate was diluted with EtOAc (20 mL) and water (20 mL). The organic layer was separated, washed with brine (2 × 30 mL), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc = 10:1 to 1:1) to obtain 4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenol as a yellow solid. Yield: 300 mg. LCMS method C: Rt = 0.705 min; (M + H) + = 233.1.

[0570] Step 2: tert-Butyl 7-(3-(4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyridin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate [Chemical formula]

[0571] To a solution of 4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenol (250 mg, 1.08 mmol) in DMSO (25 mL) were added 7-(3-bromopyridin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylic acid tert-butyl (412 mg, 1.08 mmol), CuI (206 mg, 1.08 mmol), 2-picolinic acid (266 mg, 2.16 mmol), and K3PO4 (916 mg, 4.32 mmol). The resulting mixture was purged with N2 for 10 minutes and stirred at 110 °C in an oil bath under N2 for about 24 hours. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2 × 30 mL). The organic layer was washed with brine (3 × 40 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (EtOAc) to give tert-butyl 7-(3-(4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyridin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate as a yellow solid. Yield: 25 mg. LCMS method C: Rt = 0.747 min; (M+H) + = 534.1.

[0572] Steps 3 - 4: 5-((7-(3-(4-Fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyridin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1H-benzo[...

Claims

1. A compound of formula I: 【Chemical 1】 or a pharmaceutically acceptable salt thereof [wherein, A, B, D, and E are each independently selected from -C(R A1 )(R A2 ), -C(R A1 )(R A2 )-C(R A1 )(R A2 ), -C(R A1 )(R A2 )-O-, -C(R A1 )(R A2 )-NR A3 -, -C(=O)-, -C(R A1 )(R A2 )-C(=O)-, and -N=C(NH 2 )-, where one or fewer of A, B, D, and E is -C(R A1 )(R A2 )-O-, -C(R A1 )(R A2 )-NR A3 -, -C(R A1 )(R A2 )-C(=O)-, -C(=O)-, or -N=C(NH 2 ); U is N or CR U wherein R U is H, halo, CN, OH, C 1-4 alkyl, C 1-4 alkoxy, amino, C 1-4 alkylamino, or C 2-8 dialkylamino; W is N or CR W wherein R W is H, halo, CN, OH, C 1-4 alkyl, C 1-4 alkoxy, amino, C 1-4 alkylamino, or C 2-8 dialkylamino; X is N or CR X wherein, when X is N, the atom of L directly bonded to X is other than N, O, or S; X and R is H, halo, CN, OH, C 1-4 alkyl, C 1-4 alkoxy, amino, C 1-4 alkylamino, or C 2-8 dialkylamino; L is selected from -C 1-6 alkylene- and -(C 1-4 alkylene) a -Q-(C 1-4 alkylene) b wherein -(C 1-4 alkylene) a -Q-(C 1-4 alkylene) b -based C 1-6 alkylene groups and any -(C 1-4 alkylene) b -groups are optionally substituted with one, two, three substituents independently selected from halo, CN, OH, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy, amino, C 1-3 alkylamino, and di(C 1-3 alkyl)amino; Q is -O-, -S-, -S(=O)-, -S(=O) 2 -, -C(=O)-, -C(=O)NR q1 -, -C(=O)O-, -OC(=O)NR q1 -, -NR q1 -, -NR q1 C(=O)O-, -NR q1 C(=O)NR q1 , -S(=O) 2 NR q1 -, -C(=NR q2 ), or -C(=NR q2 )-NR q1 -, where R q1 is independently selected from H, C 1-6 alkyl, and CN; Cy is a linking C 6-14 aryl, C 3-18 cycloalkyl, 5- to 16-membered heteroaryl, or 4- to 18-membered heterocycloalkyl group, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R Cy and is optionally substituted with 1, 2, 3, or 4 substituents independently selected therefrom; Each R Cy is halo, C 1-6 alkyl, C 1-4 haloalkyl, C 1-4 cyanoalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, CN, NO 2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , C(=NR e1 )NR c1 R d1 , NR c1 C(=NR e1 )NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 C(O)NR c1 R d1 , NR c1 S(O)R b1 , NR c1 S(O) 2 R b1 , NR c1 S(O) 2 NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , and S(O) 2 NR c1 R d1 is independently selected from, where C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 Aryl, C 3-10 Cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from CN, NO 2 , OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , OC(O)R b1 , OC(O)NR c1 R d1 , C(=NR e1 ), NR c1 R d1 , NR c1 C(=NR e1 ), NR c1 R d1 , NR c1 R d1 , NR c1 , C(O)R b1 , NR c1 , C(O)OR a1 , NR c1 , C(O)NR c1 R d1 , NR c1 , S(O)R b1 , NR c1 , S(O) 2 R b1 , NR c1 , S(O) 2 , NR c1 R d1 , S(O)R b1 , S(O)NR c1 R d1 , S(O) 2 R b1 , and S(O) 2 , NR c1 R d1 optionally substituted with 1, 2, 3, or 4 substituents independently selected therefrom; R 1 is H, Cy 1 , halo, C 1-6 alkyl, C 1-4 haloalkyl, C 1-4 cyanoalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CN, NO 2 , OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , C(=NR e2 )NR c2 R d2 , NR c2 C(=NR e2 )NR c2 R d2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 C(O)NR c2 R d2 , NR c2 S(O)R b2 , NR c2 , S(O) 2 R b2 , NR c2 , S(O) 2 , NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O) 2 R b2 , and S(O) 2 , NR c2 R d2 and wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each halo, CN, NO 2 , OR a2 , SR a2 , C(O)R b2 、 C(O)NR c2 R d2 、 C(O)OR a2 、 OC(O)R b2 、 OC(O)NR c2 R d2 、 C(=NR e2 )NR c2 R d2 、 NR c2 C(=NR e2 )NR c2 R d2 、 NR c2 R d2 、 NR c2 C(O)R b2 、 NR c2 C(O)OR a2 、 NR c2 C(O)NR c2 R d2 、 NR c2 S(O)R b2 、 NR c2 S(O) 2 R b2 、 NR c2 S(O) 2 NR c2 R d2 、 S(O)R b2 、 S(O)NR c2 R d2 、 S(O) 2 R b2 、 and S(O) 2 NR c2 R d2 optionally substituted with 1, 2, 3, or 4 substituents independently selected from; Y is O, S, CR Y1 R Y2 , or NR Y3 , where R Y1 , R Y2 , and R Y3 are each independently selected from H and C 1-4 alkyl; Z is Cy 2 , halo, C 1-6 alkyl, C 1-4 haloalkyl, C 1-4 cyanoalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CN, NO 2 , OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , C(=NR e3 )NR c3 R d3 , NR c3 C(=NR e3 )NR c3 R d3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)OR a3 , NR c3 C(O)NRcR d3 , NR c3 S(O)R b3 , NR c3 S(O) 2 R b3 , NR c3 S(O) 2 NR c3 R d3 , S(O)R b3 , S(O)NR c3 R d3 , S(O) 2 R b3 , S(O) 2 NR c3 R d3 , and P(O)R c3 R d3 and wherein said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each independently Cy 2 , halo, CN, NO 2 , CN, NO 2 , OR a3 、 SR a3 、 C(=O)R b3 、 C(=O)NR c3 R d3 、 C(=O)OR a3 、 OC(=O)R b3 、 OC(=O)NR c3 R d3 、 C(=NR e3 )NR c3 R d3 、 NR c3 C(=NR e3 )NR c3 R d3 、 NR c3 R d3 、 NR c3 C(=O)R b3 、 NR c3 C(=O)OR a3 、 NR c3 C(=O)NR c3 R d3 、 NR c3 S(=O)R b3 、 NR c3 S(=O) 2 R b3 、 NR c3 S(=O) 2 NR c3 R d3 、 S(=O)R b3 、 S(=O)NR c3 R d3 、 S(=O) 2 R b3 、 and S(=O) 2 NR c3 R d3 are optionally substituted by; Each R 2 and R 3 is independently selected from H, halo, C 1-6 alkyl, C 1-4 haloalkyl, C 1-4 cyanoalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CN, NO 2 , OR a4 , SR a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , OC(O)R b4 , OC(O)NR c4 R d4 , C(=NR e4 )NR c4 R d4 , NR c4 C(=NR e4 )NR c4 R d4 , NR c4 R d4 , NR c4 C(O)R b4 , NR c4 C(O)OR a4 , NR c4 C(O)NR c4 R d4 , NR c4 S(O)R b4 , NR c4 S(O) 2 R b4 , NR c4 S(O) 2 NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 [[ID=9?]] 2 R b4 , and S(O) 2 NR c4 R d4 and is independently selected, where said C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are each independently selected from halo, CN, NO 2 , OR a4 , SR a4 , C(O)R​ b4 , C(O)NR c4 R d4 , C(O)OR a4 , OC(O)R b4 , OC(O)NR c4 R d4 , C(=NR e4 ), NR c4 R d4 , NR c4 C(=NR e4 ), NR c4 R d4 , NR c4 R d4 , NR c4 C(O)R b4 , NR c4 C(O)OR a4 , NR c4 C(O)NR c4 R d4 , NR c4 S(O)R b4 , NR c4 S(O) 2 R b4 , NR c4 S(O) 2 NR c4 R d4 , S(O)R b4 , S(O)NR c4 R d4 , S(O) 2 R b4 , and S(O) 2 NR c4 R d4 are independently selected from; Each R A1 is independently selected from H, halo, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, amino, C 1-4 alkylamino, C 2-8 dialkylamino, CN, NO 2 , and OH; Each R A2 is independently selected from H, halo, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, amino, C 1-4 alkylamino, C 2-8 dialkylamino, CN, NO 2 , and OH; Each R A3 is independently selected from H, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C(O)R z , and C(O)OR z , where said C 1-4 alkyl is optionally substituted by phenyl, C 1-4 alkoxy, C 1-4 haloalkoxy, CN, NO 2 , or OH; R z is H, C 1-4 alkyl, or phenyl; Each Cy 1 is independently selected from C 6-14 aryl, C 3-18 cycloalkyl, 5- to 16-membered heteroaryl, and 4- to 18-membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from RC y1 ; optionally substituted with 1, 2, 3, or 4 substituents independently selected from; Each Cy 2 is independently selected from C 6-14 aryl, C 3-18 cycloalkyl, 5- to 16-membered heteroaryl, and 4- to 18-membered heterocycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from RC y2 ; optionally substituted with; Each RC y1 and RC y2 is halo, C 1-6 alkyl, C 1-4 haloalkyl, C 1-4 cyanoalkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl, CN, NO 2 , OR a5 , SR a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)OR a5 , OC(O)R b5 , OC(O)NR c5 R d5 , C(=NR e5 )NR c5 R d5 , NR c5 C(=NR e5 )NR c5 R d5 , NR c5 R d5 , NR c5 C(O)R b5 , NR c5 C(O)OR a5 , NR c5 C(O)NR c5 R d5 , NR c5 S(O)R b5 , NR c5 S(O) 2 R b5 , NR c5 S(O) 2 NR c5 R d5 , S(O)R b5 , S(O)NR c5 R d5 , S(O) 2 R b5 , and S(O) 2 NR c5 R d5 is independently selected from, where said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 Cycloalkyl, 5- or 6-membered heteroaryl, and 4- to 7-membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from CN, NO 2 , OR a5 , SR a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)OR a5 , OC(O)R b5 , OC(O)NR c5 R d5 , C(=NR e5 ), NR c5 R d5 , NR c5 C(=NR e5 ), NR c5 R d5 , NR c5 R d5 , NR c5 C(O)R b5 , NR c5 C(O)OR a5 , NR c5 C(O)NR c5 R d5 , NR c5 S(O)R b5 , NR c5 S(O) 2 R b5 , NR c5 S(O) 2 , NR c5 R d5 , S(O)R b5 , S(O)NR c5 R d5 , S(O) 2 R b5 , and S(O) 2 , NR c5 R d5 and are optionally substituted with 1, 2, 3, or 4 substituents independently selected therefrom; Each R a1 、R b1 、R c1 、R d1 、R a2 、R b2 、R c2 、R d2 、R a3 、R b3 、R c3 、R d3 、R a4 、R b4 、R c4 、R d4 、R a5 、R b5 、R c5 、and R d5 are independently selected from H, C 1-6 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl, C 3-10 cycloalkyl-C 1-6 alkyl, (5- to 10-membered heteroaryl)-C 1-6 alkyl, and (4- to 10-membered heterocycloalkyl)-C 1-6 alkyl, and said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkenyl, C 6-10 argon, C-10 cycloalkyl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocycloalkyl, C 6-10 aryl-C 1-6 alkyl, C 3-10 cycloalkyl-C 1-6 alkyl, (5- to 10-membered heteroaryl)-C 1-6 alkyl, and (4- to 10-membered heterocycloalkyl)-C 1-6 alkyl are each optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R g- ; Each R e1 、R e2 、R e3 、R e4 、and R e5 is independently selected from H, C 1-4 alkyl, and CN; Each R 9 is independently selected from OH, NO 2 , CN, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-4 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, cyano-C 1-3 alkyl, HO-C 1-3 alkyl, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, thiol, C 1-6 alkylthio, C 1-6 alkylsulfinyl, C 1-6 alkylsulfonyl, carboxy, aminocarbonyl, C 1-6 alkylcarbonyl, and C 1-6 alkoxycarbonyl; n is 0 or 1; m is 0 or 1; p is 0, 1, 2, or 3; q is 0, 1, or 2; a is 0 or 1; and b is 0 or 1, wherein any cycloalkyl or heterocycloalkyl group is optionally further substituted with one or two oxo groups].

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Y is O.

3. Y is NR Y3 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Y is NR

4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein U is N.

5. U is CR U The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein U is CR.

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein W is N.

7. W is CR W The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein W is CR.

8. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein X is N.

9. X is CR X The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein X is CR.

10. A, B, D, and E are each independently selected from -C(R A1 )(R A2 )- or -C(R A1 )(R A2 )-C(R A1 )(R A2 ), the compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof.

11. A, B, D, and E are each independently —CH 2 — or —CH 2 —CH 2 —, a compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof.

12. The spiro moiety represented by the following formula 【Chemical 2】 (wherein e and f represent the bonding points to the remaining part of the molecule) is as follows: [Chemical Formula 3] Selected from, the compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof.

13. The spiro moiety represented by the following formula 【Chemical Formula 4】 (wherein e and f represent the bonding points to the remaining part of the molecule) is as follows: 【Chemical Formula 5】 Selected from, the compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof.

14. L is selected from halo, CN, OH, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy, amino, C 1-3 alkylamino, and di(C 1-3 alkyl)amino, and is optionally substituted with 1, 2, or 3 substituents independently selected from -C 1-6 alkylene-, a compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof.

15. L is selected from methylene, ethylene, and -CH 2 -CH(OH)-, the compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof.

16. The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein L is methylene.

17. L is selected from -(C 1-4 alkylene)- a -Q-(C 1-4 alkylene)- b -, where -(C 1-4 alkylene)- a -Q-(C 1-4 alkylene)- b - group, any C 1-4 alkylene group is optionally substituted with 1, 2, or 3 substituents independently selected from halo, CN, OH, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy, amino, C 1-3 alkylamino, and di(C 1-3 alkyl)amino, the compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof.

18. L is selected from -C(O)-CH 2 -, -C(O)-CH 2 -CH 2 -, C(O)-, -NH-CH 2 -, NH, -C(O)-CH(NH 2 ), -, -NH-CH(CH 3 ), -, -N(CH 3 ), -C(O)-, N(CH 3 ), -CH 2 -, -CH 2 -CH 2 -O-, and -C(O)-NH-, the compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof.

19. Cy is a linked phenyl, C 3-18 cycloalkyl, 5- to 10-membered heteroaryl, or 4- to 9-membered heterocycloalkyl group, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R Cy The compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, optionally substituted with the above.

20. Cy is a linked phenyl, C 3-18 cycloalkyl, 5- to 10-membered heteroaryl, or 4- to 9-membered heterocycloalkyl group, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R Cy The compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, optionally substituted with.

21. Cy is of the formula: 【Chemical Formula 6】 (each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R Cy ), a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof.

22. Cy is of the formula: 【Chemical Formula 7】 A linking group having, the compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof.

23. Z is Cy 2 or C(O)NR c3 R d3 The compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein Z is Cy or C(O)NRR'.

24. The compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein n is 0.

25. The compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein n is 1.

26. The compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, wherein m is 0.

27. The compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, wherein m is 1.

28. The compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein p is 0.

29. The compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein p is 1.

30. The compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein q is 0.

31. The compound according to any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein q is 1.

32. The compound according to any one of claims 1 and 6 to 27, or a pharmaceutically acceptable salt thereof, having formula IIa, IIb, IIIa, or IIIb: 【Chemical 8】

33. The compound according to any one of claims 1, 4, 5, and 14 to 27, or a pharmaceutically acceptable salt thereof, having formula IVa, IVb, IVc, IVd, IVe, or IVf: 【Chemical Formula 9】

34. The compound according to claim 1, wherein the compound is selected from the following: 5-Fluoro-N,N-diisopropyl-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide; N-Ethyl-5-fluoro-N-isopropyl-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide; 5-Fluoro-2-((4-(7-((1-(2-hydroxyethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-N,N-diisopropylbenzamide; N-Ethyl-5-fluoro-2-((4-(7-((1-(2-hydroxyethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-N-isopropylbenzamide; 5-Fluoro-N-(2-hydroxyethyl)-N-isopropyl-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide; 5-Fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide; 5-Fluoro-N,N-diisopropyl-2-((4-(7-(((1s,4s)-4-(methylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide; 5-((7-(5-(2-(Amino(cyclopentyl)methyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one; 5-((7-(5-(2-(Cyclopentyl(dimethylamino)methyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one; N-(Cyclopentyl(5-fluoro-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)phenyl)methyl)acetamide; 6-((7-(5-(4-Fluoro-2-(1-hydroxy-2-methylpropyl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-3,3-dimethylindolin-2-one; 6-((7-(5-(4-Fluoro-2-isobutyrylphenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-3-methyl-2-oxoindoline-3-carbonitrile; 5-Fluoro-2-((4-(6-(3-(4-fluorophenyl)propanoyl)-2,6-diazaspiro[3.4]octan-2-yl)pyrimidin-5-yl)oxy)-N,N-diisopropylbenzamide; 5-((7-(5-(4-fluoro-2-(1-isopropyl-1H-pyrazol-5-yl)phenoxy)pyrimidin-4-yl)-3-oxo-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one; N-(4-Fluoro-2-(5-isopropyl-3-methylisoxazol-4-yl)phenyl)-4-(6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-amine; 4-(5-Fluoro-2-((4-(6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)phenyl)-5-isopropyl-3-methylisoxazole; N-(5-Fluoro-2'-isopropyl-[1,1'-biphenyl]-2-yl)-4-(6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-amine; 5-Fluoro-2-((4-(2-(2-hydroxy-2-methylpropyl)-2,7-diazaspiro[3.5]nonan-7-yl)pyrimidin-5-yl)amino)-N,N-diisopropylbenzamide; 5-((7-(5-(2-(dimethylphosphoryl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one; 2-(5-(4-Fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)-N-(4-fluorobenzyl)-5-oxa-2-azaspiro[3.4]octan-7-amine; 4-(((2-(5-((5-Fluoro-2'-isopropyl-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)amino)methyl)benzonitrile; 7-(5-(4-Fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)-N-(4-fluorobenzyl)-1-oxa-7-azaspiro[4.4]nonan-3-amine; 5-Fluoro-N-isopropyl-N-methyl-2-((4-(7-(((1r,4r)-4-(methylcarbamoyl)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide; 2-((4-(7-Amino-7-(4-cyanobenzyl)-2-azaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide; 5-Fluoro-2-((4-(7-hydroxy-8-(((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2-azaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-N,N-diisopropylbenzamide; 2-((4-(7-Amino-8-(((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2-azaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide; 5-Fluoro-2-((4-(8-(4-fluorobenzyl)-7-(2-hydroxyethyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-N,N-diisopropylbenzamide; 6-((7-(5-(2-Chloro-4-fluorophenoxy)pyrimidin-4-yl)-2-azaspiro[4.4]nonan-2-yl)methyl)-1-methyl-1H-benzo[d]imidazol-2(3H)-one; 5-((7-(3-(4-Fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyridin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one; 5-((7-(5-(2-(3-Cyclopropyl-1-methyl-6-oxo-1,6-dihydropyridin-2-yl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one; N-(5-Fluoro-2'-isopropyl-[1,1'-biphenyl]-2-yl)-4-(6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-3-amine; 2-(5-((4',5-Difluoro-2'-(2-fluoropropan-2-yl)-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-yl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane; 5-Fluoro-N-isopropyl-2-((4-(6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)benzenesulfonamide; 5-((7-(5-(4-Fluoro-2-(2-methoxybutan-2-yl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one; 5-((7-(5-(4-Fluoro-2-(3-hydroxypentan-3-yl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one; 2-(5-Fluoro-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)phenyl)-N-methylcyclopropanecarboxamide; 5-((7-(5-(4-Fluoro-2-(3-hydroxy-3-methylbutyl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one; 2-(5-Fluoro-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)phenyl)cyclopropanecarboxylic acid methyl; 2-(5-Fluoro-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)phenyl)-N-methylcyclopropanecarboxamide; 6-((2-(5-(2-chloro-4-fluorophenoxy)pyrimidin-4-yl)-2,6-diazaspiro[3.4]octan-6-yl)methyl)-3,3-dimethylindolin-2-one; 2-(6-(5-(2-chloro-4-fluorophenoxy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptane-2-carbonyl)-2,3-dihydro-1H-indene-5-sulfonamide; 5-((7-(5-((5-fluoro-2'-isopropyl-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one; 5-((7-(5-((5-fluoro-2'-isopropyl-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one; 2-Cyclopropyl-5'-fluoro-2'-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-[1,1'-biphenyl]-4-carbonitrile; 2-Cyclopropyl-5'-fluoro-2'-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-[1,1'-biphenyl]-4-carboxamide; 2-Cyclopropyl-5'-fluoro-2'-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-[1,1'-biphenyl]-4-carboxylic acid; 2-Cyclopropyl-5'-fluoro-N,N-dimethyl-2'-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-[1,1'-biphenyl]-4-carboxamide; 5-((7-(2-Chloro-5-(4-fluoro-2-(1-isopropyl-1H-pyrazol-5-yl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one; 5-((7-(5-((4,5-difluoro-2'-isopropyl-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one; 5'-Fluoro-2-methyl-2'-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-[1,1'-biphenyl]-4-carbonitrile; 5-((7-(5-((2'-cyclopropyl-5-fluoro-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one; 5-((7-(5-((5-fluoro-2'-(trifluoromethyl)-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one; 5'-Fluoro-2,6-dimethyl-2'-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-[1,1'-biphenyl]-4-carbonitrile; 2-Cyclopropyl-3',5'-difluoro-2'-(((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-[1,1'-biphenyl]-4-carbonitrile; 5-((7-(5-(4-Fluoro-2-(2-isopropyl-1H-imidazol-1-yl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one; 5-((7-(5-(2-(Cyclopropylmethoxy)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one; Ethyl 2-(7-(5-(((4'-cyano-2'-cyclopropyl-5-fluoro-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)thiazole-4-carboxylate; 2-(7-(5-(((4'-cyano-2'-cyclopropyl-5-fluoro-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)thiazole-4-carboxylic acid; 2-(7-(5-(((4'-cyano-2'-cyclopropyl-5-fluoro-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)-N-methylthiazole-4-carboxamide; 2-(7-(5-(((4'-cyano-2'-cyclopropyl-5-fluoro-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)-N,N-dimethylthiazole-4-carboxamide; 7-Benzyl-2-(5-(4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)-2-azaspiro[4.4]nonane; 5-((7-(5-((5-Fluoro-2'-(1-hydroxyethyl)-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one; 5-Fluoro-N-isopropyl-N-methyl-2-((4-(7-(3-(2-oxooxazolidin-3-yl)benzyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide; 5-Fluoro-N-isopropyl-N-methyl-2-((4-(7-(4-(2-oxooxazolidin-3-yl)benzyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide; 5-((7-(5-((5-Fluoro-2'-(2-hydroxypropan-2-yl)-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one; 2-(1,4-Dioxaspiro[4.5]decane-8-ylmethyl)-6-(5-(4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptane; 4-((6-(5-(4-Fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)cyclohexanol; 2-Cyclopropyl-5'-fluoro-2'-((4-(6-((4-hydroxycyclohexyl)methyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)-[1,1'-biphenyl]-4-carbonitrile; 2-(5-((5-Fluoro-2'-(1-methoxyethyl)-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-yl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane; 5-(5-Fluoro-2-((4-(6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)phenyl)-2,3-dihydro-1H-inden-2-amine; 5-((7-(5-((5-Fluoro-2'-(1-hydroxypropan-2-yl)-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one; 5-((7-(5-(4-Fluoro-2-(morpholinomethyl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one; 1-(7-(5-((2'-Ethyl-5-fluoro-[1,1'-biphenyl]-2-yl)amino)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan-2-yl)-2-methylpropan-2-ol; 1-((6-(5-(4-Fluoro-2-(1-isopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenoxy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)cyclohexan-1-ol; N-(2-Amino-2-oxoethyl)-N-(5-fluoro-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)phenyl)isobutyramide; N-(5-Fluoro-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)phenyl)propane-2-sulfonamide; tert-Butyl 7-(5-(4-fluoro-2-(N-methylisobutyramido)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate; N-(5-Fluoro-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)phenyl)-N-methylisobutyramide; 5-((7-(5-(4-Fluoro-2-isobutylphenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one; 2-(3-((2'-Ethyl-5-fluoro-[1,1'-biphenyl]-2-yl)methyl)pyridin-4-yl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane; N-(((1r,4r)-4-((2-(5-(2-(3-cyclopropyl-1-methyl-6-oxo-1,6-dihydropyridin-2-yl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)cyclohexyl)-2,2,2-trifluoroacetamide; N-((4-((2-(5-(2-(3-cyclopropyl-1-methyl-6-oxo-1,6-dihydropyridin-2-yl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)cyclohexyl)methanesulfonamide; 5-((7-(5-(2-(3-cyclopropyl-1-methyl-6-oxo-1,6-dihydropyridin-2-yl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1-(2-hydroxyethyl)-1H-benzo[d]imidazol-2(3H)-one; (1r,4r)-4-(2-(6-(5-(2-(2-cyclopropylpyridin-3-yl)-4-fluorophenoxy)pyrimidin-4-yl)-,2,6-diazaspiro[3.3]heptan-2-yl)ethyl)cyclohexan-1-amine; (((1r,4r)-4-(((2-(5-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenoxy)pyrimidin-4-yl)-2-azaspiro[3.3]heptan-6-yl)amino)methyl)cyclohexyl)carbamic acid tert-butyl; (((1r,4r)-4-((2-(5-(2-(N-ethylisobutyramide)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)cyclohexyl)carbamic acid tert-butyl; (((1r,4r)-4-((2-(5-(2-(N-ethylisobutyramide)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)cyclohexyl)carbamic acid methyl; N-Ethyl-N-(5-fluoro-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)phenyl)isobutyramide; 2-((4-(6-(2-(((1r,4r)-4-(3,3-dimethylbutanamido)cyclohexyl)ethyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide; ((1r,4r)-4-(2-(6-(5-(2-(2-cyclopropylpyridin-3-yl)-4-fluorophenoxy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)cyclohexyl)carbamic acid tert-butyl; 5-Fluoro-2-((4-(7-(2-hydroxy-2-methylpropyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-N,N-diisopropylbenzamide; 2-((4-(7-(((3-cyano-3-methyl-2-oxoindolin-6-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide; (5-Fluoro-2-((4-(7-(((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)phenyl)carbamic acid methylethyl; 5-Fluoro-2-((4-(7-(((1-(2-hydroxyethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-N-isopropyl-N-methylbenzamide; 5-Fluoro-N-isopropyl-N-methyl-2-((4-(6-(((tetrahydro-2H-pyran-4-yl)amino)-2-azaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)benzamide; 5-Fluoro-N-isopropyl-N-methyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide; tert-Butyl ((1r,4r)-4-((2-(5-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)cyclohexyl)carbamate; Methyl ((1r,4r)-4-((2-(5-(4-fluoro-2-(isopropyl(methyl)carbamoyl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)cyclohexyl)carbamate; N-(tert-Butyl)-2-(5-(4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)-2-azaspiro[3.4]octan-6-amine; 2-((4-(7-(((1r,4r)-4-(3,3-dimethylureido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide; 5-Fluoro-2-((4-(7-(((4-hydroxycyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-N,N-diisopropylbenzamide; 5-Fluoro-2-((4-(6-(((4-hydroxycyclohexyl)methyl)-2,6-diazaspiro[3.4]octan-2-yl)pyrimidin-5-yl)oxy)-N,N-diisopropylbenzamide; 2-((4-(7-(((1,4-dioxaspiro[4.5]dec-8-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide; 5-Fluoro-N,N-diisopropyl-2-((4-(7-(((tetrahydro-2H-pyran-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide; 5-Fluoro-N,N-diisopropyl-2-((4-(6-neopentyl-2,6-diazaspiro[3.4]octan-2-yl)pyrimidin-5-yl)oxy)benzamide; 2-((4-(6-(Cyclopropylmethyl)-2,6-diazaspiro[3.4]octan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide; 2-((4-(6-(6-Cyano-1,2,3,4-tetrahydronaphthalen-2-yl)-2,6-diazaspiro[3.4]octan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide; 5-Fluoro-N,N-diisopropyl-2-((4-(6-(2-((1r,4r)-4-pivalamidocyclohexyl)ethyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)benzamide; N-(2-((4-(6-(Cyclohexylmethyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)-5-fluorophenyl)-N-ethylisobutyramide; N-Ethyl-5-fluoro-N-isopropyl-2-((4-(7-((1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide; 2-(5-(2-(Cyclopentyloxy)-4-fluorophenoxy)pyrimidin-4-yl)-7-((tetrahydro-2H-pyran-4-yl)methyl)-2,7-diazaspiro[4.4]nonane; 2-(5-(2-Cyclopropoxy-4-fluorophenoxy)pyrimidin-4-yl)-7-((tetrahydro-2H-pyran-4-yl)methyl)-2,7-diazaspiro[4.4]nonane; N-Ethyl-N-(5-fluoro-2-((4-(7-((tetrahydro-2H-pyran-4-yl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)phenyl)isobutyramide; 5-Fluoro-N,N-diisopropyl-2-((4-(6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.4]octan-2-yl)pyrimidin-5-yl)oxy)benzamide; 5-Fluoro-N,N-diisopropyl-2-((4-(6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)benzamide; 2-((4-(6-(2-(4-cyanophenyl)acetyl)-2,6-diazaspiro[3.4]octan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide; 5-Fluoro-2-((4-(6-(6-fluoro-1,2,3,4-tetrahydronaphthalen-2-yl)-2,6-diazaspiro[3.4]octan-2-yl)pyrimidin-5-yl)oxy)-N,N-diisopropylbenzamide; ((1r,4r)-4-(2-(6-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)cyclohexyl)carbamic acid tert-butyl; 2-((4-(6-(2-(4-cyanophenyl)acetyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N,N-diisopropylbenzamide; N-Ethyl-N-(5-fluoro-2-((4-(6-(5-(methylsulfonyl)-2,3-dihydro-1H-inden-2-carbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)phenyl)isobutyramide; 3-(((2-(5-(4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)-2-azaspiro[3.3]heptan-6-yl)amino)methyl)bicyclo[1.1.1]heptane-1-carbonitrile; N-Ethyl-N-(5-fluoro-2-((4-(6-(2-(4-(methylsulfonyl)phenyl)acetyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)phenyl)isobutyramide; N-(2-((4-(6-(5-bromo-2,3-dihydro-1H-inden-2-carbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)-5-fluorophenyl)-N-ethylisobutyramide; N-Ethyl-N-(5-fluoro-2-((4-(6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)phenyl)isobutyramide; N-Cyclopropyl-5-fluoro-N-isopropyl-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide; 2-((4-(7-((1-(2-acetamidoethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropyl-N-methylbenzamide; 2-((4-(7-((1-(2-(dimethylamino)ethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropyl-N-methylbenzamide; 2-((4-(7-((3-cyano-3-methyl-2-oxoindolin-6-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropyl-N-methylbenzamide; 5-((7-(5-(4-fluoro-2-(1-isopropyl-1H-pyrazol-5-yl)phenoxy)-2-methylpyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one; 2-((4-(2-(2-(4-cyanophenyl)acetyl)-2,6-diazaspiro[3.4]octan-6-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropyl-N-methylbenzamide; 2-((4-(7-((1-ethyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropyl-N-methylbenzamide; 5-Fluoro-N-isopropyl-2-((4-(7-((1-(2-methoxyethyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-N-methylbenzamide; 4-(2-(6-(5-(4-Fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)-2,6-diazaspiro[3.4]octan-2-yl)-2-oxoethyl)benzonitrile; 5-((7-(5-(4-Fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1-(2-methoxyethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one; 1-(6-(5-(4-Fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-2-(6-methoxypyridin-3-yl)ethan-1-one; 6-(2-(6-(5-(4-Fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-2-oxoethyl)-3,3-dimethylindolin-2-one; (((1r,4r)-4-(2-(6-(5-(4-Fluoro-2-(isopropyl(methyl)carbamoyl)phenoxy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)cyclohexyl)carbamic acid tert-butyl; 5-((7-(5-(4-Fluoro-2-((isopropyl(methyl)amino)methyl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one; N-Ethyl-N-(5-fluoro-2-((4-(6-isobutyl-2,6-diazaspiro[3.4]octan-2-yl)pyrimidin-5-yl)oxy)phenyl)isobutyramide; N-(2-((4-(6-((4,4-difluorocyclohexyl)methyl)-2,6-diazaspiro[3.4]octan-2-yl)pyrimidin-5-yl)oxy)-5-fluorophenyl)-N-ethylisobutyramide; ((1r,4r)-4-(2-(6-(5-(4-fluoro-2-(N-methylisobutyramide)phenoxy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)cyclohexyl)carbamic acid tert-butyl; 2-(5-(4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)-7-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-5-oxa-2-azaspiro[3.4]octane; 4-(((2-(5-(4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)-2-azaspiro[3.3]heptan-6-yl)amino)methyl)-1-methylcyclohexane-1-carbonitrile; 4-(1-((2-(5-(4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)-2-azaspiro[3.3]heptan-6-yl)amino)ethyl)benzonitrile; 5-fluoro-N-isopropyl-N-methyl-2-((4-(7-(4-(2-oxooxazolidin-3-yl)benzyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide; N-((1r,4r)-4-(2-(6-(5-((4'-cyano-2'-cyclopropyl-5-fluoro-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)cyclohexyl)acetamide; (5-fluoro-2-((4-(7-(((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)phenyl)(isopropyl)carbamic acid methyl; 2-((4-(7-(((1H-indazol-6-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropyl-N-methylbenzamide; 2-((4-(7-((3-cyano-1H-indazol-6-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropyl-N-methylbenzamide; tert-Butyl ((1r,4r)-4-((7-(5-(2-(cyclopentyloxy)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)cyclohexyl)carbamate; 4-((2-(5-(4-Fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)-2-azaspiro[3.3]heptan-6-yl)amino)-1-methylcyclohexanecarbonitrile; 4-(2-(2-(5-(4-Fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)-2,6-diazaspiro[3.4]octan-6-yl)-2-oxoethyl)benzonitrile; 5-((7-(5-(4-Fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one; 2-Cyclopropyl-5'-fluoro-2'-((4-(6-((4-hydroxycyclohexyl)methyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)-[1,1'-biphenyl]-4-carbonitrile; 4-(((2-(5-(4-Fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)-2-azaspiro[3.3]heptan-6-yl)amino)methyl)benzonitrile; 5-((7-(5-(2-(2,5-dimethylpyrrolidine-1-carbonyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzimidazol-2-one; 5-((7-(5-(4-Fluoro-2-(pyrrolidine-1-carbonyl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzimidazol-2-one; 5-((7-(5-(4-Fluoro-2-(morpholine-4-carbonyl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one; N-Ethyl-N-(5-fluoro-2-((4-(6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.4]octan-2-yl)pyrimidin-5-yl)oxy)phenyl)isobutyramide; 7-(5-(4-Fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)-N-(4-fluorobenzyl)-1-oxa-7-azaspiro[4.4]nonan-3-amine; N-(2-((4-(6-(cyclohexylmethyl)-2,6-diazaspiro[3.4]octan-2-yl)pyrimidin-5-yl)oxy)-5-fluorophenyl)-N-ethylisobutyramide; N-Benzyl-2-(5-(4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)-5-oxa-2-azaspiro[3.4]octan-7-amine; 5-((7-(5-(4-Fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one; 5-((7-(5-((5-Fluoro-2'--(prop-1-en-2-yl)-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one; 2-(5-(4-Fluoro-2-(2-isopropoxypyridin-3-yl)phenoxy)pyrimidin-4-yl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane; 5-Fluoro-N-isopropyl-N-methyl-2-((4-(7-((1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide; Ethyl (5-fluoro-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)phenyl)(methyl)carbamate; N-Cyclopropyl-5-fluoro-N-methyl-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide; 5-Fluoro-N-methyl-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-N-phenylbenzamide; 2-((4-(6-(Cyclohexylmethyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropyl-N-methylbenzamide; 2-(5-(2-(Cyclopentyloxy)-4-fluorophenoxy)pyrimidin-4-yl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane; 2-Cyclopropyl-5'-fluoro-2'-((4-(7-((2-oxo-2,3-dihydrobenz[d]oxazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-[1,1'-biphenyl]-4-carbonitrile; Methyl (3-((7-(5-((4'-cyano-2'-cyclopropyl-5-fluoro-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)phenyl)carbamate; 2'-((4-(7-((1H-benzo[d][1,2,3]triazol-6-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-2-cyclopropyl-5'-fluoro-[1,1'-biphenyl]-4-carbonitrile; N-(2-Chloro-4-((7-(5-((4'-cyano-2'-cyclopropyl-5-fluoro-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)phenyl)acetamide; N,N-Diethyl-5-fluoro-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide; 5-Fluoro-N-isopropyl-N-methyl-2-((4-(7-((2-oxo-2,3-dihydrobenz[d]oxazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide; N-(tert-Butyl)-5-fluoro-N-methyl-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide; 1-(7-(5-(4-Fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)-2-methylpropan-2-ol; 2-(5-(2-(2-Cyclopropylpyridin-3-yl)-4-fluorophenoxy)pyrimidin-4-yl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane; 6-((7-(5-(4-Fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-3,3-dimethylindolin-2-one; 6-((7-(5-(2-(2-Cyclopropylpyridin-3-yl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-3,3-dimethylindolin-2-one; 5-((7-(5-(2-(2-Cyclopropylpyridin-3-yl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one; 4-(((2-(5-(4-Fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)(methyl)amino)methyl)benzonitrile; 6-(((7-(5-(4-Fluoro-2-(2,2,2-trifluoroethoxy)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-3,3-dimethylindolin-2-one; 5-Fluoro-N-isopropyl-N-methyl-2-((4-(7-(((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide; N-(Cyclohexylmethyl)-2-(5-(4-Fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)-5-oxa-2-azaspiro[3.4]octan-7-amine; N-(5-Fluoro-2-((4-(7-(((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)phenyl)-N-(2-hydroxyethyl)isobutyramide; N-Ethyl-N-(5-Fluoro-2-((4-(7-(((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)phenyl) isobutyramide; N-(5-Fluoro-2-((4-(7-(((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)phenyl)-N-(2,2,2-trifluoroethyl)isobutyramide; N-(((1r,4r)-4-((7-(5-(((4'-cyano-2'-cyclopropyl-5-fluoro-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)cyclohexyl)acetamide; tert-Butyl ((1r,4r)-4-(2-(6-(5-((4'-cyano-2'-cyclopropyl-5-fluoro-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)ethyl)cyclohexyl)carbamate; 5-((7-(5-(4-Fluoro-2-(5-isopropylthiazol-4-yl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzimidazol-2-one; N-((1s,4s)-4-((7-(5-((4'-cyano-2'-cyclopropyl-5-fluoro-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)cyclohexyl)acetamide; 2-Cyclopropyl-2'-((4-(7-((1-ethyl-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5'-fluoro-[1,1'-biphenyl]-4-carbonitrile; 3-((7-(5-(2-(Cyclopentyloxy)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1H-indole-6-carbonitrile; 6-((7-(5-(2-(Cyclopentyloxy)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-3,3-dimethylindolin-2-one; 2-((4-(7-((6-cyano-1H-indol-3-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropyl-N-methylbenzamide; 2-Cyclopropyl-5'-fluoro-2'-((4-(7-(4-(2-oxopyrrolidin-1-yl)benzyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-[1,1'-biphenyl]-4-carbonitrile; 2-Cyclopropyl-5'-fluoro-2'-((4-(7-((2-oxoindolin-6-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-[1,1'-biphenyl]-4-carbonitrile; 6-((7-(5-(4-Fluoro-2-(1-isopropyl-1H-pyrazol-5-yl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1H-benzo[d][1,2,3]triazole; 2-Cyclopropyl-3',5'-difluoro-2'-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-[1,1'-biphenyl]-4-carbonitrile; 3-((7-(5-(2-(Cyclopropylmethoxy)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1H-indole-6-carboxamide; 3-((7-(5-(2-(Cyclopropylmethoxy)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1H-indole-6-carbonitrile; 2-((4-(7-((3,3-Dimethyl-2-oxoindolin-6-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropyl-N-methylbenzamide; 2'-((4-(6-(4-Cyanophenethyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)-2-cyclopropyl-5'-fluoro-[1,1'-biphenyl]-4-carbonitrile; 2-Cyclopropyl-5'-fluoro-2'-((4-(7-((2-oxoindolin-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-[1,1'-biphenyl]-4-carbonitrile; 2-Cyclopropyl-2'-((4-(7-((3,3-dimethyl-2-oxoindolin-6-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-5'-fluoro-[1,1'-biphenyl]-4-carbonitrile; 2-Amino-2-cyclohexyl-1-(7-(5-(4-fluoro-2-(1-isopropyl-1H-pyrazol-5-yl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)ethanone; Methyl (5-fluoro-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)phenyl)(methyl)carbamate; 5-((7-(5-(2-(benzyloxy)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one; 5-((7-(5-(4-fluoro-2-methoxyphenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one; 5-Fluoro-N-isopropyl-N-methyl-2-((4-(7-((3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide; 5-((7-(5-(4-fluoro-2-(2-methylpyrrolidine-1-carbonyl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one; 5-((7-(5-(2-((1s,4s)-7-azabicyclo[2.2.1]heptane-7-carbonyl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one; 5-((7-(5-((2'-(1,1-difluoroethyl)-5-fluoro-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one; 2-cyclopropyl-5'-fluoro-2'-((4-(6-((4-hydroxytetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)-[1,1'-biphenyl]-4-carbonitrile; 2-cyclopropyl-5'-fluoro-2'-((4-(6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)-[1,1'-biphenyl]-4-carbonitrile; 5-fluoro-N-isopropyl-N-methyl-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide; 5-((7-(5-(4-fluoro-2-(1-isopropyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one; 5-((7-(5-(4-fluoro-2-(2-isopropyl-5-oxopyrrolidin-1-yl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one; (1r,4r)-4-((7-(5-((5-fluoro-2'-isopropyl-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)cyclohexan-1-amine; ((1r,4r)-4-((7-(5-((5-fluoro-2'-isopropyl-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)cyclohexyl)carbamic acid tert-butyl; N-(4-((7-(5-((5-fluoro-2'-isopropyl-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)phenyl)acetamide; 5-Fluoro-N-isopropyl-N-methyl-2-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)benzenesulfonamide; Ethyl 5'-fluoro-2'-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-[1,1'-biphenyl]-2-carboxylate; 5-((7-(5-(4-Fluoro-2-(4-isopropylthiazol-5-yl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one; 5-Fluoro-N-isopropyl-N-methyl-2-((4-(6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)benzamide; 5'-Fluoro-2-methyl-2'-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-[1,1'-biphenyl]-4-carbonitrile; 4-(2-(6-(5-(4-Fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-2-oxoethyl)benzonitrile; 4-(2-(6-(5-((5-fluoro-2'-isopropyl-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-2-oxoethyl)benzonitrile; 1-(6-(5-((5-Fluoro-2'-isopropyl-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)-2-(4-(methylsulfonyl)phenyl)ethan-1-one; 5'-Fluoro-2-methyl-2'-((4-(7-((2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)methyl)-2,7-diazaspiro[4.4]nonan-2-yl)pyrimidin-5-yl)oxy)-[1,1'-biphenyl]-3-carbonitrile; 2-((3,3-Difluorocyclohexyl)methyl)-6-(5-(4-fluoro-2-(1-isopropyl-1H-pyrazol-5-yl)phenoxy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptane; 2-((3,3-Difluorocyclohexyl)methyl)-6-(5-(4-fluoro-2-(4-isopropylpyrimidin-5-yl)phenoxy)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptane; 4-(((2-(5-(4-fluoro-2-(1-isopropyl-1H-pyrazol-5-yl)phenoxy)pyrimidin-4-yl)-5-oxa-2-azaspiro[3.4]octan-7-yl)amino)methyl)benzonitrile; 5-((7-(5-(2-(2-ethylpyridin-3-yl)-4-fluorophenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one; 5-((7-(5-(4-fluoro-2-isopentylphenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one; 5-((7-(5-(4-fluoro-2-isobutylphenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one; 5-((7-(5-(4-fluoro-2-(1-isopropyl-1H-pyrazol-5-yl)phenoxy)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one; 2-(5-((5-Fluoro-2'-isopropyl-[1,1'-biphenyl]-2-yl)oxy)pyrimidin-4-yl)-6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptane; N-Ethyl-5-fluoro-N-isopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)benzamide; 5-Fluoro-N,N-diisopropyl-2-((4-(6-((tetrahydro-2H-pyran-4-yl)amino)-2-azaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)benzamide; 5-Fluoro-N,N-diisopropyl-2-((4-(6-(methyl(tetrahydro-2H-pyran-4-yl)amino)-2-azaspiro[3.3]heptan-2-yl)pyrimidin-5-yl)oxy)benzamide; tert-Butyl ((1r,4r)-4-((7-(5-((2-(diisopropylcarbamoyl)-4-fluorophenyl)amino)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan-2-yl)methyl)cyclohexyl)carbamate; 1-((6-(5-((5-Fluoro-2'-isopropyl-[1,1'-biphenyl]-2-yl)amino)pyrimidin-4-yl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)cyclohexan-1-ol; 5-((7-(5-((5-Fluoro-2'-isopropyl-[1,1'-biphenyl]-2-yl)amino)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one; N-(4-Fluoro-2-(4-isopropylpyrimidin-5-yl)phenyl)-4-(6-((tetrahydro-2H-pyran-4-yl)methyl)-2,6-diazaspiro[3.3]heptan-2-yl)pyrimidin-5-amine; N-(5-Fluoro-2'-isopropoxy-[1,1'-biphenyl]-2-yl)-4-(2-isobutyl-2,7-diazaspiro[3.5]nonan-7-yl)pyrimidin-5-amine; N-(5-Fluoro-2'-isopropyl-[1,1'-biphenyl]-2-yl)-4-(2-isobutyl-2,7-diazaspiro[3.5]nonan-7-yl)pyrimidine-5-amine; N-(2'-Ethyl-5-fluoro-[1,1'-biphenyl]-2-yl)-4-(2-isobutyl-2,7-diazaspiro[3.5]nonan-7-yl)pyrimidine-5-amine; 5-Fluoro-N,N-diisopropyl-2-((4-(2-(4-(methylsulfonamido)cyclohexyl)-2,7-diazaspiro[3.5]nonan-7-yl)pyrimidine-5-yl)amino)benzamide; 5-((7-(3-((5-Fluoro-2'-isopropyl-[1,1'-biphenyl]-2-yl)oxy)pyridin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one; 2'-((4-(7-Amino-7-benzyl-2-azaspiro[4.4]nonan-2-yl)pyrimidine-5-yl)oxy)-2-cyclopropyl-5'-fluoro-[1,1'-biphenyl]-4-carbonitrile; ((1r,4r)-4-((2-(5-(2-(diisopropylcarbamoyl)-4-fluorophenoxy)pyrimidine-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)methyl)cyclohexyl)carbamic acid tert-butyl; 2-((4-(3-(4-Acetamidobenzyl)-2-amino-4-oxo-1,3,7-triazaspiro[4.4]non-1-en-7-yl)pyrimidine-5-yl)oxy)-5-fluoro-N-isopropyl-N-methylbenzamide; and N-Ethyl-2-((4-(7-(((1r,4r)-4-(ethylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidine-5-yl)oxy)-5-fluoro-N-isopropylbenzamide; or a pharmaceutically acceptable salt thereof.

35. The compound according to claim 1, which is 5-fluoro-N,N-diisopropyl-2-((4-(7-(((1r,4r)-4-(methylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidine-5-yl)oxy)benzamide, or a pharmaceutically acceptable salt thereof.

36. A pharmaceutically acceptable salt of the compound according to claim 35, which is a bis-methanesulfonate.

37. A pharmaceutically acceptable salt of the compound according to claim 35, which is a bis-hydrochloride.

38. A pharmaceutically acceptable salt of the compound according to claim 35, which is a sesquifumarate.

39. A crystalline form of the salt according to any one of claims 36 to 38.

40. The crystalline form according to claim 39, which is substantially anhydrous.

41. The crystalline form according to claim 39, which is hydrated or solvated.

42. The crystalline form according to claim 39, which is hydrated.

43. The crystalline form according to claim 39, which is a monohydrate.

44. The compound according to claim 1, which is N-ethyl-2-((4-(7-(((1r,4r)-4-(ethylsulfonamido)cyclohexyl)methyl)-2,7-diazaspiro[3.5]nonan-2-yl)pyrimidin-5-yl)oxy)-5-fluoro-N-isopropylbenzamide, or a pharmaceutically acceptable salt thereof.

45. A pharmaceutically acceptable salt of the compound according to claim 44, which is a bis-methanesulfonate.

46. A pharmaceutically acceptable salt of the compound according to claim 44, which is a bis-hydrochloride.

47. A pharmaceutically acceptable salt of the compound according to claim 44, which is a sesquifumarate.

48. A crystalline form of the salt according to any one of claims 45 to 47.

49. The crystalline form according to claim 48, which is substantially anhydrous.

50. The crystalline form according to claim 48, which is hydrated or solvated.

51. The crystalline form according to claim 48, which is hydrated.

52. The crystalline form according to claim 48, which is a monohydrate.

53. A pharmaceutical composition comprising the compound according to any one of claims 1 to 35 and 44 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

54. A pharmaceutical composition comprising the salt or crystalline form according to any one of claims 36 to 43 and 45 to 52, and at least one pharmaceutically acceptable carrier.

55. A method for inhibiting the interaction between menin and MLL, comprising contacting menin and MLL with the compound according to any one of claims 1 to 35 and 44, or a pharmaceutically acceptable salt thereof.

56. A method for inhibiting the interaction between menin and MLL, comprising contacting menin and MLL with a salt or crystal form according to any one of claims 36 to 43 and 45 to 52.

57. A method for treating cancer in a patient, comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 35 and 44, or a pharmaceutically acceptable salt thereof.

58. A method for treating cancer in a patient, comprising administering to the patient a therapeutically effective amount of a salt or crystal form according to any one of claims 36 to 43 and 45 to 52.

59. The method according to claim 57 or 58, wherein the cancer is a hematological cancer.

60. The method according to claim 57 or 58, wherein the cancer is leukemia.

61. The method according to claim 57 or 58, wherein the cancer is lymphoma.

62. The cancer is mixed-lineage leukemia (MLL), MLL-related leukemia, MLL-related leukemia, MLL-positive leukemia, MLL-induced leukemia, rearranged mixed-lineage leukemia (MLL-r), MLL rearrangement or leukemia associated with rearrangement of the MLL gene, acute leukemia, chronic leukemia, indolent leukemia, lymphoblastic leukemia, lymphocytic leukemia, myeloid leukemia, myeloid leukemia, pediatric leukemia, acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), acute granulocytic leukemia, acute non-lymphocytic leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), therapy-related leukemia, myelodysplastic syndrome (MDS), myeloproliferative disorder (MPD), myeloproliferative neoplasm (MPN), plasma cell neoplasm, multiple myeloma, myelodysplasia, cutaneous T-cell lymphoma, lymphoma tumor, AIDS-related lymphoma, thymoma, thymic carcinoma, mycosis fungoides, Alibert-Bazin syndrome, granulomatous polyps, Sézary syndrome, hairy cell leukemia, T-cell prolymphocytic leukemia (T-PLL), large granular lymphocytic leukemia, meningeal leukemia, leukemic leptomeningitis, multiple myeloma, Hodgkin lymphoma, non-Hodgkin lymphoma (malignant lymphoma), and Waldenström macroglobulinemia. The method according to claim 57 or 58.

63. A method for treating insulin resistance, prediabetes, diabetes, or the risk of diabetes in a patient, comprising administering to the patient a therapeutically effective amount of the compound according to any one of claims 1 to 35 and 44, or a pharmaceutically acceptable salt thereof.

64. A method for treating insulin resistance, prediabetes, diabetes, or the risk of diabetes in a patient, comprising administering to the patient a therapeutically effective amount of the salt or crystalline form according to any one of claims 36 to 43 and 45 to 52.

65. A method for treating hyperglycemia in a patient, comprising administering to the patient a therapeutically effective amount of the compound according to any one of claims 1 to 35 and 44, or a pharmaceutically acceptable salt thereof.

66. A method for treating hyperglycemia in a patient, comprising administering to the patient a therapeutically effective amount of the salt or crystalline form according to any one of claims 36 to 43 and 45 to 52.

Images