Smarca2 degraders and uses thereof

Abstract

The present disclosure provides compounds represented by Formula (I), or a pharmaceutically acceptable salt and / or stereoisomer thereof: wherein Ra, Rb, Rc, R7, R8, R9, R10, X3, W, L, and E are as defined in the specification. Compounds represented by Formula (I) are SMARCA2 protein degraders and are thus useful for treating cancer and other diseases.

Description

SMARCA2 DEGRADERS AND USES THEREOFBACKGROUNDField

[0001] The present disclosure provides Proteolysis Targeting Chimera (PROTAC) compounds and the use of such PROTAC compounds for the treatment of diseases or disorders dependent on SMARCA2 in mammals. Degradation of SMARCA2 may provide, for example, an anti-tumor effect. The present disclosure thus provides the use of SMARCA2 degraders and pharmaceutical compositions comprising SMARCA2 degraders for the treatment of cancer. It also provides intermediate compounds that may be useful in the preparation of such PROTACs.Background

[0002] Traditional "small molecule" drugs reversibly (or sometimes irreversibly) bind to a target protein as a means of modulating a given biological activity. In contrast, PROTACs bind to their target proteins reversibly, but then bring about the target protein's degradation. Having achieved this effect, the PROTAC is in theory able to repeat this process with another target protein. Accordingly, unlike traditional small molecule inhibitors, the PROTAC-driven degradation mechanism can in theory operate in a sub-stoichiometric manner - meaning that more modest exposures of a PROTAC compound could still achieve a desired level of efficacy in vivo. In practice, this means that the degradation power (DC50and Dmax) of a PROTAC may have an improved effect over that reflected by its binding affinity.

[0003] PROTAC molecules are described as having three parts - (1) a part that is capable of binding to the protein to be degraded, (2) a second part that is capable of binding to an E3 ubiquitin ligase, and (3) a linker that connects parts (1) and (2) together. In use, the PROTAC binds to both the target protein and E3 ubiquitin ligase simultaneously to form a ternary complex. The E3 ligase then recruits an E2 conjugating enzyme to the ternary complex, which ubiquitinates the target protein. This has the effect of labelling the target protein for degradation by the cell's proteasome machinery. A PROTAC can then dissociate from the target protein and initiate another cycle of this process in a catalytic manner. Meanwhile, the ubiquitinated target proteins are recognized by the cell's proteasome machinery and are then degraded by it. This PROTAC-mediated approach may be valuable as a method of treating certain diseases, including cancer.

[0004] SMARCA4 is a frequently mutated in several tumor types - including lung, liver, colon, skin, bladder, esophageal, gastric, brain, endometrial, cervical and ovarian cancers. Furthermore, it has been established that SMARCA2 is essential for growth of tumors harboring such SMARCA4 mutations. Accordingly, selective suppression of SMARCA2 has been proposed as a therapeutic strategy against cancers that may include SMARCA4 mutations. Accordingly, selective suppression of SMARCA2 may beuseful against a number of cancer types, including lung, liver, colon, skin, bladder, esophageal, gastric, brain, endometrial, cervical and ovarian cancers.

[0005] WO2019 / 207538 discloses certain PROTAC compounds described as " SMARCA 2 / 4 degraders" and WO2020251969 discloses PROTAC compounds which target one or more of SMARCA2, SMARCA4 and PB1. W02019 / 195201 also discloses 'bifunctional' compounds described as modulators of SMARCA2. WO2019 / 213005 relates to compounds that are said to degrade PBRM1. WO2018 / 144649 and WO2021 / 053495 also disclose certain PROTAC molecules. WO2021 / 053555 discloses glue degrader compounds which bind to the E3 ubiquitin ligase, cereblon.

[0006] As part of developing a PROTAC against cancer, there is a need to develop further PROTAC compounds with a combination of beneficial / improved properties that make them more suitable for use as a therapeutic drug for human use. Properties of interest during pharmaceutical discovery and development may relate to selectivity profile, absorption / bioavailability, distribution, metabolism, elimination, toxicity and side -effect profile, stability, manufacturability, and so on.BRIEF SUMMARY

[0007] In one aspect, the present disclosure provides PROTAC compounds represented by Formula (I) or Formula (II), below, and the pharmaceutically acceptable salts thereof. In another aspect, the present disclosure provides any one or more of the PROTAC compounds of Compound List 1, below, and the pharmaceutically acceptable salts thereof. Compounds having Formula (I) or Formula (II), and the pharmaceutically acceptable salts thereof, and the compounds of Compound List 1, and the pharmaceutically acceptable salts thereof, are collectively referred to as " Compounds of the Disclosure" or individually as a " Compound of the Disclosure." Compounds of the Disclosure exhibit protein degradation activity against SMARCA2. Compounds of the Disclosure also may have a beneficial degree of selectivity to minimize certain undesirable off-target degradation activities. As such, Compounds of the Disclosure may be useful in the treatment of cancer.

[0008] Compounds of the Disclosure also may have a surprisingly beneficial combination of properties of relevance in the context of pharmaceutical discovery and development. Structural features found in all three regions of a PROTAC have the potential to operate (collectively or in some cases separately) towards delivering a beneficial combination and / or balance of such additional beneficial properties. Avoidance of off-target activity in pharmaceutical development is often important to avoid or reduce unwanted toxicities, side-effects or other problems with tolerability when used in patients.

[0009] As well as being degraders of SMARCA2, Compounds of the Disclosure have a surprising and beneficial combination of properties relating, for example, to chemical and metabolic stability, e.g. in human microsomes and to hydrolysis at pH 7.4, and selectivity against SALL4 and / or Ikaros (IKZF1) -which is expected to provide an improved safety profile for use in vivo. Without wishing to be bound byany particular theory, it is believed that degradation of SALL4 and Ikaros (IKZF1 ) amongst others may risk serious unwanted effects in humans, for example, developmental toxicities or bone marrow toxicities.

[0010] Also, in this regard, it has been found that molecules that degrade SMARCA2 can often also degrade SMARCA4, which is regarded as an undesirable off-target activity. Compounds of the Disclosure may show a beneficial selectivity profile by achieving a potent degree of degradation against SMARCA2 while having a margin of selectivity, i.e., relatively lower degradation, against SMARCA4. In a similar manner in the development of a SMARCA2 PROTAC for use in cancer, it is also regarded as beneficial to have a potent degree of degradation against SMARCA2 while having a good margin of selectivity, i.e., relatively lower degradation, against PBRM1. Compounds of the Disclosure may show a beneficial selectivity profile between SMARCA2 and PBRM1. Thus, in combination, Compounds of the Disclosure may show high potency against SMARCA2 while simultaneously achieving a beneficial selectivity profile with respect to SALL4 and / or Ikaros (IKZF1), and in some cases a surprisingly beneficial margin of selectivity against SMARCA4 and / or PBRM1.

[0011] In another aspect, the present disclosure provides pharmaceutical compositions comprising a Compound of the Disclosure and one or more pharmaceutically acceptable excipients.

[0012] In another aspect, the present disclosure provides methods of degrading SMARCA2 protein in a human, comprising administering to a human in need thereof an effective amount of a Compound of the Disclosure.

[0013] In another aspect, the present disclosure provides methods of reducing SMARCA2 protein in a human, comprising administering to a human in need thereof an effective amount of a Compound of the Disclosure.

[0014] In another aspect, the present disclosure provides methods of treating cancer in a human, comprising administering to a human in need thereof an effective amount of a Compound of the Disclosure.

[0015] In another aspect, the present disclosure provides a Compound of the Disclosure, or pharmaceutical composition thereof, for use in degrading SMARCA2 protein in a human.

[0016] In another aspect, the present disclosure provides a Compound of the Disclosure, or pharmaceutical composition thereof, for use in reducing SMARCA2 protein in a human.

[0017] In another aspect, the present disclosure provides a Compound of the Disclosure, or pharmaceutical composition thereof, for use in treating cancer in a human.

[0018] In another aspect, the present disclosure provides use of a Compound of the Disclosure, or pharmaceutical composition thereof in the manufacture of a medicament for degrading SMARCA2 protein in a human.

[0019] In another aspect, the present disclosure provides use of a Compound of the Disclosure, or pharmaceutical composition thereof in the manufacture of a medicament for reducing SMARCA2 protein in a human.

[0020] In another aspect, the present disclosure provides use of a Compound of the Disclosure, or pharmaceutical composition thereof in the manufacture of a medicament for treating cancer in a human.

[0021] In another aspect, the present disclosure provides methods of preparing Compounds of the Disclosure.

[0022] In another aspect, the present disclosure provides intermediates used to prepare Compounds of the Disclosure.

[0023] Additional embodiments and advantages of the disclosure will be set forth, in part, in the description that follows, and will flow from the description, or can be learned by practice of the disclosure. The embodiments and advantages of the disclosure will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing summary and the following detailed description are exemplary and explanatory only and are not restrictive of the invention as claimed.DETAILED DESCRIPTIONI. Compounds of the Disclosure

[0024] Many embodiments of this disclosure are detailed throughout the specification.

[0025] In one embodiment, Compounds of the Disclosure are compounds having Formula (I), or pharmaceutically acceptable salt thereof:R7(I),wherein:

[0026] E is:

[0027] X1is -CR3= or -N=;

[0028] R3is H, halogen, or (Ci-Ce)alkyl;

[0029] X2is -CR4= or -N=;

[0030] R4is H, halogen, or (Ci-Ce)alkyl;

[0031] X3is -CH2CH2- or -CH2-O-CH2-;

[0032] R5ais H, halogen, (Ci-Ce)alkyl, (C3-C6)cycloalkyl, 4- to 6-membered heterocycloalkyl, -CN, aryl, or 5- or 6-membered heteroaryl, wherein (Ci-Ce)alkyl is optionally substituted with 1 to 3 substituents independently selected from halogen or -CN; and 4- to 6-membered heterocycloalkyl, aryl, or 5- or 6-membered heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halogen, -CN, or (Ci-Ce)alkyl;

[0033] R5bis H, (Ci-C6)alkyl, or (C3-C6)cycloalkyl;

[0034] R1is H, halogen, (Ci-C6)alkyl, (Ci-C6)alkoxy, or

[0035] R2is H, halogen, (Ci-C6)alkyl, (Ci-C6)alkoxy, or^N^NR11

[0036] with the provisos:

[0037] (i) when R1is H, halogen, (Ci-Ce)alkyl, or (Ci-Ce)alkoxy, then R2is:NR11; and

[0038] (ii) when R2is H, halogen, (Ci-Ce)alkyl, or (Ci-Ce)alkoxy, then R1is:^N^NR11

[0039] R6is H, (Ci-Ce)alkyl, or -CN;

[0040] R7is H, halogen, (Ci-Ce)alkyl, -CN, or (C3-Ce)cycloalkyl, wherein (Ci-Ce)alkyl is optionally substituted with 1 to 3 halogen;

[0041] R8is H, halogen, (Ci-Ce)alkyl, -CN, or (C3-Ce)cycloalkyl, wherein (Ci-Ce)alkyl is optionally substituted with 1 to 3 halogen;

[0042] R9is H, halogen, (Ci-Ce)alkyl, -CN, or (C3-Ce)cycloalkyl, wherein (Ci-Ce)alkyl is optionally substituted with 1 to 3 halogen;

[0043] R10is H, halogen, (Ci-Ce)alkyl, -CN, or (C3-C6)cycloalkyl, wherein (Ci-Ce)alkyl is optionally substituted with 1 to 3 halogen;

[0044] R11is H or -(Ci-C6)alkyl-O-P(=O)-(OH)2;

[0045] W is -C(=O)-, -S(=O)2-, -CH2-, -C≡C-, or direct bond;

[0046] L is -G’-G2-G3-, wherein G3is attached to E;

[0047] G1is (Ci-Ce)alkylenyl; 4- to 6-membered heterocycloalkylenyl optionally substituted with 1 to 3 substituents independently selected from halogen, (Ci-Ce)alkyl, halo(Ci-C3)alkyl, (Ci-Ce)alkoxy, or -CN; or 7- to 11 -membered heterocycloalkylenyl optionally substituted with 1 to 3 substituents independently selected from halogen, (Ci-Ce)alkyl, halo(Ci-C3)alkyl, (Ci-Ce)alkoxy, or -CN;

[0048] G2is (Ci-Ce)alkylenyl or a direct bond; and

[0049] G3is 4- to 6-membered heterocycloalkylenyl optionally substituted with 1 to 3 substituents independently selected from halogen, (Ci-Ce)alkyl, halo(Ci-C3)alkyl, (Ci-Ce)alkoxy, or -CN, or 7- to 11-membered heterocycloalkylenyl optionally substituted with 1 to 3 substituents independently selected from halogen, (Ci-C6)alkyl, halo(Ci-C3)alkyl, (Ci-C6)alkoxy, or -CN;

[0050] Rais hydrogen or halogen;

[0051] Rbis hydrogen or halogen; and

[0052] Rcis hydrogen or -CH2OP(=O)(OH)2.

[0053] In another embodiment, Compounds of the Disclosure are compounds, or pharmaceutically acceptable salt thereof, having Formula (II):R7Et Y^cR10R9wherein R7, R8, R9, R10, W, L, and E are as defined in connection with Formula (I).

[0054] In another embodiment, Compounds of the Disclosure are compounds, or pharmaceutically acceptable salt thereof, having Formula (I) or Formula (II), wherein W is -C(=O)-.

[0055] In another embodiment, Compounds of the Disclosure are compounds, or pharmaceutically acceptable salt thereof, having Formula (I) or Formula (II), wherein W is -CH2-.

[0056] In another embodiment, Compounds of the Disclosure are compounds, or pharmaceutically acceptable salt thereof, having Formula (I) or Formula (II), wherein W is a direct bond.

[0057] In another embodiment, Compounds of the Disclosure are compounds, or pharmaceutically acceptable salt thereof, having Formula (I) or Formula (II), wherein W is a -S(=O)2-.

[0058] In another embodiment, Compounds of the Disclosure are compounds, or pharmaceutically acceptable salt thereof, having Formula (I) or Formula (II), wherein X1is -CR3= and R3is H.

[0059] In another embodiment, Compounds of the Disclosure are compounds, or pharmaceutically acceptable salt thereof, having Formula (I) or Formula (II), wherein X1is -CR3= and R3is halogen.

[0060] In another embodiment, Compounds of the Disclosure are compounds, or pharmaceutically acceptable salt thereof, having Formula (I) or Formula (II), wherein X1is -CR3= and R3is (Ci-Ce)alkyl.

[0061] In another embodiment, Compounds of the Disclosure are compounds, or pharmaceutically acceptable salt thereof, having Formula (I) or Formula (II), wherein X1is -N=.

[0062] In another embodiment, Compounds of the Disclosure are compounds, or pharmaceutically acceptable salt thereof, having Formula (I) or Formula (II), wherein X2is -CR4= and R4is H.

[0063] In another embodiment, Compounds of the Disclosure are compounds, or pharmaceutically acceptable salt thereof, having Formula (I) or Formula (II), wherein X2is -CR4= and R4is halogen.

[0064] In another embodiment, Compounds of the Disclosure are compounds, or pharmaceutically acceptable salt thereof, having Formula (I) or Formula (II), wherein X2is -CR4= and R4is (Ci-Ce)alkyl.

[0065] In another embodiment, Compounds of the Disclosure are compounds, or pharmaceutically acceptable salt thereof, having Formula (I) or Formula (II), wherein R6is H.

[0066] In another embodiment, Compounds of the Disclosure are compounds, or pharmaceutically acceptable salt thereof, having Formula (I) or Formula (II), wherein R6is (Ci-Ce)alkyl.

[0067] In another embodiment, Compounds of the Disclosure are compounds, or pharmaceutically acceptable salt thereof, having Formula (I) or Formula (II), wherein R6is -CN.

[0068] In another embodiment, Compounds of the Disclosure are compounds, or pharmaceutically acceptable salt thereof, having Formula (I) or Formula (II), wherein:

[0069] R1is:NR11; and

[0070] R2is H, halogen, (Ci-Ce)alkyl, or (Ci-Ce)alkoxy.

[0071] In another embodiment, Compounds of the Disclosure are compounds, or pharmaceutically acceptable salt thereof, having Formula (I) or Formula (II), wherein:

[0072] R2is:NR11; and

[0073] R1is H, halogen, (Ci-Ce)alkyl, or (Ci-Ce)alkoxy.

[0074] In another embodiment, Compounds of the Disclosure are compounds, or pharmaceutically acceptable salt thereof, having Formula (I) or Formula (II), wherein E is E-l.

[0075] In another embodiment, Compounds of the Disclosure are compounds, or pharmaceutically acceptable salt thereof, having Formula (I) or Formula (II), wherein R5ais hydrogen.

[0076] In another embodiment, Compounds of the Disclosure are compounds, or pharmaceutically acceptable salt thereof, having Formula (I) or Formula (II), wherein R5ais (Ci-Ce)alkyl optionally substituted with 1 to 3 substituents independently selected from halogen or -CN.

[0077] In another embodiment, Compounds of the Disclosure are compounds, or pharmaceutically acceptable salt thereof, having Formula (I) or Formula (II), wherein R5ais (C3-Ce)cycloalkyl.

[0078] In another embodiment, Compounds of the Disclosure are compounds, or pharmaceutically acceptable salt thereof, having Formula (I) or Formula (II), wherein R5ais 4- to 6-membered heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from halogen, -CN, or (Ci-Ce)alkyl.

[0079] In another embodiment, Compounds of the Disclosure are compounds, or pharmaceutically acceptable salt thereof, having Formula (I) or Formula (II), wherein R5ais -CN.

[0080] In another embodiment, Compounds of the Disclosure are compounds, or pharmaceutically acceptable salt thereof, having Formula (I) or Formula (II), wherein R5ais aryl optionally substituted with 1 to 3 substituents independently selected from halogen, -CN, or (Ci-Ce)alkyl.

[0081] In another embodiment, Compounds of the Disclosure are compounds, or pharmaceutically acceptable salt thereof, having Formula (I) or Formula (II), wherein R5ais 5- or 6-membered heteroaryl optionally substituted with 1 to 3 substituents independently selected from halogen, -CN, or (Ci-Ce)alkyl.

[0082] In another embodiment, Compounds of the Disclosure are compounds, or pharmaceutically acceptable salt thereof, having Formula (I) or Formula (II), wherein E-l is:

[0083] In another embodiment, Compounds of the Disclosure are compounds, or pharmaceutically acceptable salt thereof, having Formula (I) or Formula (II), wherein E is E-2.

[0084] In another embodiment, Compounds of the Disclosure are compounds, or pharmaceutically acceptable salt thereof, having Formula (I) or Formula (II), wherein R5bis hydrogen.

[0085] In another embodiment, Compounds of the Disclosure are compounds, or pharmaceutically acceptable salt thereof, having Formula (I) or Formula (II), wherein R5bis (C1-C6)alkyl.

[0086] In another embodiment, Compounds of the Disclosure are compounds, or pharmaceutically acceptable salt thereof, having Formula (I) or Formula (II), wherein R5bis (C3-C6)cycloalkyl.

[0087] In another embodiment, Compounds of the Disclosure are compounds, or pharmaceutically acceptable salt thereof, having Formula (I) or Formula (II), wherein E-2 is:

[0088] In another embodiment, Compounds of the Disclosure are compounds, or pharmaceutically acceptable salt thereof, having Formula (I) or Formula (II), wherein:

[0089] R7is halogen, (C1-C6)alkyl, -CN, or (C3-C6)cycloalkyl, wherein (C1-C6)alkyl is optionally substituted with 1 to 3 halogen; and

[0090] R8, R9, and R10are H.

[0091] In another embodiment, Compounds of the Disclosure are compounds, or pharmaceutically acceptable salt thereof, having Formula (I) or Formula (II), wherein:

[0092] R8is halogen, (C1-C6)alkyl, -CN, or (C3-C6)cycloalkyl, wherein (C1-C6)alkyl is optionally substituted with 1 to 3 halogen; and

[0093] R7, R9, and R10are H.

[0094] In another embodiment, Compounds of the Disclosure are compounds, or pharmaceutically acceptable salt thereof, having Formula (I) or Formula (II), wherein:

[0095] R9is halogen, (C1-C6)alkyl, -CN, or (C3-C6)cycloalkyl, wherein (C1-C6)alkyl is optionally substituted with 1 to 3 halogen; and

[0096] R7, R8, and R10are H.

[0097] In another embodiment, Compounds of the Disclosure are compounds, or pharmaceutically acceptable salt thereof, having Formula (I) or Formula (II), wherein:

[0098] R10is halogen, (C1-C6)alkyl, -CN, or (C3-C6)cycloalkyl, wherein (C1-C6)alkyl is optionally substituted with 1 to 3 halogen; and

[0099] R7, R8, and R9are H.

[0100] In another embodiment, Compounds of the Disclosure are compounds, or pharmaceutically acceptable salt thereof, having Formula (I) or Formula (II), wherein R7, R8, R9, and R10are H.

[0101] In another embodiment, Compounds of the Disclosure are compounds, or pharmaceutically acceptable salt thereof, having Formula (I) or Formula (II), wherein G1is 4- to 6-membered heterocycloalkylenyl optionally substituted with 1 to 3 substituents independently selected from halogen, (Ci-C6)alkyl, halo(Ci-C3)alkyl, (Ci-C6)alkoxy, or -CN.

[0102] In another embodiment, Compounds of the Disclosure are compounds, or pharmaceutically acceptable salt thereof, having Formula (I) or Formula (II), wherein G1is:wherein the bond marked with an "*" is attached to G2.

[0103] In another embodiment, Compounds of the Disclosure are compounds, or pharmaceutically acceptable salt thereof, having Formula (I) or Formula (II), wherein G1is 7- to 11 -membered heterocycloalkylenyl optionally substituted with 1 to 3 substituents independently selected from halogen, (Ci-C6)alkyl, halo(Ci-C3)alkyl, (Ci-C6)alkoxy, or -CN

[0104] In another embodiment, Compounds of the Disclosure are compounds, or pharmaceutically acceptable salt thereof, having Formula (I) or Formula (II), wherein G1is:wherein the bond marked with an "*" is attached to G2.

[0105] In another embodiment, Compounds of the Disclosure are compounds, or pharmaceutically acceptable salt thereof, having Formula (I) or Formula (II), wherein G2is a direct bond.

[0106] In another embodiment, Compounds of the Disclosure are compounds, or pharmaceutically acceptable salt thereof, having Formula (I) or Formula (II), wherein G2is (C1-C6)alkylenyl.

[0107] In another embodiment, Compounds of the Disclosure are compounds, or pharmaceutically acceptable salt thereof, having Formula (I) or Formula (II), wherein G2is -CH2- or -CH(CH3)-.

[0108] In another embodiment, Compounds of the Disclosure are compounds, or pharmaceutically acceptable salt thereof, having Formula (I) or Formula (II), wherein G3is 4- to 6-membered heterocycloalkylenyl optionally substituted with 1 to 3 substituents independently selected from halogen, (Ci-C6)alkyl, halo(Ci-C3)alkyl, (Ci-C6)alkoxy, or -CN.

[0109] In another embodiment, Compounds of the Disclosure are compounds, or pharmaceutically acceptable salt thereof, having Formula (I) or Formula (II), wherein G3is:wherein the bond marked with an "*" is attached to E.

[0110] In another embodiment, Compounds of the Disclosure are compounds, or pharmaceutically acceptable salt thereof, having Formula (I) or Formula (II), wherein G3is 7- to 11 -membered heterocycloalkylenyl optionally substituted with 1 to 3 substituents independently selected from halogen, (Ci-C6)alkyl, halo(Ci-C3)alkyl, (Ci-C6)alkoxy, or-CN.

[0111] In another embodiment, Compounds of the Disclosure are compounds, or pharmaceutically acceptable salt thereof, having Formula (I) or Formula (II), wherein G3is:HO> ■■■', IO CP,,orK» wherein the bond marked with an "*" is attached to E.

[0112] In another embodiment, Compounds of the Disclosure are compounds, or pharmaceutically acceptable salt thereof, having Formula (I) or Formula (II), wherein L is:wherein the bond marked with an "*" is attached to E.

[0113] In another embodiment, Compounds of the Disclosure are any one or more of the compounds of Compound List 1, or a pharmaceutically acceptable salt thereof.Compound List 1

[0114] l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo [3.2.1 ]octan-8-yl]benzoyl] -4-piperidyl]methyl] -4-piperidyl] -2 -methyl -indol-4-yl]hexahydropyrimidine-2, 4-dione;

[0115] l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo [3.2.1 ]octan-8-yl]benzoyl] -4-piperidyl]methyl] -4-piperidyl]pyrrolo [2,3 -c]pyridin-4-yl]hexahydropyrimidine-2, 4-dione;

[0116] l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo [3.2.1 ]octan-8-yl] -2 -methyl -benzoyl] -4-piperidyl]methyl] -4-piperidyl] indol-5 -yl]hexahydropyrimidine-2, 4-dione;

[0117] l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-methyl-benzoyl]-4-fluoro-4-piperidyl]methyl]-4-piperidyl]-3-methyl-indol-5-yl]hexahydro-pyrimidine-2, 4-dione;

[0118] l-[l-[l-[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan- 8-yl]benzoyl]-4-piperidyl]-4-piperidyl]indol-4-yl]hexahydropyrimidine-2, 4-dione;

[0119] l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo [3.2.1 ]octan-8-yl]benzoyl] -4-piperidyl]methyl] -4-piperidyl] -5 -methyl-indol-4-yl]hexahydropyrimidine-2, 4-dione;

[0120] l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]benzoyl]-4-piperidyl]methyl]-4-piperidyl]indol-4-yl]hexahydropyrimidine-2,4-dione;

[0121] l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo [3.2.1 ]octan-8-yl]benzoyl] -4-piperidyl]methyl] -4-piperidyl] -7 -fluoro-indol-4-yl]hexahydropyrimidine-2, 4-dione;

[0122] l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]benzoyl]-4-methyl-4-piperidyl]methyl]-4-piperidyl]indol-4-yl]hexahydropyrimidine-2, 4-dione;

[0123] l-[l-[l-[[l-[4-[3-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8-yl]benzoyl]-4-piperidyl]methyl]-4-piperidyl]-6-methyl-indol-4-yl]hexahydropyrimidine-2,4-dione;

[0124] l-[3-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8-yl]benzoyl]-4-piperidyl]methyl]-4-piperidyl]-lH-indol-6-yl]hexahydropyrimidine-2, 4-dione;

[0125] l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8-yl]-2-fluoro-benzoyl]-4-piperidyl]methyl]-4-piperidyl]indol-5-yl]hexahydropyrimidine-2, 4-dione;

[0126] l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8-yl]-2-chloro-benzoyl]-4-piperidyl]methyl]-4-piperidyl]indol-5-yl]hexahydropyrimidine-2,4-dione;

[0127] l-[l-[l-[[l-[4-[3-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8-yl]benzoyl]-4-fluoro-4-piperidyl]methyl]-4-piperidyl]-3-methyl-indol-4-yl]hexahydro-pyrimidine-2, 4-dione;

[0128] l-[l-[l-[2-[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8-yl]benzoyl]-4-piperidyl]ethyl]-4-piperidyl]indol-4-yl]hexahydropyrimidine-2, 4-dione;

[0129] l-[l-[l-[[2-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8-yl]benzoyl]-2-azaspiro[3.3]heptan-6-yl]methyl]-4-piperidyl]indol-4-yl]hexahydropyrimidine-2,4-dione

[0130] l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8-yl]benzoyl]-4-fluoro-4-piperidyl]methyl]-4-piperidyl]-3-cyclopropyl-indol-5-yl]hexahydro-pyrimidine-2, 4-dione;

[0131] l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8-yl]benzoyl]-4-fluoro-4-piperidyl]methyl]-4-piperidyl]-3-methyl-indol-5-yl]hexahydro-pyrimidine-2, 4-dione;

[0132] l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8-yl]-2-fluoro-benzoyl]-4-fluoro-4-piperidyl]methyl]-4-piperidyl]-3-methyl-indol-5-yl]hexahydro-pyrimidine-2, 4-dione;

[0133] l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8-yl]benzoyl]-4-piperidyl]methyl]-4-piperidyl]-3-cyclopropyl-indol-5-yl]hexahydropyrimidine-2,4-dione;

[0134] l-[l-[-(3R,4R)-l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]benzoyl]-4-fluoro-4-piperidyl]methyl]-3-methyl-4-piperidyl]indol-5-yl] hexahydropyrimidine -2,4 -dione;

[0135] or

[0136] l-[l-[-(3S,4S)-l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]benzoyl]-4-fluoro-4-piperidyl]methyl]-3-methyl-4-piperidyl]indol-5-yl]hexahydropyrimidine-2, 4-dione;

[0137] l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8-yl]benzoyl]-4-fluoro-4-piperidyl]methyl]-4-piperidyl]-4-methyl-indol-5-yl]hexahydro-pyrimidine-2, 4-dione;

[0138] l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8-yl]benzoyl]-4-fluoro-4-piperidyl]methyl]-4-piperidyl]-7-methyl-indol-5-yl]hexahydro-pyrimidine-2, 4-dione;

[0139] l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8-yl]benzoyl]-4-fluoro-4-piperidyl]methyl]-4-piperidyl]indol-4-yl]hexahydropyrimidine-2, 4-dione;

[0140] l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]benzoyl] -4-[[4-[5-(2,4-dioxohexahydropyrimidin- 1 -yl)indol- 1 -yl] - 1 -piperidyl]methyl]piperidine-4-carbonitrile;

[0141] l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8-yl]benzoyl]-4-fluoro-4-piperidyl]methyl]-4-piperidyl]-3-(2-pyridyl)indol-5-yl]hexahydro-pyrimidine-2, 4-dione;

[0142] l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8-yl]benzoyl]-4-fluoro-4-piperidyl]methyl]-4-piperidyl]-6-methyl-indol-5-yl]hexahydro-pyrimidine-2, 4-dione;

[0143] l-[l-[l-[[l-[4-[3-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8-yl]benzoyl]-4-piperidyl]methyl]-4-piperidyl]-3-methyl-indol-5-yl]hexahydropyrimidine-2,4-dione;

[0144] l-[l-[l-[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]benzoyl]-4-piperidyl]-4-piperidyl]indol-5-yl]hexahydropyrimidine-2, 4-dione;

[0145] l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8-yl]benzoyl]-4-piperidyl]methyl]-4-piperidyl]indol-5-yl]hexahydropyrimidine-2, 4-dione;

[0146] l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8-yl]benzoyl]-4-fluoro-4-piperidyl]methyl]-4-piperidyl]pyrrolo[2,3-c]pyridin-4-yl]hexahydro-pyrimidine-2, 4-dione;

[0147] l-[l-[rel-(3S,4S)-l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo [3.2.1 ]octan-8-yl]benzoyl] -4-fluoro-4-piperidyl]methyl] -3 -methyl -4-piperidyl]indol-5 -yl]hexahydropyrimidine-2, 4-dione;

[0148] l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl] -2 -fluoro-benzoyl] -4-fluoro-4-piperidyl]methyl] -4-piperidyl] -5-(2,4-dioxohexahydropyrimidin- 1 -yl)indole -3 -carbonitrile;

[0149] l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]benzoyl] -4-fluoro-4-piperidyl]methyl] -4-piperidyl] -5 -(2,4-dioxohexahydropyrimidin- 1 -yl)indole-3 -carbonitrile;

[0150] l-[l-[l-[2-[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8-yl]benzoyl]-4-piperidyl]ethyl]-4-piperidyl]indol-5-yl]hexahydropyrimidine-2, 4-dione;

[0151] l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8-yl]benzoyl]-4-fluoro-4-piperidyl]methyl]-4-piperidyl]-3-isopropyl-indol-5-yl]hexahydro-pyrimidine-2, 4-dione;

[0152] l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8-yl]benzoyl]-4-piperidyl]methyl]-4-piperidyl]-3-isopropyl-indol-5-yl]hexahydropyrimidine-2,4-dione;

[0153] l-[l-[l-[[l-[4-[3-[3-Amino-6-(5-fluoro-2-hydroxy-phenyl)pyridazin-4-yl]-3,8-diazabicyclo [3.2.1 ]octan-8-yl]benzoyl] -4-fluoro-4-piperidyl]methyl] -4-piperidyl]indol-5 -yl]hexahydropyrimidine-2, 4-dione;

[0154] l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8-yl]benzoyl]-4-fluoro-4-piperidyl]methyl]-4-piperidyl]-5-methyl-indol-4-yl]hexahydro-pyrimidine-2, 4-dione;

[0155] l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8-yl]benzoyl]-4-fluoro-4-piperidyl]methyl]-4-piperidyl]-3-(l-methylpyrazol-4-yl)indol-5-yl]hexa-hydropyrimidine-2, 4-dione;

[0156] l-[l-[l-[[2-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8-yl]benzoyl]-2-azaspiro[3.3]heptan-6-yl]methyl]-4-piperidyl]indol-5-yl]hexahydropyrimidine-2,4-dione;

[0157] l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl) yridazine-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]phenyl]sulfonyl-4-piperidyl]methyl]-4-piperidyl]indol-4-yl]hexahydropyrimidine-2, 4-dione;

[0158] l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl) yridazine-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]benzoyl] -4-piperidyl]methyl] -4-piperidyl] -5 -(2,4-dioxohexahydropyrimidin- 1 -yl)indole-3 -carbonitrile;

[0159] l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8-yl]benzoyl]-4-fluoro-4-piperidyl]methyl]-4-piperidyl]-7-fluoro-indol-5-yl]hexahydropyrimidine-2,4-dione;

[0160] l-[3-[4-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8-yl]benzoyl]-4-piperidyl]methyl]piperazin-l-yl]-lH-indol-6-yl]hexahydropyrimidine-2, 4-dione;

[0161] l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8-yl]benzoyl]-4-methoxy-4-piperidyl]methyl]-4-piperidyl]indol-5-yl]hexahydropyrimidine-2,4-dione;

[0162] l-[l-[l-[[(lR,5S,6s)-3-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo-[3.2. l]octan-8-yl]benzoyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-4-piperidyl]indol-4-yl]hexahydro-pyrimidine-2, 4-dione;

[0163] l-[l-[l-[3-[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8-yl]benzoyl]-4-piperidyl]propyl]-4-piperidyl]indol-5-yl]hexahydropyrimidine-2, 4-dione;

[0164] l-[3-[4-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8-yl]benzoyl]-4-piperidyl]methyl]piperazin-l-yl]-l-methyl-indol-6-yl]hexahydropyrimidine-2,4-dione;

[0165] l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8-yl]benzoyl]-4-(difluoromethyl)-4-piperidyl]methyl]-4-piperidyl]indol-5-yl]hexahydro-pyrimidine-2, 4-dione;

[0166] l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8-yl]benzoyl]-4-fluoro-4-piperidyl]methyl]-4-piperidyl]-3-methyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2, 4-dione;

[0167] l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8-yl]benzoyl]-4-fluoro-4-piperidyl]methyl]-4-piperidyl]indol-5-yl]hexahydropyrimidine-2, 4-dione;

[0168] l-[l-[(lR,3s,5S)-8-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo- [3.2.1]octan-8-yl]benzoyl]-4-fluoro-4-piperidyl]methyl]-8-azabicyclo[3.2.1]octan-3-yl]indol-5-yl]hexa-hydropyrimidine-2, 4-dione;

[0169] 2-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8-yl]benzoyl]-4-fluoro-4-piperidyl]methyl]-4-piperidyl]-5-(2,4-dioxohexahydropyrimidin-l-yl)-indol-3 -yl] acetonitrile;

[0170] l-[l-[3-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8-yl]benzoyl]-4-fluoro-4-piperidyl]methyl]-3-azaspiro[5.5]undecan-9-yl]-3-methyl-indol-5-yl]-hexahydropyrimidine-2, 4-dione;

[0171] l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]benzoyl] -4-fluoro-4-piperidyl]methyl] -4-piperidyl] -4-(2,4-dioxohexahydropyrimidin- 1 -yl)indole-2-carbonitrile;

[0172] l-[l-[-(3S,4S)-l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo [3.2.1 ]octan-8-yl]benzoyl] -4-piperidyl]methyl] -3 -fluoro-4-piperidyl]indol-5 -yl]hexahydropyrimidine-2, 4-dione;

[0173] or

[0174] l-[l-[-(3R,4R)-l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo [3.2.1 ]octan-8-yl]benzoyl] -4-piperidyl]methyl] -3 -fluoro-4-piperidyl] indol-5 -yl]hexahydropyrimidine-2, 4-dione;

[0175] l-[l-[rel-(3R,4R)-l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diaza-bicyclo[3.2.1]octan-8-yl]benzoyl]-4-piperidyl]methyl]-3-fluoro-4-piperidyl]indol-5-yl]hexahydro-pyrimidine-2, 4-dione;

[0176] l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8-yl]benzoyl]-4-fluoro-4-piperidyl]methyl]-4-piperidyl]-3-chloro-indol-5-yl]hexahydropyrimidine-2,4-dione;

[0177] l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8-yl]benzoyl]-4-fluoro-4-piperidyl]methyl]-4-piperidyl]-2-methyl-indol-5-yl]hexahydro-pyrimidine-2, 4-dione;

[0178] l-[l-[l-[[l-[4-[3-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8-yl]benzoyl]-4-fluoro-4-piperidyl]methyl]-4-piperidyl]-2,3-dimethyl-indol-5-yl]hexahydro-pyrimidine-2, 4-dione;

[0179] l-[l-[l-[[l-[[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8-yl]phenyl]methyl]-4-fluoro-4-piperidyl]methyl]-4-piperidyl]-3-methyl-indol-5-yl]hexahydro-pyrimidine-2, 4-dione;

[0180] l-[3-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8-yl]benzoyl]-4-fluoro-4-piperidyl]methyl]-4-piperidyl]-l-methyl-indol-6-yl]hexahydro-pyrimidine-2, 4-dione;

[0181] l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8-yl]benzoyl]-4-fluoro-4-piperidyl]methyl]-4-piperidyl]indolin-5-yl]hexahydropyrimidine-2,4-dione;

[0182] l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]benzoyl] -4-fluoro-4-piperidyl]methyl] -4-piperidyl] -5 -(2,4-dioxohexahydropyrimidin- 1 -yl)-4-fluoro-indole -3 -carbonitrile;

[0183] l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8-yl]benzoyl]-4-fluoro-4-piperidyl]methyl]-4-piperidyl]-4-fluoro-indol-5-yl]hexahydropyrimidine-2,4-dione;

[0184] l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo [3.2.1 ]octan-8-yl]benzoyl] -4-fluoro-4-piperidyl]methyl] -4-piperidyl] -4-fluoro-3 -methyl -indol-5-yl]hexahydropyrimidine-2, 4-dione;

[0185] l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo [3.2.1 ]octan-8-yl]benzoyl] -4-fluoro-4-piperidyl]methyl] -4-piperidyl] -4-fluoro-pyrrolo [2,3 -b]pyridin-5-yl]hexahydropyrimidine-2, 4-dione;

[0186] 5-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-[4- [ [4- [5 -(2,4-dioxohexahydropyrimidin- 1 -yl)-4-fluoro-3 -methyl -indol- 1 -yl] - 1 -piperidyl]methyl] -4-fluoro-piperidine- 1 -carbonyl]benzonitrile;

[0187] l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo [3.2.1 ]octan-8-yl]benzoyl] -4-fluoro-4-piperidyl]methyl] -4-piperidyl] -3 -cyclobutyl -indol-5 -yl]hexahydropyrimidine-2, 4-dione;

[0188] l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo [3.2.1 ]octan-8-yl]benzoyl] -4-fluoro-4-piperidyl]methyl] -4-piperidyl] -3 -cyclopropyl -pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2, 4-dione;

[0189] 5-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-[4- [ [4 - [5 -(2,4-dioxohexahydropyrimidin- 1 -y 1) -3 -methyl -indol- 1 -yl] - 1 -piperidyl]methyl] -4-fluoro-piperidine-1 -carbonyl] -3 -fluoro-benzonitrile;

[0190] l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo [3.2.1 ]octan-8-yl]benzoyl] -4-fluoro-4-piperidyl]methyl] -4-piperidyl] -3 -phenyl -indol-5 -yl]hexahydropyrimidine-2, 4-dione;

[0191] l-[3-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo [3.2.1 ]octan-8-yl]benzoyl] -4-fluoro-4-piperidyl]methyl] -4-piperidyl] - 1 -cyclobutyl -indol-6-yl]hexahydropyrimidine-2, 4-dione;

[0192] l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-3-fluoro-benzoyl]-4-fluoro-4-piperidyl]methyl]-4-piperidyl]-4-fluoro-indol-5-yl]hexahydropyrimidine-2, 4-dione;

[0193] l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo [3.2.1 ]octan-8-yl]benzoyl] -4-fluoro-4-piperidyl]methyl] -4-piperidyl] -3 -ethyl -indol-5 -yl]hexahydropyrimidine-2, 4-dione;

[0194] [3-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo [3.2.1 ]octan-8-yl]benzoyl] -4-fluoro-4-piperidyl]methyl] -4-piperidyl] -3 -methyl -indol-5 -yl] -2,6-dioxo-hexahydropyrimidin-l-yl]methyl dihydrogen phosphate;

[0195] [2-[6-Amino-5-[8-[4-[4-[[4-[5-(2,4-dioxohexahydropyrimidin-l-yl)-3-methyl-indol-l-yl]-l-piperidyl]methyl]-4-fluoro-piperidine-l-carbonyl]phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]pyridazin-3-yl]phenoxy]methyl dihydrogen phosphate;

[0196] l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo [3.2.1 ]octan-8-yl]benzoyl] -4-fluoro-4-piperidyl]methyl] -4-piperidyl] -3 -cyclobutyl -pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2, 4-dione;

[0197] l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo [3.2.1 ]octan-8-yl]benzoyl] -4-fluoro-4-piperidyl]methyl] -4-piperidyl] -4,6-difluoro-indol-5 -yl]hexahydropyrimidine-2, 4-dione;

[0198] l-[3-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo [3.2.1 ]octan-8-yl] -2,6-difluoro-benzoyl] -4-fluoro-4-piperidyl]methyl] -4-piperidyl] - 1 -cyclobutyl-indol-6-yl]hexahydropyrimidine-2, 4-dione;

[0199] 5-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-[4- [ [4 - [3 -cyclopropyl-5 -(2,4-dioxohexahydropyrimidin- 1 -yl)pyrrolo[2,3 -b]pyridin- 1 -yl] - 1 -piperidyl]methyl] -4-fluoro-piperidine- 1 -carbonyl] -3-fluoro-benzonitrile;

[0200] l-[l-[l-[[l-[4-[(lR,5S)-3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-8-azabicyclo [3.2.1 ]octan-8-yl]benzoyl] -4-fluoro-4-piperidyl]methyl] -4-piperidyl] indol-5 -yl]hexahydropyrimidine-2, 4-dione;

[0201] l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8 diazabicyclo[3.2.1]octan-8-yl]benzoyl] -4-fluoro-4-piperidyl]methyl] -4-piperidyl] -3 -( 1 -methylazetidin-3 -yl)indol-5 yl]hexahydropyrimidine-2, 4-dione;

[0202] l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo [3.2.1 ]octan-8-yl]benzoyl] -4-fluoro-4-piperidyl]methyl] -4-piperidyl] -3 -(trifluoromethyl)pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2, 4-dione;

[0203] l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-3-fluoro-benzoyl]-4-fluoro-4-piperidyl]methyl]-4-piperidyl]-6-fluoro-indol-5-yl]hexahydropyrimidine-2, 4-dione;

[0204] l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-fluoro-6-hydroxy-phenyl)pyridazin-4-yl]-3,8-diazabicyclo [3.2.1 ]octan-8-yl]benzoyl] -4-fluoro-4-piperidyl]methyl] -4-piperidyl] -3 -methyl -indol-5 -yl]hexahydropyrimidine-2, 4-dione;

[0205] l-[3-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-benzoyl]-4-piperidyl]methyl]-4-piperidyl]-l-cyclobutyl-7-fluoro-indol-6-yl]hexahydropyrimidine-2, 4-dione;

[0206] l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo [3.2.1 ]octan-8-yl]benzoyl] -4-piperidyl]methyl] -4-piperidyl] -7 -methyl-indol-4-yl]hexahydropyrimidine-2, 4-dione;

[0207] l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-6-methyl-benzoyl]-4-fluoro-4-piperidyl]methyl]-4-piperidyl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2, 4-dione;

[0208] l-[3-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-methyl-benzoyl]-4-fluoro-4-piperidyl]methyl]-4-piperidyl]-l-cyclobutyl-pyrrolo[3,2-b]pyridin-6-yl]hexahydropyrimidine-2, 4-dione;

[0209] l-[3-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-benzoyl]-4-fluoro-4-piperidyl]methyl]-4-piperidyl]-l-cyclobutyl-pyrrolo[3,2-b]pyridin-6-yl]hexahydropyrimidine-2, 4-dione;

[0210] l-[3-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-chloro-benzoyl]-4-fluoro-4-piperidyl]methyl]-4-piperidyl]-l-cyclobutyl-pyrrolo[3,2-b]pyridin-6-yl]hexahydropyrimidine-2, 4-dione;

[0211] l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo [3.2.1 ]octan-8-yl]benzoyl] -4-fluoro-4-piperidyl]methyl] -4-piperidyl] -4,6-difluoro-3 -methyl -indol-5-yl]hexahydropyrimidine-2, 4-dione;

[0212] l-[l-[l-[l-[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]benzoyl]-4-piperidyl]ethyl]-4-piperidyl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2, 4-dione;

[0213] l-[3-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo [3.2.1 ]octan-8-yl] -2 -fluoro-6-methyl -benzoyl] -4-fluoro-4-piperidyl]methyl] -4-piperidyl] - 1 -cyclobutyl-indol-6-yl]hexahydropyrimidine-2, 4-dione;

[0214] l-[3-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-methyl-benzoyl]-4-fluoro-4-piperidyl]methyl]-4-piperidyl]-l-cyclopropyl-indol-6-yl]hexahydropyrimidine-2, 4-dione;

[0215] l-[3-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo [3.2.1 ]octan-8-yl]benzoyl] -4-fluoro-4-piperidyl]methyl] -4-piperidyl] - 1 -cyclopropyl -indol-6-yl]hexahydropyrimidine-2, 4-dione;

[0216] l-[3-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo [3.2.1 ]octan-8-yl] -2 -chloro-benzoyl] -4-fluoro-4-piperidyl]methyl] -4-piperidyl] - 1 -cyclopropyl-indol-6-yl]hexahydropyrimidine-2, 4-dione;

[0217] l-[l-[(lS,5R)-8-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]benzoyl]-4-fluoro-4-piperidyl]methyl]-8-azabicyclo[3.2.1]octan-3-yl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2, 4-dione;

[0218] [3-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo [3.2.1 ]octan-8-yl]benzoyl] -4-fluoro-4-piperidyl]methyl] -4-piperidyl] -3 -cyclopropyl -pyrrolo [2,3 -b]pyridin-5 -yl] -2,6-dioxo-hexahydropyrimidin- 1 -yl]methyl dihydrogen phosphate;

[0219] l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo [3.2.1 ]octan-8-yl]benzoyl] -4-fluoro-4-piperidyl]methyl] -4-piperidyl] -3 -cyclopropyl -4-fluoro-indol-5-yl]hexahydropyrimidine-2, 4-dione;

[0220] l-[l-[l-[[l-[4-[(lR,5S)-3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo [3.2.1 ]octan-8-yl]benzoyl] -4-fluoro-4-piperidyl]methyl] -4-piperidyl] -3 -cyclopropyl-6-fluoro-indol-5-yl]pyrimidine-2, 4-dione;

[0221] l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-3-fluoro-benzoyl]-4-fluoro-4-piperidyl]methyl]-4-piperidyl]-4-fluoro-3-methyl-indol-5-yl]hexahydropyrimidine-2, 4-dione;

[0222] l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo [3.2.1 ]octan-8-yl] -3 -fluoro-benzoyl] -4-fluoro-4-piperidyl]methyl] -4-piperidyl] -3 -cyclopropyl-indol-5-yl]hexahydropyrimidine-2, 4-dione;

[0223] l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo [3.2.1 ]octan-8-yl]benzoyl] -4-fluoro-4-piperidyl]methyl] -4-piperidyl] -6-fluoro-indol-5 -yl]hexahydropyrimidine-2, 4-dione;

[0224] 5-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-[4- [ [4 - [5 -(2,4-dioxohexahydropyrimidin- 1 -yl)-4-fluoro-3 -methyl -indol- 1 -yl] - 1 -piperidyl]methyl] -4-fluoro-piperidine- 1 -carbonyl] -3 -fluoro-benzonitrile;

[0225] l-[l-[(3R*,4R*)-l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo [3.2.1 ]octan-8-yl]benzoyl] -4-fluoro-4-piperidyl]methyl] -3 -methyl -4-piperidyl] -3 -cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2, 4-dione;

[0226] or

[0227] l-[l-[(3S*,4S*)-l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo [3.2.1 ]octan-8-yl]benzoyl] -4-fluoro-4-piperidyl]methyl] -3 -methyl -4-piperidyl] -3 -cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2, 4-dione;

[0228] l-[3-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-methyl-benzoyl]-4-fluoro-4-piperidyl]methyl]-4-piperidyl]-l-cyclobutyl-7-fluoro-indol-6-yl]hexahydropyrimidine-2, 4-dione;

[0229] l-[l-[l-[2-[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]benzoyl]-4-fluoro-4-piperidyl]ethyl]-4-piperidyl]indol-4-yl]hexahydropyrimidine-2, 4-dione;

[0230] l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo [3.2.1 ]octan-8-yl]benzoyl] -4-fluoro-4-piperidyl]methyl] -4-piperidyl] -4-methyl-pyrrolo [2,3 -b]pyridin-5-yl]hexahydropyrimidine-2, 4-dione;

[0231] l-[3-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-benzoyl]-4-fluoro-4-piperidyl]methyl]-4-piperidyl]-l-cyclobutyl-7-fluoro-indol-6-yl]hexahydropyrimidine-2, 4-dione;

[0232] l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo [3.2.1 ]octan-8-yl]benzoyl] -4-fluoro-4-piperidyl]methyl] -4-piperidyl] -3 -phenyl -pyrrolo [2,3 -b]pyridin-5-yl]hexahydropyrimidine-2, 4-dione;

[0233] l-[3-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo [3.2.1 ]octan-8-yl]benzoyl] -4-fluoro-4-piperidyl]methyl] -4-piperidyl] - 1 -cyclobutyl-7 -fluoro-indol-6-yl]hexahydropyrimidine-2, 4-dione;

[0234] l-[3-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-chloro-benzoyl]-4-fluoro-4-piperidyl]methyl]-4-piperidyl]-l-cyclobutyl-7-fluoro-indol-6-yl]hexahydropyrimidine-2, 4-dione;

[0235] l-[3-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo [3.2.1 ]octan-8-yl]benzoyl] -4-fluoro-4-piperidyl]methyl] -4-piperidyl] - 1 -cyclobutyl -pyrrolo[3,2-b]pyridin-6-yl]hexahydropyrimidine-2, 4-dione;

[0236] l-[l-[(3S*,4R*)-l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo [3.2.1 ]octan-8-yl]benzoyl] -4-fluoro-4-piperidyl]methyl] -3 -methyl -4-piperidyl] -3 -cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2, 4-dione;

[0237] or

[0238] l-[l-[(3R*,4S*)-l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo [3.2.1 ]octan-8-yl]benzoyl] -4-fluoro-4-piperidyl]methyl] -3 -methyl -4-piperidyl] -3 -cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2, 4-dione;

[0239] l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo [3.2.1 ]octan-8-yl]benzoyl] -4-fluoro-4-piperidyl]methyl] -4-piperidyl] -5 -fluoro-indol-4-yl]hexahydropyrimidine-2, 4-dione;

[0240] l-[l-[(3S*,4S*)-l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo [3.2.1 ]octan-8-yl]benzoyl] -4-fluoro-4-piperidyl]methyl] -3 -methyl -4-piperidyl] -3 -cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2, 4-dione;

[0241] or

[0242] l-[l-[(3R*,4R*)-l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]benzoyl]-4-fluoro-4-piperidyl]methyl]-3-methyl-4-piperidyl]-3-cyclopropyl -pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2, 4-dione;

[0243] l-[l-[(3R*,4S*)-l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo [3.2.1 ]octan-8-yl]benzoyl] -4-fluoro-4-piperidyl]methyl] -3 -methyl -4-piperidyl] -3 -cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2, 4-dione;

[0244] or

[0245] l-[l-[(3S*,4R*)-l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo [3.2.1 ]octan-8-yl]benzoyl] -4-fluoro-4-piperidyl]methyl] -3 -methyl -4-piperidyl] -3 -cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2, 4-dione;

[0246] l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo [3.2.1 ]octan-8-yl]benzoyl] -4-fluoro-4-piperidyl]methyl] -4-piperidyl]pyrrolo [2,3 -b]pyridin-4-yl]hexahydropyrimidine-2, 4-dione;

[0247] l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo [3.2.1 ]octan-8-yl] -2 -cyclopropyl -benzoyl] -4-fluoro-4-piperidyl]methyl] -4-piperidyl] -3 -cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2, 4-dione;

[0248] l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-benzoyl]-4-fluoro-4-piperidyl]methyl]-4-piperidyl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2, 4-dione;

[0249] l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo [3.2.1 ]octan-8-yl] -2-(trifluoromethyl)benzoyl] -4-fluoro-4-piperidyl]methyl] -4-piperidyl] -3 -cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2, 4-dione;

[0250] l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo [3.2.1 ]octan-8-yl] -2 -methyl -benzoyl] -4-fluoro-4-piperidyl]methyl] -4-piperidyl] -3 -cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2, 4-dione;

[0251] l-[3-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo [3.2.1 ]octan-8-yl] -2 -methyl -benzoyl] -4-piperidyl]methyl] -4-piperidyl] - 1 -cyclobutyl -indol-6-yl]hexahydropyrimidine-2, 4-dione;

[0252] l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2,6-difluoro-benzoyl]-4-fluoro-4-piperidyl]methyl]-4-piperidyl]-3-methyl-indol-5-yl]hexahydropyrimidine-2, 4-dione;

[0253] l-[3-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo [3.2.1 ]octan-8-yl] -2 -cyclopropyl -benzoyl] -4-fluoro-4-piperidyl]methyl] -4-piperidyl] - 1 -cyclobutyl-indol-6-yl]hexahydropyrimidine-2, 4-dione;

[0254] l-[3-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo [3.2.1 ]octan-8-yl]benzoyl] -4-fluoro-4-piperidyl]methyl] -4-piperidyl] - 1 -methyl -indol-7 -yl]hexahydropyrimidine-2, 4-dione;

[0255] l-[3-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo [3.2.1 ]octan-8-yl] -2 -chloro-benzoyl] -4-piperidyl] methyl] -4-piperidyl] - 1 -cyclobutyl -indol-6-yl]hexahydropyrimidine-2, 4-dione;

[0256] l-[3-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-benzoyl]-4-fluoro-4-piperidyl]methyl]-4-piperidyl]-l-cyclobutyl-indol-6-yl]hexahydropyrimidine-2, 4-dione;

[0257] l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]benzoyl] -4-[[4-[3 -cyclopropyl-5 -(2,4-dioxohexahydropyrimidin- 1 -yl)pyrrolo [2,3 -b]pyridin- 1 -yl] - 1 -piperidyl]methyl]piperidine-4-carbonitrile;

[0258] l-[3-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo [3.2.1 ]octan-8-yl] -2-(trifluoromethyl)benzoyl] -4-fluoro-4-piperidyl]methyl] -4-piperidyl] - 1 -cyclobutyl-indol-6-yl]hexahydropyrimidine-2, 4-dione;

[0259] l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-chloro-benzoyl]-4-fluoro-4-piperidyl]methyl]-4-piperidyl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2, 4-dione;

[0260] l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2,6-difluoro-benzoyl]-4-fluoro-4-piperidyl]methyl]-4-piperidyl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2, 4-dione;

[0261] l-[3-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-chloro-benzoyl]-4-fluoro-4-piperidyl]methyl]-4-piperidyl]-l-cyclobutyl-indol-6-yl]hexahydropyrimidine-2, 4-dione;

[0262] l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo [3.2.1 ]octan-8-yl]benzoyl] -4-fluoro-4-piperidyl]methyl] -4-piperidyl] -4-methoxy-pyrrolo[2,3 -b]pyridin-5-yl]hexahydropyrimidine-2, 4-dione;

[0263] l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo [3.2.1 ]octan-8-yl]benzoyl] -4-piperidyl]methyl] -4-piperidyl] -3 -cyclopropyl -pyrrolo [2,3 -b]pyridin-5-yl]hexahydropyrimidine-2, 4-dione;

[0264] l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]phenyl]-4-piperidyl]methyl]-4-piperidyl]indol-4-yl]hexahydropyrimidine-2,4-dione;

[0265] l-[l-[7-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]phenyl]-4-piperidyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-methyl-indol-5-yl]hexahydropyrimidine-2, 4-dione;

[0266] l-[l-[7-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]phenyl]-4-piperidyl]methyl]-7-azaspiro[3.5]nonan-2-yl]-3-cyclopropyl-pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2, 4-dione;

[0267] l-[l-[3-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]phenyl]-4-piperidyl]methyl]-3-azaspiro[5.5]undecan-9-yl]-3-methyl-indol-5-yl]hexahydropyrimidine-2, 4-dione;

[0268] l-[l-[l-[[l-[4-[7-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3-oxa-7,9-diazabicyclo [3.3.1 ]nonan-9-yl]benzoyl] -4-fluoro-4-piperidyl]methyl] -4-piperidyl] -3 -cyclopropyl -pyrrolo[2,3-b]pyridin-5-yl]hexahydropyrimidine-2, 4-dione;

[0269] l-[l-[l-[[l-[4-[7-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3-oxa-7,9-diazabicyclo[3.3.1]nonan-9-yl]benzoyl]-4-piperidyl]methyl]-4-piperidyl]-2-methyl-indol-4-yl]hexahydropyrimidine-2, 4-dione;

[0270] 1 -( 1 -(3 -(( 1 -(4-(3 -(3 -amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-3, 8 -diazabicyclo [3.2.1] octan- 8-yl)-2-fluorophenyl)piperidin-4-yl)methyl)-3-azaspiro[5.5]undecan-9-yl)-3-ethyl-lH-pyrrolo[2,3-b]pyridin-5-yl)dihydropyrimidine-2,4(lH,3H) -dione;

[0271] 1 -( 1 -(3 -(( 1 -(4-(3 -(3 -amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-3, 8 -diazabicyclo [3.2.1] octan- 8-yl)-2-fluorophenyl)piperidin-4-yl)methyl)-3 -azaspiro [5.5]undecan-9-yl)-3 -cyclopropyl- IH-pyrrolo [2,3 -b]pyridin-5-yl)dihydropyrimidine-2,4(lH,3H)-dione;

[0272] 1 -( 1 -(3 -(( 1 -(4-(3 -(3 -amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-3, 8 -diazabicyclo [3.2.1] octan- 8-yl)phenyl)piperidin-4-yl)methyl)-3-azaspiro[5.5]undecan-9-yl)-3-cyclopropyl-lH-pyrrolo[2,3-b]pyridin-5-yl)dihydropyrimidine-2,4(lH,3H) -dione;

[0273] 1 -( 1 -(3 -(( 1 -(4-(3 -(3 -amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-3, 8 -diazabicyclo [3.2.1] octan- 8-yl)phenyl)piperidin-4-yl)methyl)-3-azaspiro[5.5]undecan-9-yl)-3-ethyl-lH-pyrrolo[2,3-b]pyridin-5-yl)dihydropyrimidine-2,4(lH,3H)-dione;

[0274] 1 -( 1 -(3 -(( 1 -(4-(3 -(3 -amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-3, 8 -diazabicyclo [3.2.1] octan- 8 -y 1) -3 -fluorophenyl)piperidin-4-yl)methyl)-3 -azaspiro [5.5]undecan-9-yl)-3 -cyclopropyl- IH-pyrrolo [2,3 -b]pyridin-5-yl)dihydropyrimidine-2,4(lH,3H) -dione;

[0275] 1 -( 1 -(3 -(( 1 -(4-(3 -(3 -amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-3, 8 -diazabicyclo [3.2.1 ]octan- 8-yl)-3-fluorophenyl)piperidin-4-yl)methyl)-3-azaspiro[5.5]undecan-9-yl)-3-ethyl-lH-pyrrolo[2,3-b]pyridin-5-yl)dihydropyrimidine-2,4(lH,3H)-dione;

[0276] 1 -( 1 -(9-(( 1 -(4-(3 -(3 -amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-3,8 -diazabicyclo [3.2.1 ]octan- 8-yl)-2-fluorophenyl)piperidin-4-yl)methyl)-l,5-dioxa-9-azaspiro[5.5]undecan-3-yl)-3-ethyl-lH-pyrrolo[2,3-b]pyridin-5-yl)dihydropyrimidine-2,4(lH,3H)-dione;

[0277] l-(l-(9-((l-(4-(3-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-fluorophenyl)piperidin-4-yl)methyl)-l,5-dioxa-9-azaspiro[5.5]undecan-3-yl)-3-cyclopropyl-lH-pyrrolo[2,3-b]pyridin-5-yl)dihydropyrimidine-2,4(lH,3H)-dione;

[0278] 1 -( 1 -(9-(( 1 -(4-(3 -(3 -amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-3, 8 -diazabicyclo [3.2.1] octan- 8-yl)-2-fluorophenyl)piperidin-4-yl)methyl)-l,5-dioxa-9-azaspiro[5.5]undecan-3-yl)-3-methyl-lH-indol-5-yl)dihydropyrimidine-2,4( lH,3H)-dione; and / or

[0279] 1 -( 1 -(9-(( 1 -(4-(3 -(3 -amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-3, 8 -diazabicyclo [3.2.1] octan- 8-yl)-2-fluorophenyl)piperidin-4-yl)methyl)-l,5-dioxa-9-azaspiro[5.5]undecan-3-yl)-lH-indol-4-yl)dihydropyrimidine-2,4(lH,3H)-dione.

[0280] In another embodiment, the present disclosure provides pharmaceutical compositions comprising a Compound of the Disclosure and one or more pharmaceutically acceptable excipients.

[0281] Compounds of the Disclosure may have one or more chiral centres and it will be recognised that such compounds may be prepared, isolated and / or supplied with or without the presence of one or more of the other possible enantiomeric and / or diastereomeric isomers of the compounds, or that such isomers may be provided in any relative proportions. The preparation of enantioenriched or enantiopure and / or diastereoenriched or diastereopure compounds may be carried out by standard techniques of organic chemistry that are well known in the art, for example by synthesis from enantioenriched or enantiopure starting materials, and / or by use of an appropriately enantioenriched or enantiopure catalyst during synthesis, and / or by resolution of a racemic or partially enriched mixture of stereoisomers, for example via chiral chromatography. The scope of the present disclosure includes mixtures of stereoisomers as well aspurified enantiomers or enantiomerically / diastereomerically enriched mixtures. It is to be understood that the present disclosure includes all combinations and subsets of the particular groups defined hereinabove.

[0282] In one embodiment, the present disclosure provides a composition comprising a Compound of the Disclosure optionally together with one or more of the other stereoisomeric forms of the compound, if any, wherein the Compound of the Disclosure is present within the composition with a diastereomeric excess (%de) of > 55%.

[0283] In another embodiment, the %de in the above-mentioned composition is > 90%.

[0284] In another embodiment, the %de in the above-mentioned composition is > 95%.

[0285] In another embodiment, the %de in the above-mentioned composition is > 98%.

[0286] In another embodiment, the %de in the above-mentioned composition is > 99%.

[0287] In another embodiment, the present disclosure provides a composition comprising a Compound of the Disclosure optionally together with one or more of the other stereoisomeric forms of the compound, if any, wherein the Compound of the Disclosure is present within the composition with an enantiomeric excess (%ee) of > 55%.

[0288] In another embodiment, the %ee in the above-mentioned composition is > 90%.

[0289] In another embodiment, the %ee in the above-mentioned composition is > 95%.

[0290] In another embodiment, the %ee in the above-mentioned composition is > 98%.

[0291] In another embodiment, the %ee in the above-mentioned composition is > 99%.

[0292] In another embodiment, the present disclosure provides a composition comprising a Compound of the Disclosure optionally together with one or more of the other stereoisomeric forms of the compound, if any, wherein the Compound of the Disclosure is present within the composition with an enantiomeric excess (%ee) of > 90% and a diastereomeric excess (%de) of > 90%.

[0293] In another embodiment, the present disclosure provides a composition comprising a Compound of the Disclosure optionally together with one or more of the other stereoisomeric forms of the compound, if any, wherein the the %ee and %de of the Compound of the Disclosure take any combination of values, e.g., the %ee is <5% and the %de is > 80%; the %ee is <5% and the %de is > 90%; the %ee is <5% and the %de is > 95%; the %ee is <5% and the %de is > 98%; the %ee is > 95% and the %de is > 95%; the %ee is > 98% and the %de is > 98%; or the %ee is > 99% and the %de is > 99%.

[0294] Compounds of the Disclosure may be prepared, used or supplied in amorphous form, crystalline form, or semicrystalline form, and any given Compound of the Disclosure may be formed into more than one crystalline / polymorphic forms, including hydrated, e.g., hemi-hydrate, a mono-hydrate, a di-hydrate, a tri-hydrate or other stoichiometry of hydrate, and / or solvated forms. The present disclosure encompasses any and all such solid forms of Compounds of the Disclosure.

[0295] The present disclosure encompasses the preparation and use of salts of Compounds of the Disclosure. Pharmaceutically acceptable salts include, amongst others, those described in Berge, J. Pharm.Sci., 66, 1-19, (1977) or those listed in P. H. Stahl and C. G. Wermuth, editors, Handbook of Pharmaceutical Salts; Properties, Selection and Use, Second Edition Stahl / Wermuth: Wiley- VCH / VHCA (2011) (see http: / / www.wiley.com / WileyCDA / WileyTitle / productCd-3906390519.html).

[0296] Suitable pharmaceutically acceptable salts can include acid or base addition salts.

[0297] Such base addition salts can be formed by reaction of a Compound of the Disclosure with the appropriate base, optionally in a suitable solvent such as an organic solvent, to give the salt which can be isolated by a variety of methods, including crystallisation and filtration.

[0298] Such acid addition salts can be formed by reaction of a Compound of the Disclosure with the appropriate acid, optionally in a suitable solvent such as an organic solvent, to give the salt which can be isolated by a variety of methods, including crystallisation and filtration.

[0299] Salts may be prepared in situ during the final isolation and purification of a Compound of the Disclosure. If a basic compound of a Compound of the Disclosure is isolated as a salt, the corresponding free base form of that compound may be prepared by any suitable method known to the art, including treatment of the salt with an inorganic or organic base. Similarly, if a Compound of the Disclosure containing a carboxylic acid or other acidic functional group is isolated as a salt, the corresponding free acid form of that compound may be prepared by any suitable method known to the art, including treatment of the salt with an inorganic or organic acid.

[0300] It will be understood that if a Compound of the Disclosure contains two or more basic moieties, the stoichiometry of salt formation may include 1, 2 or more equivalents of acid. Such salts would contain 1, 2 or more acid counterions, for example, a dihydrochloride salt.

[0301] Stoichiometric and non-stoichiometric forms of a pharmaceutically acceptable salt of a Compound of the Disclosure are included within the scope of the specification, including sub-stoichiometric salts, for example where a counterion contains more than one acidic proton.

[0302] Representative pharmaceutically acceptable acid addition salts include, but are not limited to, 4-acetamidobenzoate, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate (besylate), benzoate, bisulfate, bitartrate, butyrate, calcium edetate, camphorate, camphorsulfonate (camsylate), caprate (decanoate), caproate (hexanoate), caprylate (octanoate), cinnamate, citrate, cyclamate, digluconate, 2,5-dihydroxybenzoate, disuccinate, dodecylsulfate (estolate), edetate (ethylenediaminetetraacetate), estolate (lauryl sulfate), ethane- 1,2-disulfonate (edisylate), ethane sulfonate (esylate), formate, fumarate, galactarate (mucate), gentisate (2,5-dihydroxybenzoate), glucoheptonate (gluceptate), gluconate, glucuronate, glutamate, glutarate, glycerophosphorate, glycolate, hexylresorcinate, hippurate, hydrabamine (N,N'-di(dehydroabietyl)-ethylenediamine), hydrobromide, hydrochloride, hydroiodide, hydroxynaphthoate, isobutyrate, lactate, lactobionate, laurate, malate, maleate, malonate, mandelate, methanesulfonate (mesylate), methylsulfate, mucate, naphthalene-l,5-disulfonate (napadisylate), naphthalene-2-sulfonate (napsylate), nicotinate, nitrate, oleate, palmitate, p-aminobenzenesulfonate, p-aminosalicyclate, pamoate (embonate), pantothenate, pectinate, persulfate, phenylacetate, phenylethylbarbiturate, phosphate,polygalacturonate, propionate, -toluene sulfonate (tosylate), pyroglutamate, pyruvate, salicylate, sebacate, stearate, subacetate, succinate, sulfamate, sulfate, tannate, tartrate, teoclate (8-chlorotheophyllinate), thiocyanate, triethiodide, undecanoate, undecylenate, and valerate.

[0303] Representative pharmaceutically acceptable base addition salts include, but are not limited to, aluminium, 2-amino-2-(hydroxymethyl)-l,3-propanediol (TRIS), arginine, benethamine (N-benzylphenethylamine), benzathine (N, N ’-dibenzylethylenediamine), bis-(2-hydroxyethyl)amine. bismuth, calcium, chloroprocaine, choline, clemizole (1- chlorobenzyl-2-pyrrolildine-r-ylmethylbenzimidazole), cyclohexylamine, dibenzylethylenediamine, diethylamine, diethyltriamine, dimethylamine, dimethylethanolamine, dopamine, ethanolamine, ethylenediamine, L-histidine, iron, isoquinoline, lepidine, lithium, lysine, magnesium, meglumine (JV-methylglucamine), piperazine, piperidine, potassium, procaine, quinine, quinoline, sodium, strontium, / -butylamine, tromethamine (tris(hydroxymethyl)aminomethane). and zinc.

[0304] The present disclosure also includes isotopically-labeled compounds, which are identical to a Compound of the Disclosure except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into Compounds of the Disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine, and iodine, such as2H,3H,11C,13C,14C,15N,17O,18O,31P,32P,35S,18F,36C1,123I, and125I.

[0305] Compounds of the Disclosure that contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the disclosure. Isotopically-labeled compounds of the disclosure, for example those into which radioactive isotopes such as3H,14C are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e.,3H, and carbon-14, i.e.,14C, isotopes are particularly used for their ease of preparation and detectability.11C and18F isotopes are particularly useful in PET (positron emission tomography), and125I isotopes are particularly useful in SPECT (single photon emission computerized tomography), all useful in brain imaging. Further, substitution with heavier isotopes such as deuterium, i.e.,2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be used in some circumstances. Isotopically labeled Compounds of the Disclosure can generally be prepared by carrying out the procedures disclosed in the Schemes and / or in the Examples below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

[0306] In another embodiment, the present disclosure provides a pharmaceutical composition comprising a comprising a Compound of the Disclosure and one or more excipients (also referred to as carriers and / or diluents in the pharmaceutical arts). The excipients are acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof, i.e., the patient.II. Methods of Use

[0307] It is known that SMARCA4 mutations may be present in certain tumor / cancer types, including lung, liver, colon skin, bladder, cervical and ovarian tumors / cancers, and that SMARCA2 is essential for growth of tumors containing such SMARCA4 mutations. Accordingly, Compounds of the Disclosure may be of value as anti-cancer agents / anti-tumor agents, in particular against cancer / tumor types known to harbor SMARCA4 mutations, for example, lung cancer, liver cancer, colon cancer, skin cancer, bladder cancer, liver cancer, cervical cancer and ovarian cancer.

[0308] Compounds of the Disclosure may also be of value against cancer types / tumors sensitive to the degradation of SMARCA2, for example, lung cancer, liver cancer, colon cancer, skin cancer, bladder cancer, liver cancer, cervical cancer and ovarian cancer.

[0309] Compounds of the Disclosure may also be of value as anti-tumor agents, in particular as selective inhibitors of the proliferation, survival, motility, dissemination and invasiveness of mammalian cancer cells leading to inhibition of tumor growth and survival and to inhibition of metastatic tumor growth. In particular, Compounds of the Disclosure may be of value as anti-proliferative and anti-invasive agents in the containment and / or treatment of solid tumor disease.

[0310] Compounds of the Disclosure may also be useful in the prevention or treatment of those tumors which are sensitive to degradation of SMARCA2 and that are involved in the signal transduction steps which lead to the proliferation and survival of tumor cells and the migratory ability and invasiveness of metastasising tumor cells. Further, Compounds of the Disclosure may be useful in the prevention or treatment of those tumors which are mediated alone or in part by degradation of SMARCA2, i.e., the compounds may be used to produce an SMARCA2 degradation effect in a subject, e.g., a warm-blooded animal, e.g., a human, in need of such treatment.

[0311] In one embodiment, the present disclosure provides a Compound of the Disclosure or pharmaceutical composition thereof for use in the treatment of cancer.

[0312] In another embodiment, the present disclosure provides a Compound of the Disclosure or pharmaceutical composition thereof for use in the treatment of a solid tumor.

[0313] In another embodiment, the present disclosure provides a Compound of the Disclosure or pharmaceutical composition thereof for use in the treatment of a SMARCA2-sensitive tumor type.

[0314] In another embodiment, the present disclosure provides a Compound of the Disclosure or pharmaceutical composition thereof for use in the treatment of tumor types that harbor SMARCA4 mutations.

[0315] In another embodiment, the present disclosure provides a Compound of the Disclosure or pharmaceutical composition thereof for use in the treatment of lung, liver, colon, skin, bladder, cervical or ovarian cancer.

[0316] In another embodiment, the present disclosure provides a Compound of the Disclosure or pharmaceutical composition thereof for use in the treatment of SMARCA4-mutated cancer.

[0317] The amount of the Compound of the Disclosure that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the subject being treated and the particular route of administration.

[0318] The size of the dose for therapeutic or prophylactic purposes of Compounds of the Disclosure will naturally vary according to the nature and severity of the disease state, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine.

[0319] In another embodiment, the present disclosure provides a Compound of the Disclosure or pharmaceutical composition thereof for use as a medicament.

[0320] In another embodiment, the present disclosure provides a Compound of the Disclosure or pharmaceutical composition thereof for use in therapy.

[0321] In another embodiment, the present disclosure provides a Compound of the Disclosure or pharmaceutical composition thereof for use in a method of treatment of the human or animal body by therapy.

[0322] In another embodiment, the present disclosure provides a Compound of the Disclosure or pharmaceutical composition thereof for use in the production of an anti-proliferative effect, for example, in a warm-blooded animal such as a human.

[0323] In another embodiment, the present disclosure provides the use of a Compound of the Disclosure or pharmaceutical composition thereof for the manufacture of a medicament for the production of an anti-proliferative effect, for example, in a warm-blooded animal such as a human.

[0324] In another embodiment, the present disclosure provides a method for producing an antiproliferative effect in a warm-blooded animal, such as man, in need of such effect, which comprises administering to the animal an effective amount of a Compound of the Disclosure or pharmaceutical composition thereof.

[0325] In another embodiment, the present disclosure provides a Compound of the Disclosure or pharmaceutical composition thereof for use as an anti-invasive agent in the containment and / or treatment of solid tumor disease, for example: in a warm-blooded animal such as a human,.

[0326] In another embodiment, the present disclosure provides the use of a Compound of the Disclosure or pharmaceutical composition thereof for the manufacture of a medicament for use as an anti-invasive agent in the containment and / or treatment of solid tumor disease, for example, in a warm-blooded animal such as a human.

[0327] In another embodiment, the present disclosure provides a method for producing an anti -invasive effect by the containment and / or treatment of solid tumor disease, in a warm-blooded animal, such as man, in need of such effect, which comprises administering to the animal an effective amount of a Compound of the Disclosure or pharmaceutical composition thereof.

[0328] In another embodiment, the present disclosure provides a Compound of the Disclosure or pharmaceutical composition thereof for use in the prevention or treatment of cancer, for example, in a warmblooded animal such as a human.

[0329] In another embodiment, the present disclosure provides the use of a Compound of the Disclosure or pharmaceutical composition thereof for the manufacture of a medicament for the prevention or treatment of cancer, for example, in a warm-blooded animal such as a human.

[0330] In another embodiment, the present disclosure provides a method for the prevention or treatment of cancer in a warm-blooded animal, such as man, in need of such treatment, which comprises administering to the animal an effective amount of a Compound of the Disclosure or pharmaceutical composition thereof.

[0331] In another embodiment, the present disclosure provides a Compound of the Disclosure or pharmaceutical composition thereof for use in the prevention or treatment of solid tumor(s), for example, in a warm-blooded animal such as a human.

[0332] In another embodiment, the present disclosure provides the use of a Compound of the Disclosure or pharmaceutical composition thereof for the manufacture of a medicament for the prevention or treatment of solid tumor(s), for example, in a warm-blooded animal such as a human.

[0333] In another embodiment, the present disclosure provides a method for the prevention or treatment of solid tumor(s) in a warm-blooded animal, such as man, in need of such treatment, which comprises administering to the animal an effective amount of a Compound of the Disclosure or pharmaceutical composition thereof.

[0334] In another embodiment, the present disclosure provides a Compound of the Disclosure or pharmaceutical composition thereof for use in the prevention or treatment of tumor types that are sensitive to degradation of SMARCA2.

[0335] In another embodiment, the present disclosure provides the use of a Compound of the Disclosure or pharmaceutical composition thereof for the manufacture of a medicament for the prevention or treatment of those tumor types that are sensitive to degradation of SMARCA2.

[0336] In another embodiment, the present disclosure provides a method for the prevention or treatment of those tumor types that are sensitive to degradation of SMARCA2, in a warm-blooded animal, such as man, in need of such treatment, which comprises administering to the animal an effective amount of a Compound of the Disclosure or pharmaceutical composition thereof. Tumor types that are sensitive to degradation of SMARCA2 include, for example, lung tumor, liver tumor, colon tumor, skin tumor, bladder tumor, cervical tumor and ovarian tumor.

[0337] In another embodiment, the d present isclosure provides a Compound of the Disclosure or pharmaceutical composition thereof for use in providing a degrading effect on SMARCA2, for example, in a warm-blooded animal such as a human.

[0338] In another embodiment, the present disclosure provides the use of a Compound of the Disclosure or pharmaceutical composition thereof for the manufacture of a medicament for providing a degrading effect on SMARCA2, for example, in a warm-blooded animal such as a human.

[0339] In another embodiment, the present disclosure provides a method for providing a degrading effect on SMARCA2 in a warm-blooded animal, such as man, in need of such effect, which comprises administering to the animal an effective amount of a Compound of the Disclosure or pharmaceutical composition thereof.

[0340] In another embodiment, the present disclosure provides a Compound of the Disclosure or pharmaceutical composition thereof for use in providing a selective degrading effect on SMARCA2 in, for example, a warm-blooded animal such as man.

[0341] In another embodiment, the present disclosure provides the use of a Compound of the Disclosure or pharmaceutical composition thereof for the manufacture of a medicament for providing a selective degrading effect on SMARCA2, for example, in a warm-blooded animal such as a human.

[0342] In another embodiment, the present disclosure provides a method for providing a selective degrading effect on SMARCA2 in a warm-blooded animal, such as man, in need of such effect, which comprises administering an effective amount of a Compound of the Disclosure or pharmaceutical composition thereof. SMARCA2 has been found to be essential for growth of tumors containing SMARCA4 mutations and certain tumor / cancer types are associated with such SMARCA4 mutations.

[0343] In another embodiment, the present disclosure provides a Compound of the Disclosure or pharmaceutical composition thereof for use in the treatment of tumor types that harbor SMARCA4 mutations.

[0344] In another embodiment, the present disclosure provides the use of a Compound of the Disclosure or pharmaceutical composition thereof for the manufacture of a medicament for the prevention or treatment of those tumor types that harbor SMARCA4 mutations.

[0345] In another embodiment, the present disclosure provides a method for the prevention or treatment of those tumor types that harbor SMARCA4 mutations in a warm-blooded animal, such as man, in need of such prevention or treatment, which comprises administering to the animal an effective amount of a Compound of the Disclosure or pharmaceutical composition thereof. Tumor types known to harbor SMARCA4 mutations include lung tumors, liver tumors, colon tumors, skin tumors, bladder tumors, cervical tumors and ovarian tumors, e.g., lung cancer, liver cancer, colon cancer, skin cancer, bladder cancer, cervical cancer and ovarian cancer.

[0346] In another embodiment, the present disclosure provides a Compound of the Disclosure or pharmaceutical composition thereof for use in the treatment of lung, liver, colon, skin, bladder, cervical or ovarian cancer.

[0347] In another embodiment, the present disclosure provides the use of a Compound of the Disclosure or pharmaceutical composition thereof for the manufacture of a medicament for the treatment of lung, liver, colon, skin, bladder, cervical or ovarian cancer.

[0348] In another embodiment, the present disclosure provides a method for treating lung, liver, colon, skin, bladder, cervical or ovarian cancer in a warm-blooded animal, such as man, in need of such treatment, which comprises administering to the animal an effective amount of a Compound of the Disclosure or pharmaceutical composition thereof.

[0349] In another embodiment where cancer is mentioned herein, the cancer is lung cancer.

[0350] In another embodiment where cancer is mentioned herein, the cancer is liver cancer.

[0351] In another embodiment where cancer is mentioned herein, the cancer is colon cancer.

[0352] In another embodiment where cancer is mentioned herein, the cancer is skin cancer.

[0353] In another embodiment where cancer is mentioned herein, the cancer is bladder cancer.

[0354] In another embodiment where cancer is mentioned herein, the cancer is cervical cancer.

[0355] In another embodiment where cancer is mentioned herein, the cancer is ovarian cancer.

[0356] In another embodiment, the present disclosure provides a Compound of the Disclosure or pharmaceutical composition thereof for use in the treatment of a SMARCA4-mutated cancer.

[0357] In another embodiment, the present disclosure provides the use of a Compound of the Disclosure or pharmaceutical composition thereof for the manufacture of a medicament for the treatment of a SMARCA4-mutated cancer.

[0358] In another embodiment, the present disclosure provides method for treating a SMARCA4-mutated cancer in a warm-blooded animal, such as man, in need of such treatment, which comprises administering an effective amount of a Compound of the Disclosure or pharmaceutical composition thereof.III. Definitions

[0359] As used herein, the term "alkyl" represents a saturated, straight or branched hydrocarbon moiety having the specified number of carbon atoms. The term "(Ci-C6)alkyl" refers to an alkyl moiety containing from 1 to 6 carbon atoms. Exemplary alkyls include, but are not limited to, methyl, ethyl, w-propyl. isopropyl, w-butyl. isobutyl, s-butyl. / -butyl, pentyl, and hexyl.

[0360] The term "halo(Ci-C3)alkyl" as used herein by itself or part of another group refers to a (Ci-Cs)alkyl group substituted by one, two, or three halogen atoms. Exemplary halo(Ci-C3)alkyl groups include, but are not limited to, -CH2F, -CHF2, and -CF3.

[0361] The term "alkylenyl" as used herein by itself or part of another group refers to a divalent form of an alkyl group having the specified number of carbon atoms. For example, the term "(Ci-C6)alkylenyl" refers to an alkylenyl moiety containing from 1 to 6 carbon atoms. The alkylenyl may be optionally substituted with one, two, or three substituents independently selected from halogen, cyano, and (Ci-Ce)alkoxy. Exemplary alkylenyl groups include, but are not limited to, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2(CH2)2CH2-, and -CH2(CH2)3CH2-.

[0362] " Alkoxy" refers to a group containing an alkyl radical, defined hereinabove, attached through an oxygen linking atom. The term "(Ci-C6)alkoxy" refers to a straight- or branched-chain hydrocarbon radical having at least 1 and up to 6 carbon atoms attached through an oxygen linking atom. Exemplary "(Ci-C6)alkoxy" groups useful in the present specification include methoxy, ethoxy, w-propoxy. isopropoxy, M-butoxy, s-butoxy. isobutoxy, and / -butoxy.

[0363] The term "cycloalkylenyl" as used herein by itself or part of another group refers to a divalent form of a cycloalkyl group having the specified number of carbon atoms in the ring. For example, the term "(C3-C6)cycloalkylenyl" refers to an cycloalkylenyl moiety containing from 3 to 6 carbon atoms in the ring. The cycloalkylenyl may be optionally substituted with one, two, or three substituents independently selected from halogen, (Ci-Ce)alkyl, cyano, and (Ci-Ce)alkoxy. Exemplary cycloalkylenyl groups include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexy:

[0364] The term "heterocycloalkyl" as used herein by itself or part of another group refers to group or moiety comprising a non-aromatic, monovalent, monocyclic, bicyclic, or spirocyclic radical, which is saturated or partially unsaturated, having 4- to 11 -ring atoms, which includes carbon and one or two heteroatoms selected independently from oxygen, sulfur, and / or nitrogen.

[0365] The term "4- to 6-membered heterocycloalkylenyl" as used herein by itself or part of another group refers to a divalent form of a monocyclic or bicyclic heterocycloalkyl having 4, 5, or 6 ring atoms, which includes carbon and one or two heteroatoms selected independently from oxygen, sulfur, and / or nitrogen. The 4- to 6-membered heterocycloalkylenyl may be optionally substituted with one, two, or three substituents independently selected from halogen, (Ci-Ce)alkyl, halo(Ci-C3)alkyl, cyano, or (Ci-Ce)alkoxy. In one embodiment, the 4- to 6-membered heterocycloalkylenyl is a divalent form of an optionally substituted azetidine. In another embodiment, the the 4- to 6-membered heterocycloalkyleny is a divalent form of an optionally substituted piperidinyl. In another embodiment, the heterocycloalkyleny is a divalent form of an optionally substituted piperazinyl. Exemplary heterocycloalkylenyl groups include, but are not limited to:

[0366] The term "7- to 11-membered heterocycloalkylenyl" as used herein by itself or part of another group refers to a divalent form of a bicyclic (including bridged bicyclic), fused ring systems, or spirocyclicheterocycloalkyl having 7, 8, 9, 10, or 11 ring atoms, which includes carbon and one, two, or three heteroatoms selected independently from oxygen, sulfur, and / or nitrogen. The 7- to 11-membered heterocycloalkylenyl may be optionally substituted with one, two, or three substituents independently selected from halogen, (Ci-Ce)alkyl, halo(Ci-C3)alkyl, cyano, or (Ci-Ce)alkoxy. Exemplary 7- to 11-membered heterocycloalkylenyl groups include, but are not limited to:1-01 HOO POCM HOCDHXNOOH

[0367] " Aryl" refers to optionally substituted monocyclic, fused bicyclic, or fused tricyclic groups having 6 to 14 carbon atoms and having at least one aromatic ring that complies with Huckel's Rule. Examples of "aryl" groups are phenyl, naphthyl, indenyl, dihydroindenyl, anthracenyl, phenanthrenyl, and the like.

[0368] " Heteroaryl" represents a group or moiety comprising an aromatic monovalent monocyclic or bicyclic radical, containing 5 to 10 ring atoms, including 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. This term also encompasses bicyclic heterocyclic-aryl compounds containing an aryl ring moiety fused to a heterocycloalkyl ring moiety, containing 5 to 10 ring atoms, including 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, or bicyclic heterocyclic-heteroaryl compounds containing a heteroaryl ring moiety fused to a heterocycloalkyl ring moiety, containing 5 to 10 ring atoms, including 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. Illustrative examples of heteroaryls useful in the present specification include, but are not limited to, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, benzofuranyl, isobenzofuryl, 2,3 -dihydrobenzofuryl, 1,3-benzodioxolyl, dihydrobenzodioxinyl, benzothienyl, indolizinyl, indolyl, isoindolyl, dihydroindolyl, benzimidazolyl, dihydrobenzimidazolyl, benzoxazolyl, dihydrobenzoxazolyl, benzthiazolyl, benzoisothiazolyl, dihydrobenzoisothiazolyl, indazolyl, imidazopyridinyl, pyrazolopyridinyl, benzotriazolyl, triazolopyridinyl, purinyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl, 1,5-naphthyridinyl, 1,6-naphthyridinyl, 1,7-naphthyridinyl, 1,8-naphthyridinyl, and pteridinyl. Examples of 5-membered "heteroaryl" groups include furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, and isothiazolyl.Examples of 6-membered "heteroaryl" groups include oxo-pyridyl, pyridinyl, pyridazinyl, pyrazinyl, and pyrimidinyl. Examples of 6,6-fused "heteroaryl" groups include quinolinyl, isoquinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl, 1,5-naphthyridinyl, 1,6-naphthyridinyl, 1,7-naphthyridinyl, 1,8-naphthyridinyl, and pteridinyl. Examples of 6,5-fused "heteroaryl" groups include benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, indolizinyl, indolyl, isoindolyl, and indazolyl.

[0369] The term "5- to 10-membered heteroarylenyl" as used herein by itself or part of another group refers to a divalent form of a "heteroaryl" group. Examples of "5- to 10-membered heteroarylenyl" groups include:

[0370] As used herein, "5- or 6-membered heteroaryl" represents a group or moiety comprising an aromatic monovalent monocyclic radical, containing 5 or 6 ring atoms, including at least one carbon atom and 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Selected 5 -membered heteroaryl groups contain one nitrogen, oxygen, or sulfur ring heteroatom, and optionally contain 1, 2, or 3 additional nitrogen ring atoms. Selected 6-membered heteroaryl groups contain 1, 2, or 3 nitrogen ring heteroatoms. Illustrative examples of 5- or 6-membered heteroaryl groups useful in the present specification include, but are not limited to furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, and triazinyl.

[0371] The terms "halogen" and "halo" represent fluoro, chloro, bromo, or iodo substituents.

[0372] " Hydroxy" as used herein by itself or as part of a group refers to the radical -OH.

[0373] The term "cyano" as used herein by itself or as part of a group refers to the radical -CN.

[0374] As used herein, the term "optionally" means that the subsequently described event(s) may or may not occur and includes both event(s) that occur and event(s) that do not occur. As such, use of the term "optionally" includes instances where the feature is present, and also instances where the feature is not present. For example, "methyl optionally substituted by one or more F" includes -CH3, -CH2F, -CHF2and -CF3.

[0375] In present disclosure, a group such as " A-B-C" where B is defined as "a direct bond" equates to " A-C," i.e., where A and C are directly linked to each other by a covalent bond.

[0376] The term “substituted” means that one or more hydrogens on the designated atom or group is replaced by the indicated substituent(s) provided that any atom(s) bearing such substituent(s) maintains its permitted valency where the skilled person understands that the standard valencies of carbon, nitrogen and oxygen are 4, 3 and 2 respectively.

[0377] " Pharmaceutically acceptable" refers to those compounds (including salts), materials, compositions, and dosage forms which are, within the scope of sound medical judgment, suitable for use incontact with the tissues of human beings and animals without excessive toxicity, irritation, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0378] As used herein, the term "treatment" refers to alleviating the specified condition, eliminating or reducing one or more symptoms of the condition, slowing or eliminating the progression of the condition, and delaying the reoccurrence of the condition in a previously afflicted or diagnosed patient or subject.

[0379] The term "effective amount" means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought, for instance, by a researcher or clinician

[0380] The term "therapeutically effective amount" means any amount which, as compared to a corresponding subject who has not received such amount, results in improved treatment, healing, or amelioration of a disease, disorder, or side effect, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function. For use in therapy, therapeutically effective amounts of a Compound of the Disclosure may be administered as the raw chemical. Additionally, the active ingredient may be presented as a pharmaceutical composition.

[0381] Compounds of the Disclosure may have asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms. The present disclosure encompasses the preparation and use of all such possible stereoisomeric forms, as well as their racemic and resolved forms, and mixtures thereof. The enantiomers and diastereomers can be separated according to methods known in the art in view of the present disclosure. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that they include both E and Z geometric isomers. All tautomers are also encompassed by the present disclosure.

[0382] As used herein, the term "stereoisomers" is a general term for all isomers of individual molecules that differ only in the orientation of their atoms in space. It includes enantiomers, atropisomers, and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereomers).

[0383] The term "chiral center" or "asymmetric carbon atom" refers to a carbon atom to which four different groups are attached.

[0384] The terms "enantiomer" and "enantiomeric" refer to a molecule that cannot be superimposed on its mirror image and hence is optically active wherein the enantiomer rotates the plane of polarized light in one direction and its mirror image compound rotates the plane of polarized light in the opposite direction. Enantiomers may be separated by chiral chromatography using methods well known in the art.

[0385] The term "racemic" or "racemate" refers to a mixture of equal parts of enantiomers and which mixture is optically inactive.

[0386] The term "absolute configuration" refers to the spatial arrangement of the atoms of a chiral molecular entity (or group) and its stereochemical description, e.g., R or S.

[0387] The stereochemical terms and conventions used in the specification are meant to be consistent with those described in Pure & Appl. Chem 68:2193 (1996), unless otherwise indicated.

[0388] The term "enantiomeric excess" or "ee" refers to a measure for how much of one enantiomer is present compared to the other. For a mixture of R and S enantiomers, the percent enantiomeric excess is defined as | R - S | * 100, where R and S are the respective mole or weight fractions of enantiomers in a mixture such that R + S = 1. With knowledge of the optical rotation of a chiral substance, the percent enantiomeric excess is defined as (([α]obs / [α]max)*100, where [α]obsis the optical rotation of the mixture of enantiomers and [a]maxis the optical rotation of the pure enantiomer. Determination of enantiomeric excess is possible using a variety of analytical techniques, including NMR spectroscopy, chiral column chromatography, or optical polarimetry. Compounds of the Disclosure that are racemic can be separated by chiral HPLC, e.g., using a CHIRALPAK IE column. In one embodiment, Compounds of the Disclosure have an ee of about 70% or more, e.g., about 80% or more, about 90% or more, about 91% or more, about 92% or more, about 93% or more, about 94% or more, about 95% or more, about 96% or more, about 97% or more, about 98% or more, or about 99% or more.

[0389] The terms "enantiomerically pure" or "enantiopure" refer to a sample of a chiral substance all of whose molecules (within the limits of detection) have the same chirality sense.

[0390] The terms "enantiomerically enriched" or "enantioenriched" refer to a sample of a chiral substance whose enantiomeric ratio is greater than 50:50. Enantiomerically enriched compounds may be enantiomerically pure. Certain compounds of the Disclosure are enantioenriched.

[0391] The term "diastereomeric excess" or "de" refers to a measure for how much of one diastereomer is present compared to another, and is defined by analogy to enantiomeric excess. Determination of diastereomeric excess is possible using a variety of analytical techniques, including NMR spectroscopy and column chromatography.

[0392] The term "diastereoenriched enriched" refer to a sample of a chiral substance whose diastereomeric ratio is greater than 50:50. Diastereoenriched enriched compounds may be diastereomerically pure. Certain compounds of the Disclosure are diastereoenriched.

[0393] The term "about," as used herein, includes the recited number ± 10%. Thus, "about 10" means 9 to 11.IV. Particular Embodiments

[0394] The present disclosure also provides the following particular embodiments.

[0395] Embodiment 1. A compound of Formula (I), or pharmaceutically acceptable salt thereof:R7

[0396] wherein:

[0397] E is:E-1 E-2or

[0398] X1is -CR3= or -N=;

[0399] R3is H, halogen, or (Ci-Ce)alkyl;

[0400] X2is -CR4= or -N=;

[0401] R4is H, halogen, or (Ci-Ce)alkyl;

[0402] X3is -CH2CH2- or -CH2-O-CH2-;

[0403] R5ais H, halogen, (Ci-Ce)alkyl, (C3-Ce)cycloalkyl, 4- to 6-membered heterocycloalkyl, -CN, aryl, or 5- or 6-membered heteroaryl, wherein (Ci-Ce)alkyl is optionally substituted with 1 to 3 substituents independently selected from halogen or -CN; and 4- to 6-membered heterocycloalkyl, aryl, or 5- or 6-membered heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halogen, -CN, or (Ci-Ce)alkyl;

[0404] R5bis H, (Ci-C6)alkyl, or (C3-C6)cycloalkyl;

[0405] R1is H, halogen, (Ci-Ce)alkyl, (Ci-Ce)alkoxy, orN NR11

[0406] R2is H, halogen, (Ci-Ce)alkyl, (Ci-Ce)alkoxy, or

[0407] with the provisos:

[0408] (i) when R1is H, halogen, (Ci-Ce)alkyl, or (Ci-Ce)alkoxy, then R2is:, N NR11

[0409] (ii) when R2is H, halogen, (Ci-Ce)alkyl, or (Ci-Ce)alkoxy, then R1is:xN NR11

[0410] R6is H, (Ci-Ce)alkyl, or -CN;

[0411] R7is H, halogen, (Ci-Ce)alkyl, -CN, or (C3-C6)cycloalkyl, wherein (Ci-Ce)alkyl is optionally substituted with 1 to 3 halogen;

[0412] R8is H, halogen, (Ci-Ce)alkyl, -CN, or (C3-C6)cycloalkyl, wherein (Ci-Ce)alkyl is optionally substituted with 1 to 3 halogen;

[0413] R9is H, halogen, (Ci-Ce)alkyl, -CN, or (C3-C6)cycloalkyl, wherein (Ci-Ce)alkyl is optionally substituted with 1 to 3 halogen;

[0414] R10is H, halogen, (Ci-Ce)alkyl, -CN, or (C3-C6)cycloalkyl, wherein (Ci-Ce)alkyl is optionally substituted with 1 to 3 halogen;

[0415] R11is H or -(Ci-C6)alkyl-O-P(=O)-(OH)2;

[0416] W is -C(=O)-, -S(=O)2-, -CH2-, -C≡C-, or direct bond;

[0417] L is -G’-G2-G3-, wherein G3is attached to E;

[0418] G1is (Ci-Ce)alkylenyl; 4- to 6-membered heterocycloalkylenyl optionally substituted with 1 to 3 substituents independently selected from halogen, (Ci-Ce)alkyl, halo(Ci-C3)alkyl, (Ci-Ce)alkoxy, or -CN; or 7- to 11 -membered heterocycloalkylenyl optionally substituted with 1 to 3 substituents independently selected from halogen, (Ci-Ce)alkyl, halo(Ci-C3)alkyl, (Ci-Ce)alkoxy, or -CN;

[0419] G2is (Ci-Ce)alkylenyl or a direct bond; and

[0420] G3is 4- to 6-membered heterocycloalkylenyl optionally substituted with 1 to 3 substituents independently selected from halogen, (Ci-Ce)alkyl, halo(Ci-C3)alkyl, (Ci-Ce)alkoxy, or -CN, or 7- to 11-membered heterocycloalkylenyl optionally substituted with 1 to 3 substituents independently selected from halogen, (Ci-Ce)alkyl, halo(Ci-C3)alkyl, (Ci-Ce)alkoxy, or -CN;

[0421] Rais hydrogen or halogen;

[0422] Rbis hydrogen or halogen; and

[0423] Rcis hydrogen or -CH2OP(=O)(OH)2.

[0424] Embodiment 2. The compound of Embodiment 1, or pharmaceutically acceptable salt thereof, having Formula (II):R7R W^ENH2 r^N^^R™N SJ R9(II).

[0425] Embodiment 3. The compound, or pharmaceutically acceptable salt thereof, according to Embodiments 1 or 2, wherein W is -C(=O)-.

[0426] Embodiment 4. The compound, or pharmaceutically acceptable salt thereof, according to Embodiments 1 or 2, wherein W is -CH2-.

[0427] Embodiment 5. The compound, or pharmaceutically acceptable salt thereof, according to Embodiments 1 or 2, wherein W is a direct bond.

[0428] Embodiment 6. The compound or pharmaceutically acceptable salt thereof according to Embodiment 1 or 2, wherein W is a -S(=O)2-.

[0429] Embodiment 7. The compound, or pharmaceutically acceptable salt thereof, according to any one of Embodiments 1-6, wherein X1is -CR3= and R3is H.

[0430] Embodiment 8. The compound, or pharmaceutically acceptable salt thereof, according to any one of Embodiments 1-6, wherein X1is -CR3= and R3is halogen.

[0431] Embodiment 9. The compound, or pharmaceutically acceptable salt thereof, according to any one of Embodiments 1-6, wherein X1is -CR3= and R3is (Ci-Ce)alkyl.

[0432] Embodiment 10. The compound, or pharmaceutically acceptable salt thereof, according to any one of Embodiments 1-6, wherein X1is -N=.

[0433] Embodiment 11. The compound, or pharmaceutically acceptable salt thereof, according to any one of Embodiments 1-10, wherein X2is -CR4= and R4is H.

[0434] Embodiment 12. The compound, or pharmaceutically acceptable salt thereof, according to any one of Embodiments 1-10, wherein X2is -CR4= and R4is halogen.

[0435] Embodiment 13. The compound, or pharmaceutically acceptable salt thereof, according to any one of Embodiments 1-10, wherein X2is -CR4= and R4is (Ci-Ce)alkyl.

[0436] Embodiment 14. The compound, or pharmaceutically acceptable salt thereof, according to any one of Embodiments 1-13, wherein R6is H.

[0437] Embodiment 15. The compound, or pharmaceutically acceptable salt thereof, according to any one of Embodiments 1-13, wherein R6is (Ci-Ce)alkyl.

[0438] Embodiment 16. The compound, or pharmaceutically acceptable salt thereof, according to any one of Embodiments 1-13, wherein R6is -CN.

[0439] Embodiment 17. The compound, or pharmaceutically acceptable salt thereof, according to any one of Embodiments 1-16, wherein:

[0440] R1is:

[0441] R2is H, halogen, (Ci-Ce)alkyl, or (Ci-Ce)alkoxy.

[0442] Embodiment 18. The compound, or pharmaceutically acceptable salt thereof, according to any one of Embodiments 1-16, wherein:

[0443] R2is:

[0444] R1is H, halogen, (Ci-Ce)alkyl, or (Ci-Ce)alkoxy.

[0445] Embodiment 19. The compound, or pharmaceutically acceptable salt thereof, according to any one of Embodiments 1-18, wherein E is E-l.

[0446] Embodiment 20. The compound, or pharmaceutically acceptable salt thereof, according to Embodiment 19, wherein R5ais hydrogen.

[0447] Embodiment 21. The compound, or pharmaceutically acceptable salt thereof, according to Embodiment 19, wherein R5ais (Ci-Ce)alkyl optionally substituted with 1 to 3 substituents independently selected from halogen or -CN.

[0448] Embodiment 22. The compound, or pharmaceutically acceptable salt thereof, according to Embodiment 19, wherein R5ais (C3-C6)cycloalkyl.

[0449] Embodiment 23. The compound, or pharmaceutically acceptable salt thereof, according to Embodiment 19, wherein R5ais 4- to 6-membered heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from halogen, -CN, or (Ci-Ce)alkyl.

[0450] Embodiment 24. The compound, or pharmaceutically acceptable salt thereof, according to Embodiment 19, wherein R5ais -CN.

[0451] Embodiment 25. The compound, or pharmaceutically acceptable salt thereof, according to Embodiment 19, wherein R5ais aryl optionally substituted with 1 to 3 substituents independently selected from halogen, -CN, or (Ci-Ce)alkyl.

[0452] Embodiment 26. The compound, or pharmaceutically acceptable salt thereof, according to Embodiment 19, wherein R5ais 5- or 6-membered heteroaryl optionally substituted with 1 to 3 substituents independently selected from halogen, -CN, or (Ci-Ce)alkyl.

[0453] Embodiment 27. The compound of Embodiment 19, wherein E-l is:NIII

[0454] Embodiment 28. The compound, or pharmaceutically acceptable salt thereof, according to any one of Embodiments 1-18, wherein E is E-2.

[0455] Embodiment 29. The compound, or pharmaceutically acceptable salt thereof, according to Embodiment 28, wherein R5bis hydrogen.

[0456] Embodiment 30. The compound, or pharmaceutically acceptable salt thereof, according to Embodiment 28, wherein R5bis (C1-C6)alkyl.

[0457] Embodiment 31. The compound, or pharmaceutically acceptable salt thereof, according to Embodiment 28, wherein R5bis (C3-C6)cycloalkyl.

[0458] Embodiment 32. The compound of Embodiment 28, wherein E-2 is:

[0459] Embodiment 33. The compound, or pharmaceutically acceptable salt thereof, according to any one of Embodiments 1-32, wherein:

[0460] R7is halogen, (C1-C6)alkyl, -CN, or (C3-C6)cycloalkyl, wherein (C1-C6)alkyl is optionally substituted with 1 to 3 halogen; and

[0461] R8, R9, and R10are H.

[0462] Embodiment 34. The compound, or pharmaceutically acceptable salt thereof, according to any one of Embodiments 1-32, wherein:

[0463] R8is halogen, (C1-C6)alkyl, -CN, or (C3-C6)cycloalkyl, wherein (C1-C6)alkyl is optionally substituted with 1 to 3 halogen; and

[0464] R7, R9, and R10are H.

[0465] Embodiment 35. The compound, or pharmaceutically acceptable salt thereof, according to any one of Embodiments 1-32, wherein:

[0466] R9is halogen, (C1-C6)alkyl, -CN, or (C3-C6)cycloalkyl, wherein (C1-C6)alkyl is optionally substituted with 1 to 3 halogen; and

[0467] R7, R8, and R10are H.

[0468] Embodiment 36. The compound, or pharmaceutically acceptable salt thereof, according to any one of Embodiments 1-32, wherein:

[0469] R10is halogen, (C1-C6)alkyl, -CN, or (C3-C6)cycloalkyl, wherein (C1-C6)alkyl is optionally substituted with 1 to 3 halogen; and

[0470] R7, R8, and R9are H.

[0471] Embodiment 37. The compound, or pharmaceutically acceptable salt thereof, according to any one of Embodiments 1-32, wherein R7, R8, R9, and R10are H.

[0472] Embodiment 38. The compound, or pharmaceutically acceptable salt thereof, according to any one of Embodiments 1-37, wherein G1is 4- to 6-membered heterocycloalkylenyl optionally substituted with 1 to 3 substituents independently selected from halogen, (Ci-Ce)alkyl, halo(Ci-C3)alkyl, (Ci-Ce)alkoxy, or -CN.

[0473] Embodiment 39. The compound, or pharmaceutically acceptable salt thereof, according Embodiment 38, wherein G1is:wherein the bond marked with an "*" is attached to G2.

[0474] Embodiment 40. The compound, or pharmaceutically acceptable salt thereof, according to any one of Embodiments 1-37, wherein G1is 7- to 11 -membered heterocycloalkylenyl optionally substituted with 1 to 3 substituents independently selected from halogen, (Ci-Ce)alkyl, halo(Ci-C3)alkyl, (Ci-Ce)alkoxy, or -CN

[0475] Embodiment 41. The compound, or pharmaceutically acceptable salt thereof, according Embodiment 40, wherein G1is:wherein the bond marked with an "*" is attached to G2.

[0476] Embodiment 42. The compound, or pharmaceutically acceptable salt thereof, according to any one of Embodiments 1-41, wherein G2is a direct bond.

[0477] Embodiment 43. The compound, or pharmaceutically acceptable salt thereof, according to any one of Embodiments 1-41, wherein G2is (C1-C6)alkylenyl.

[0478] Embodiment 44. The compound, or pharmaceutically acceptable salt thereof, according to Embodiment 43, wherein G2is -CH2- or -CH(CH3)-.

[0479] Embodiment 45. The compound, or pharmaceutically acceptable salt thereof, according to any one of Embodiments 1-44, wherein G3is 4- to 6-membered heterocycloalkylenyl optionally substituted with 1 to 3 substituents independently selected from halogen, (Ci-Ce)alkyl, halo(Ci-C3)alkyl, (Ci-Ce)alkoxy, or -CN.

[0480] Embodiment 46. The compound, or pharmaceutically acceptable salt thereof, according Embodiment 45, wherein G3is:*, orwherein the bond marked with an "*" is attached to E.

[0481] Embodiment 47. The compound, or pharmaceutically acceptable salt thereof, according to any one of Embodiments 1-44, wherein G3is 7- to 11 -membered heterocycloalkylenyl optionally substituted with 1 to 3 substituents independently selected from halogen, (Ci-Ce)alkyl, halo(Ci-C3)alkyl, (Ci-Ce)alkoxy, or -CN.

[0482] Embodiment 48. The compound, or pharmaceutically acceptable salt thereof, according to Embodiment 47, wherein G3is:HQ> *.ORH£» ' wherein the bond marked with an "*" is attached to E.

[0483] Embodiment 49. The compound, or pharmaceutically acceptable salt thereof, of any one of Embodiments 1-37, wherein L is:wherein the bond marked with an "*" is attached to E.

[0484] Embodiment 50. The compound, or pharmaceutically acceptable salt thereof, according to Embodiment 1 selected from Compound List 1.

[0485] Embodiment 51. A pharmaceutical composition comprising the compound, or pharmaceutically acceptable salt thereof, according to any one of Embodiments 1-50 and a pharmaceutically acceptable excipient.

[0486] Embodiment 52. A method of degrading SMARCA2 protein in a human, comprising administering to a human in need thereof an effective amount of the compound, or pharmaceutically acceptable salt thereof, according to any one of Embodiments 1-50, or the composition of Embodiment 51.

[0487] Embodiment 53. A method of reducing the level of SMARCA2 activity in a human, comprising administering to a human in need thereof an effective amount of the compound, or pharmaceutically acceptable salt thereof, according to any one of Embodiments 1-50, or the composition of Embodiment 51.

[0488] Embodiment 54. A method of treating cancer in a human, comprising administering to a human in need thereof an effective amount of the compound, or pharmaceutically acceptable salt thereof, according to any one of Embodiments 1-50, or the composition of Embodiment 51.

[0489] Embodiment 55. The method of Embodiment 54, wherein the cancer is a SMARCA2-sensitive cancer.

[0490] Embodiment 56. The method of Embodiment 54, wherein the cancer is a SMARCA2-mutated cancer.

[0491] Embodiment 57. The method of any one of Embodiments 54-56, wherein the cancer is a solid tumor.

[0492] Embodiment 58. The method of any one of Embodiments 54-56, wherein the cancer is lung, liver, colon, skin, bladder, cervical or ovarian cancer.

[0493] Embodiment 59. A compound, or pharmaceutically acceptable salt thereof, according to any one of Embodiments 1-50, or the composition of Embodiment 51 for use in degrading SMARCA2 protein in a human.

[0494] Embodiment 60. A compound, or pharmaceutically acceptable salt thereof, according to any one of Embodiments 1 -50, or the composition of Embodiment 51 for use in reducing the level of SMARCA2 activity in a human.

[0495] Embodiment 61. A compound, or pharmaceutically acceptable salt thereof, according to any one of Embodiments 1-50, or the composition of Embodiment 51 for use in treating cancer in a human.

[0496] Embodiment 62. The compound for use of Embodiment 61, wherein the cancer is a SMARCA2-sensitive cancer.

[0497]

[0498] Embodiment 63. The compound for use of Embodiment 61, wherein the cancer is a SMARCA2 -mutated cancer.

[0499] Embodiment 64. The compound for use of any one of Embodiments 61-63, wherein the cancer is a solid tumor.

[0500] Embodiment 65. The compound for use of any one of Embodiments 61-63, wherein the cancer is lung, liver, colon, skin, bladder, cervical or ovarian cancer.

[0501] Embodiment 66. Use of a compound, or pharmaceutically acceptable salt thereof, according to any one of Embodiments 1 -50, or the composition of Embodiment 51 in the manufacture of a medicament for degrading SMARCA2 protein in a human.

[0502] Embodiment 67. Use of a compound, or pharmaceutically acceptable salt thereof, according to any one of Embodiments 1 -50, or the composition of Embodiment 51 in the manufacture of a medicament for reducing the level of SMARCA2 activity in a human.

[0503] Embodiment 68. Use of a compound, or pharmaceutically acceptable salt thereof, according to any one of Embodiments 1 -50, or the composition of Embodiment 51 in the manufacture of a medicament for treating cancer in a human.

[0504] Embodiment 69. The compound for use of Embodiment 68, wherein the cancer is a SMARCA2-sensitive cancer.

[0505] Embodiment 70. The compound for use of Embodiment 68, wherein the cancer is a SMARCA2 -mutated cancer.

[0506] Embodiment 71. The compound for use of any one of Embodiments 68-70, wherein the cancer is a solid tumor.

[0507] Embodiment 72. The compound for use of any one of Embodiments 68-70, wherein the cancer is lung, liver, colon, skin, bladder, cervical or ovarian cancer.EXAMPLESGeneral Experimental Conditions and Abbreviations

[0508] The following abbreviations are used: AcOH = acetic acid; aq = aqueous; BINAP = (±)-2,2'-bis(diphenylphosphino)-l, T-binaphthalene; Boc = tert-butyloxy carbonyl; BrettPhos Pd G3 = [(2-di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'- triisopropyl-l, T-biphenyl)-2-(2'-amino-l, T -biphenyl)]-palladium(II) methanesulfonate; t-BuBrettPhos Pd G3 = [(2-di-tert-butylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-l, T-biphenyl)-2-(2'-amino-l, T-biphenyl)]palladium(II) methane sulfonate; (tBu)PhCphos = 2-[(tert-Butyl)phenylphosphino]-2',6'-bis(N,N-dimethylamino)biphenyl; Cs₂CO₃ = cesium carbonate; Cui = copper (I) iodide; Cphos = 2-Dicyclohexylphosphino-2',6'-bis(N,N-dimethylamino)biphenyl; DCE = 1,2-dichloroethane; DCM = dichloromethane; DIBAL-H = diisobutylaluminum hydride; DIPEA = N, N-diisopropylethylamine; DMA = N,N-dimethylacetamide; DMAP = 4-dimethylaminopyridine; DMF =N, N-dimethylformamide; DMSO = dimethylsulfoxide; EtOAc = ethyl acetate; EtOH = ethanol; EPhos = dicyclohexyl(3-isopropoxy-2',4',6'-triisopropyl-[l, T-biphenyl]-2-yl)phosphane; EPhos Pd G4 = palladium catalyst containing EPhos - CAS number: 2132978-44-8; FA = formic acid; FSC = flash silica chromatography; g = gram(s); h = hour(s); HATU = (dimethylamino)-N,N-dimethyl(3-oxido-1H-[1,2,3]triazolo[4,5-b]pyridinyl)methaniminium hexafluorophosphate; HC1 = hydrochloric acid; HPLC = high-performance liquid chromatography; KO / Bu = potassium tert-butoxide; K3PO4 = potassium phosphate tribasic; LiHMDS = lithium hexamethyldisilazide; LiOH = lithium hydroxide; M = molar; mg = milligram(s); min = minute(s); mL = milliliter(s); mmol = millimole(s); MeCN = acetonitrile; MeOH = methanol; MTBE = methyl tert-butyl ether; N2 = nitrogen gas; Na2CO3 = sodium carbonate; Na2SO4 = sodium sulfate; NEt3 = triethylamine; NH4CI = ammonium chloride; NH4HCO3 = ammonium bicarbonate; NH4OH = ammonium hydroxide; NMP = N-methyl pyrrolidinone; NMR = nuclear magnetic resonance; Na(OAc)3BH = sodium triacetoxyborohydride; Pd / C = Palladium on carbon; PdCl2(PPh3)2 = Bis(triphenylphosphine)palladium(II) dichloride; Pd(dba)2 = Palladium(0) bis(dibenzylideneacetone); Pd2(dba)3 = tris(dibenzylideneacetone)dipalladium(0); Pd(dppf)Ch = [1,1'- Bis(diphenylphosphino)ferrocene]dichloropalladium(II); iPrOH = isopropyl alcohol; PyBOP = benzotriazol- 1-yloxytripyrrolidino-phosphonium hexafluorophosphate; r.t. = room temperature (~18-25°C); RPC = reverse phase chromatography; RP-HPLC = reverse-phase high-performance liquid chromatography; RuPhos = 2-Dicyclohexylphosphino-2',6'-diisopropoxybiphenyl; RuPhos Pd G3 = (2-Dicyclohexylphosphino-2',6'-diisopropoxy-l,l'-biphenyl)[2-(2'-amino-l,l'-biphenyl)]palladium(II)methanesulfonate; SFC = supercritical fluid chromatography; SPhos Pd G2 = Chloro(2-dicyclohexylphosphino-2',6'-dimethoxy-l,l'-biphenyl)[2-(2'-amino-l,l'-biphenyl)]palladium(II); TFA = trifluoroacetic acid; THF = tetrahydrofuran; TsOH = -toluene sulfonic acid monohydrate; w.t.% = percentage by weight; Pd XPhos G3 = (2-dicyclohexylphosphino-2',4',6'-triisopropyl-l,l'-biphenyl)[2-(2'-amino- 1, 1 '-biphenyl)]palladium(II) methane sulfonate.

[0509] NMR: Proton NMR ('H NMR) was carried out at 300-500 MHz at a temperature in the range from 15-30°C in deuterated-DMSO unless otherwise specified.19F NMR was carried out in DMSO unless otherwise stated. Standard NMR abbreviations are used: s = single, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, dt = doublet of triplets, m = multiplet, br = broad.

[0510] Chromatography methods: clean-appearing fractions containing the desired product are generally identified and combined together and then concentrated under reduced pressure. Flash chromatography was performed using straight phase flash chromatography on a SP1™ Purification or SELEKT™ system from Biotage™, CombiFlash™Rf from ISCO or on Gilson system from Thermo Fisher using normal phase silica FLASH+™ (40M, 25M or 12 M), Sfär Silica HC (5g, 10g, 25g, 100g) from Biotage™ or SNAP™ KP-Sil Cartridges (340, 100, 50 or 10), Flash Column silica-CS columns from Agela, with C18-flash columns or standard flash chromatography. RP-HPLC was performed using XSelect or XB ridge columns.

[0511] In general, all solvents used were commercially available and of analytical grade. Anhydrous solvents were routinely used for reactions. Phase Separators used in the examples are ISOLUTE® Phase Separator columns.

[0512] Concentration of solutions (to partly or fully remove solvent) are generally performed under reduced pressure at r.t. or slightly above.

[0513] The intermediates and examples named below were named using BIOVIA Draw 20.1 or Chem Draw. The starting materials were obtained from commercial sources or made via literature routes.EXAMPLE 1Intermediate la:tert-Butyl 4-(4-bromo-2-methyl-1H-indol-1-yl)piperidine-1-carboxylateBrhoc

[0514] 4-Bromo-2 -methyl- IH-indole (0.252 g, 1.2 mmol) was added to a stirred mixture of tert-butyl 4-((methylsulfonyl)oxy)piperidine-l -carboxylate (0.670 g, 2.40 mmol) and Cs2CO3(0.782 g, 2.40 mmol) in DMF (3 mL) under N2. The mixture was allowed to stir at 80°C for Ih. The solids were fdtered off. The filtrate was concentrated to give the title compound (0.472 g, 100%) as a pink oil. m / z (ES+) [M+H]+= 393.0.Intermediate lb:4-Bromo-2 -methyl- 1 -(4-piperidyl)indoleBrH

[0515] 4 M HC1 in 1,4-dioxane (1.500 mL, 6.00 mmol) was added to a stirred solution of Intermediate la (0.472 g, 1.2 mmol) in MeOH (2 mL). The resulting solution was stirred at r.t. for 3h then concentrated under reduced pressure. Purification by RPC (elution gradient: 0-30% MeCN in water (0.1% FA) gave the title compound in the form of a hydrochloride salt (0.074 g, 21 %) as a pink solid, m / z (ES+) [M+H]+= 293.0.Intermediate 1c:tert-Butyl 4-[[4-(4-bromo-2 -methyl -indol- 1 -yl)- 1 -piperidyl]methyl]piperidine- 1 -carboxylateBr

[0516] tert-Butyl 4-formylpiperidine-I -carboxylate (108 mg, 0.50 mmol) was added to a stirred solution of Intermediate lb (74 mg, 0.25 mmol) in DCM (2 mL) and iPrOH (0.5 mL). The mixture was stirred at r.t for 20 min. NaBH(OAc)3 (134 mg, 0.63 mmol) was then added. The resulting suspension was stirred at r.t for 3h. The mixture was filtered and the filtrate was concentrated. Purification by FSC (gradient: 0-20% MeOH in DCM) gave the title compound (0.100 g, 81 %) as ayellow oil. m / z (ES+) [M+H]+= 490.3.Intermediate Id:tert-Butyl 4-[[4-[4-(2,4-dioxohexahydropyrimidin-1-yl)-2-methyl-indol-1-yl]-1-piperidyl]methyl]piperidine-1-carboxylateo

[0517] To an oven-dried scintillation vial was added Intermediate 1c (100 mg, 0.20 mmol), hexahydropyrimidine-2, 4-dione (69.8 mg, 0.61 mmol), Cs₂CO₃ (133 mg, 0.41 mmol), Pd(dba)2 (11.72 mg, 0.02 mmol) and EPhos (21.81 mg, 0.04 mmol). The vial was then degassed by N2. 1,4-Dioxane (3 mL) wasthen added. The mixture was then degassed by N2. The resulting mixture was stirred at 100°C for 16h. The mixture was then fdtered and then the fdtrate was concentrated. Purification by FSC (gradient: 0-100% EtOAc in hexanes) gave the title compound (0.037 g, 35 %) as a yellow solid, m / z (ES+) [M+H]+= 524.4.Intermediate le:1-[2-Methyl-1-[1-(4-piperidylmethyl)-4-piperidyl]indol-4-yl]hexahydropyrimidine-2,4-dioneo

[0518] tert-Butyldimethylsilyl triflate (32.6 pL, 0.14 mmol) was added to a stirred solution of Intermediate Id (37.2 mg, 0.07 mmol) in MeCN (2 mL). The resulting solution was stirred at r.t. for 0.5h then concentrated under reduced pressure to give the title compound (0.030 g, 100%) as a black oil. m / z (ES+) [M+H]+= 424.2.Intermediate If:tert-Butyl-8-(4-(methoxycarbonyl)phenyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylateBoc^

[0519] A flask containing methyl 4-bromobenzoate (15.0 g, 69.75 mmol), tert-butyl-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (14.81 g, 69.75 mmol), BINAP (8.69 g, 13.95 mmol), Pd(OAc)2 (1.57 g, 6.98 mmol) and Cs2CO3(68.2 g, 209.26 mmol) was purged with N2 then toluene (300 mL) was added. The mixture was stirred at 120°C for 15h. The mixture was cooled to r.t., filtered through celite, and the solids were washed with EtOAc. The filtrate was then concentrated. Purification by FSC (gradient: 0-40% EtOAc in petroleum ether) gave the title compound (21.0 g, 87 %) as a pale yellow solid. ’H NMR (DMSO-d6): 5 1.38 (9H, s), 1.67-1.74 (2H, m), 1.92-1.99 (2H, m), 3.93-3.11 (2H, m), 3.53-3.65 (2H, m), 3.77 (3H, s), 4.36-4.47 (2H, m), 6.88-6.93 (2H, m), 7.75-7.80 (2H, m); m / z (ES+) [M+MeCN]+= 387.2.Intermediate 1g:Methyl 4-(3,8-diazabicyclo[3.2. l]octan-8-yl)benzoate

[0520] 4M HC1 in 1,4-dioxane (70 mL, 280 mmol) was added to a stirred solution of Intermediate If (20.0 g, 57.73 mmol) in DCM (70 mL) and the mixture was stirred at r.t. for 3h. The precipitate was then fdtered and washed with MTBE to give the title compound in the form of a hydrochloride salt (14.2 g, 100 %) as a white solid, m / z (ES+) [M+H]+= 247.2.Intermediate Ih:Methyl 4 - [3 -(3 -amino-6-chloro-pyridazin-4-yl)-3, 8 -diazabicyclo [3.2.1 ]octan-8-yl]benzoate

[0521] A mixture of Intermediate 1g (20.0 g, 81.2 mmol), 4-bromo-6-chloropyridazin-3-amine (19.46 g, 93.38 mmol) and DIPEA (56.7 mL, 324.8 mmol) in n-butanol (100 mL) was stirred at 115°C under N2 for 15h. After cooling the mixture was poured into water (1 L) and the precipitate filtered. Trituration with diethyl ether gave the title compound (21.0 g, 69 %) as a yellow solid. ’H NMR (DMSO-t / 6): 5 1.94-1.98 (2H, m), 2.12-2.19 (2H, m), 2.72-2.74 (IH, m), 2.90-2.93 (IH, m), 3.18-3.24 (2H, m), 3.76-3.78 (3H, m), 4.51-4.57 (2H, m), 5.79-5.87 (2H, m), 6.85-6.88 (IH, m), 6.92-6.96 (2H, m), 7.76-7.80 (2H, m); m / z (ES+) [M+H]+= 374.1.Intermediate li:Methyl 4-[3-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]benzoate

[0522] A flask containing (2-hydroxyphenyl)boronic acid (0.683 g, 4.95 mmol), Intermediate Ih (1.54 g, 4.13 mmol), Pd XPhos G3 (0.524 g, 0.620 mmol) and K2CO3 (1.14 g, 8.25 mmol) was purged with N2 then a mixture of 1,4-dioxane (34.0 mL) and water (6.8 mL) was added. The mixture was then heated to 100°C for 1,5h. After cooling to r.t. the mixture was diluted with water (20 mL). The phases were separated and the aqueous portion was extracted with EtOAc (3 x 30 mL) and washed with brine (20 mL). The combined organic solutions were dried (Na2SO4) and concentrated. Purification by FSC (gradient: 50-100% EtOAc in hexanes) gave the title compound (1.038 g, 58 %) as a tan solid. ’H NMR (DMSO-d6): 5 1.97-2.02 (2H, m), 2.17-2.24 (2H, m), 3.02-3.08 (2H, m), 3.26-3.30 (2H, m), 3.74-3.80 (3H, m), 4.54-4.62 (2H, m), 5.93-6.03 (2H, m), 6.82-6.88 (2H, m), 6.94-6.99 (2H, m), 7.20-7.25 (IH, m), 7.44-7.49 (IH, m), 7.77-7.82 (2H, m), 7.87-7.91 (IH, m), 14.07-14.15 (IH, m); m / z (ES+) [M+H]+= 432.3.Intermediate Ij:4-(3-(3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)benzoic acid

[0523] A mixture of Intermediate li (12.00 g, 27.81 mmol) and LiOH (6.66 g, 278.10 mmol) in MeOH (100 mL), THF (100 mL) and water (100 mL) was stirred at 50°C for 2h then cooled to r.t. and concentrated under reduced pressure. Water (100 mL) was added and then the mixture was carefully acidified to pH 4 using IM aq. HC1. The resulting solid was collected by filtration, washed with cold water and dried to give the title compound (10.20 g, 88 %) as a yellow solid.1H NMR (DMSO-6): 52.00 (2H, d), 2.20 (2H, d), 3.08 (2H, d), 4.56 (2H, s), 6.04 (2H, s), 6.85 (2H, dd), 6.95 (2H, d), 7.17-7.29 (1H, m), 7.47 (1H, s), 7.78 (2H, d), 7.86 (1H, d) (-OH and -CO2H not observed. 2 protons unresolved with water signal); m / z (ES+) [M+H]+= 418.2.Example 1l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8- yl]benzoyl]-4-piperidyl]methyl]-4-piperidyl]-2-methyl-indol-4-yl]hexahydropyrimidine-2, 4-dione

[0524] HATU (16 mg, 0.04 mmol) was added to a stirred solution of Intermediate Ij (15 mg, 0.035 mmol), Intermediate le (15 mg, 0.04 mmol) and DIPEA (0.018 mL, 0.11 mmol) in DMF (1.0 mL). The resulting solution was stirred at r.t. for 3h. Purification by RPC (gradient: 0-40% MeCN in water with 0.1% NH4OH) gave the title compound (17 mg, 60 %) asayellow solid. ’H NMR (DMSO-d6): 51.03-1.12 (2H, m), 1.68-1.85 (5H, m), 1.93-2.01 (2H, m), 2.05-2.15 (2H, m), 2.15-2.26 (4H, m), 2.37-2.44 (6H, m), 2.68-2.77 (2H, m), 2.79-3.02 (6H, m), 3.09 (2H, br d), 3.72 (2H, br t), 3.93-4.29 (3H, m), 4.44-4.56 (2H, m), 5.88-5.99 (1H, m), 6.14 (1H, s), 6.78-6.96 (5H, m), 6.98-7.05 (1H, m), 7.17-7.23 (1H, m), 7.27 (2H, br d), 7.39-7.50 (2H, m), 7.90 (1H, br d), 10.27 (1H, s), 14.12 (1H, br s); m / z (ES+) [M+H]+= 823.5.EXAMPLE 2Intermediate 2a:tert-Butyl 4-(4-bromopyrrolo[2,3-c]pyridin-1-yl)piperidine-1-carboxylateBrhoc

[0525] Prepared in an analogous method to Intermediate la starting from 4-bromo-lH-pyrrolo[2,3-c]pyridine (1.00 g, 5.08 mmol) and tert-butyl 4-((methylsulfonyl)oxy)piperidine-l -carboxylate (4.25 g, 15.2 mmol). Purification by FSC (gradient: 0-75% EtOAc in hexanes) gave the title compound (1.45 g, 75 %) as a white solid.1H NMR (DMSO-d6): δ 1.44 (9H, s), 1.89 (2H, qd), 1.95-2.06 (2H, m), 2.97 (2H, br s), 4.14 (2H, br d), 4.78 (1H, tt), 6.52 (1H, d), 7.94 (1H, d), 8.26 (1H, s), 9.01 (1H, s); m / z (ES+) [M+H]+= 379.8.Intermediate 2b:tert-Butyl 4-[4-(2,4-dioxohexahydropyrimidin- 1 -yl)pyrrolo [2,3 -c]pyridin- 1 -yl] -piperidine- 1 -carboxylate ohoc

[0526] To an oven-dried scintillation vial was added Intermediate 2a (163 mg, 0.43 mmol), hexahydropyrimidine-2, 4-dione (147 mg, 1.29 mmol), Cs₂CO₃ (279 mg, 0.86 mmol), Pd(dba)2 (24.65 mg, 0.04 mmol) and EPhos (45.8 mg, 0.09 mmol). The vial was then degassed by N2. 1,4-dioxane (3 mL) was then added. The mixture was then degassed by N2. The resulting mixture was stirred at 100°C for 16h then cooled to r.t. and filtered through celite. The filtrate was concentrated under reduced pressure. Purification by FSC (gradient: 0-20% MeOH in DCM) gave the title compound (0.063 g, 36 %) as a yellow solid. ’H NMR (DMSO-d6): 1.44 (9H, s), 1.79-1.96 (2H, m), 1.96-2.07 (2H, m), 2.79 (2H, br t), 2.99 (2H, br d), 3.78-3.90 (2H, m), 4.14 (2H, br d), 4.66-4.89 (1H, m), 6.53 (1H, br d), 7.82 (1H, br d), 8.10 (1H, s), 8.92 (1H, s), 10.43 (1H, s); m / z (ES+) [M+H]+= 414.0.Intermediate 2c:l-[l-(4-Piperidyl)pyrrolo[2,3-c]pyridin-4-yl]hexahydropyrimidine-2, 4-dioneo

[0527] Prepared in an analogous method to Intermediate le starting from Intermediate 2b (63.2 mg, 0.15 mmol). Purification by RPC (C18, gradient: 0-40% MeCN in water with 0.1% NH4OH) gave the title compound (0.047 g, 97 %) as a white solid, m / z (ES+) [M+H]+= 314.1.Intermediate 2d:tert-Butyl 4-[[4-[4-(2,4-dioxohexahydropyrimidin-1-yl)pyrrolo[2,3-c]pyridin-1-yl]-1-piperidyl]methyl]piperidine-1-carboxylateo

[0528] Prepared in an analogous method to Intermediate 1c starting from tert-butyl 4-formylpiperidine-1 -carboxylate (86 mg, 0.41 mmol) and Intermediate 2c (63.5 mg, 0.20 mmol). Purification by FSC (gradient: 0-20% MeOH in DCM) gave the title compound (0.056 g, 54 %) as a yellow solid, m / z (ES+) [M+H]+= 511.3.Intermediate 2e:1-[1-[1-(4-Piperidylmethyl)-4-piperidyl]pyrrolo[2,3-c]pyridin-4-yl]hexahydro-pyrimidine-2,4-dione o

[0529] Prepared in an analogous method to Intermediate le starting from tert-butyldimethylsilyl trifluoromethane-sulfonate (50.5 pL, 0.22 mmol) and Intermediate 2d (56.1 mg, 0.11 mmol). The resulting solution concentrated under reduced pressure to give the title compound (0.045 g, 100%) as a black oil. m / z (ES+) [M+H]+= 411.3.Example 2l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8- yl]benzoyl]-4-piperidyl]methyl]-4-piperidyl]pyrrolo[2,3-c]pyridin-4-yl]hexahydropyrimidine-2, 4-dione

[0530] Prepared in an analogous method to EXAMPLE 1 starting from Intermediate Ij (23 mg, 0.055 mmol), Intermediate 2e (23 mg, 0.06 mmol). Purification by RPC (C18, gradient: 0-40% MeCN in water with 0.1% FA) gave the title compound in the form of a formate salt (23 mg, 51 %) as a yellow solid. ’H NMR (DMSO-d6): δ 1.02-1.12 (2H, m), 1.71-1.84 (3H, m), 1.93-2.06 (6H, m), 2.12-2.26 (6H, m), 2.77 (2H, t), 2.83-2.93 (2H, m), 2.96-3.01 (2H, m), 3.08 (2H, br d), 3.27-3.29 (2H, m), 3.81 (2H, t), 3.93-4.27 (2H, m), 4.45-4.58 (3H, m), 5.95 (2H, s), 6.50 (1H, d), 6.80-6.88 (2H, m), 6.92 (2H, d), 7.18-7.23 (1H, m), 7.24-7.29 (2H, m), 7.47 (1H, s), 7.79 (1H, d), 7.86-7.93 (1H, m), 8.07 (1H, s), 8.87 (1H, s), 10.41 (1H, br s), 14.10 (1H, br s); m / z (ES+) [M+H]+= 810.4.EXAMPLE 3Intermediate 3a:tert-Butyl 8-(4-methoxycarbonyl-3-methyl-phenyl)-3,8-diazabicyclo[3.2.1] octane-3 -carboxylate

[0531] RuPhos Pd G3 (0.100 g, 0.12 mmol), methyl 4-bromo-2 -methylbenzoate (2.00 g, 8.73 mmol), tert-butyl-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (2.00 g, 9.42 mmol), Cs₂CO₃ (2.84 g, 8.73 mmol), and RuPhos (0.100 g, 0.21 mmol) in 1,4-dioxane (20 mb) were stirred at 100°C for 18h under N2. The mixture was cooled to r.t, diluted with EtOAc (50 mb). The mixture was washed sequentially with water (20 mb) and brine (20 mb). The organic layer was dried (Na2SO4) and concentrated under reduced pressure. Purification by FSC (gradient: 0-20% EtOAc in petroleum ether) gave the title compound (2.55 g, 81 %) as a yellow solid. 'H NMR (DMSO-d6): δ 1.46 (9H, s), 1.79-1.95 (2H, m), 2.01-2.10 (2H, m), 2.60 (3H, s), 3.23 (2H, dd), 3.64 (1H, d), 3.78 (1H, d), 3.85 (3H, d), 4.28 (2H, d), 6.56-6.64 (2H, m), 7.89 (1H, d); m / z (ES+) [M+H]+=361.2.Intermediate 3b:Methyl 4-(3,8-diazabicyclo[3.2. l]octan-8-yl)-2 -methylbenzoate

[0532] 4M HC1 in 1,4-dioxane (20 mL, 80 mmol) was added to Intermediate 3a (2.5 g, 6.94 mmol). The mixture was stirred at r.t. for Ih then concentrated to give the title compound in the form of a hydrochloride salt (1.7 g, 94 %) as a red solid, m / z (ES+) [M+H]+= 261.1.Intermediate 3c:Methyl 4-[3-(3-amino-6-chloro-pyridazin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-methyl-benzoateo

[0533] Intermediate 3b (1.7 g, 6.53 mmol) was added to a solution of 4-bromo-6-chloropyridazin-3-amine (1.361 g, 6.53 mmol) and DIPEA (3.42 mL, 19.59 mmol) in NMP (20 mL). The mixture was stirred at 140°C for 3h then cooled to r.t. and diluted with EtOAc (200 mL). The mixture was washed with brine (2 x 150 mL). The organic layer was dried (Na2SO4) and concentrated. Purification by FSC (gradient: 0-10% MeOH in DCM) gave the title compound (2.00 g, 79 %) as a red oil. m / z (ES+) [M+H]+=388.1.Intermediate 3d:Methyl 4-(3-(3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl)-3,8-diazabicyclo[3.2. l]-octan-8-yl)-2- methylbenzoate

[0534] Intermediate 3c (2 g, 5.16 mmol) was added to 2-hydroxyphenylboronic acid (0.853 g, 6.19 mmol), Cs₂CO₃ (3.36 g, 10.31 mmol) and Pd(dppf)Cl2(0.377 g, 0.52 mmol) in 1,4-dioxane (40 mL) and water (4.00 mL). The mixture was stirred at 100°C for 3h and then cooled to r.t. The mixture was diluted with EtOAc (100 mL) and then filtered through celite. The filtrate was concentrated. Purification by FSC (gradient: 0-20% MeOH in DCM) gave the title compound (2.0 g, 87 %) as a grey solid, m / z (ES+) [M+H]+= 446.2.Intermediate 3e:4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2. l]octan-8-yl]-2 -methyl-benzoic acid

[0535] Prepared in an analogous method to Intermediate Ij starting from Intermediate 3d (2 g, 4.49 mmol). Purification by RPC (gradient: 0-100% MeCN in water with 0.1% FA) gave the title compound (1.40 g, 72 %) as a grey solid. 'H NMR (DMSO-d6): δ 1.92 - 2.02 (2H, m), 2.12 - 2.24 (2H, m), 3.05 (2H, br d), 3.26 (2H, br d), 4.49 - 4.57 (2H, m), 5.95 (2H, s), 6.73 - 6.79 (2H, m), 6.80 - 6.87 (2H, m), 7.18 - 7.23 (1H, m), 7.46 (1H, s), 7.75 (1H, d), 7.89 (1H, br d), 11.98 (1H, br s), 14.11 (1H, br s) (three protons are unresolved with DMSO solvent); m / z (ES+) [M+H]+= 432.2.Intermediate 3f:tert-Butyl 4-(5-bromoindol-1-yl)piperidine-1-carboxylate

[0536] Prepared in an analogous method to Intermediate la starting from 5-bromo-lH-indole (1.0 g, 5.10 mmol). Purification by FSC (gradient: 0-100% DCM in hexanes) gave the title compound (0.715 g, 37 %) as a white solid. 'H NMR (DMSO-d6): δ 1.42 (9H, s), 1.75 - 1.85 (2H, m), 1.87 - 1.95 (2H, m), 2.81 -3.04 (2H, m), 4.03 - 4.18 (2H, m), 4.49 - 4.61 (1H, m), 6.44 (1H, d), 7.23 (1H, dd), 7.53 - 7.59 (2H, m), 7.72 (1H, d); m / z (ES+) [M-‘Bu+2H]+=323.1.Intermediate 3g:tert-Butyl 4-[5-(2,4-dioxohexahydropyrimidin-1-yl)indol-1-yl]piperidine-1-carboxylate

[0537] Intermediate 3f (1.00 g, 2.64 mmol) was added to a degassed mixture of hexahydropyrimidine-2, 4-dione (1.203 g, 10.55 mmol), Cs₂CO₃ (1.718 g, 5.27 mmol), EPhos (0.085 g, 0.16 mmol) and EPhos Pd G4 (0.145 g, 0.16 mmol) in 1,4-dioxane (40 mL) at r.t under N2. The resulting mixture was stirred at 100°C for 16h and then cooled to r.t.. The mixture was filtered through celite, and then the solids were washed with 1,4-dioxane (50 mL). The filtrate was concentrated. The crude product was triturated with MTBE to give the title compound (0.850 g, 78 %) as a yellow solid.1H NMR (DMSO-d6): δ 1.42 (9H, s), 1.77 - 1.88(2H, m), 1.89 - 1.96 (2H, m),2.71 (2H, t), 2.85 - 3.06 (2H, m), 3.75 (2H, t), 4.07 - 4.19 (2H, m), 4.53 -4.60 (1H, m), 6.45 (1H, d), 7.07 (1H, dd), 7.45 (1H, d), 7.51 - 7.58 (2H, m), 10.23 (1H, s); m / z (ES+) [M+H]+= 413.0.Intermediate 3h:l-[l-(4-Piperidyl)indol-5-yl]hexahydropyrimidine-2, 4-dioneo

[0538] Prepared in an analogous method to Intermediate le starting from Intermediate 3g (2.0 g, 4.85 mmol). The resulting solid was collected by filtration, washed with MTBE and dried to give the title compound (1.80 g, 80 %) as a white solid, m / z (ES+) [M+H]+= 313.0Intermediate 3i:tert-Butyl 4-[[4-[5-(2,4-dioxohexahydropyrimidin- 1 -yl)indol- 1 -yl] - 1 -piperidyl]methyl] -piperidine- 1 - carboxylate

[0539] Prepared in an analogous method to Intermediate 1 c starting from Intermediate 3h(4.1 g, 13.13 mmol). Purification by FSC (gradient: 0-10% MeOH in DCM) gave the title compound (2.78 g, 42 %) as a white solid.1H NMR (DMSO-d6): δ 0.88 - 1.01 (2H, m), 1.38 (9H, s), 1.63 - 1.74 (3H,m), 1.90 - 2.00 (4H, m), 2.09 - 2.22 (4H, m), 2.63 - 2.78 (4H, m), 2.91 - 3.00 (2H, m), 3.75 (2H, t), 3.84 - 3.97 (2H, m), 4.27 -4.39 (1H, m), 6.44 (1H, d), 7.05 (1H, dd), 7.44 (1H, d), 7.49 - 7.56 (2H, m), 10.23 (1H, s); m / z (ES+) [M+H]+=510.4.Intermediate 3j:1-[1-[1-(4-Piperidylmethyl)-4-piperidyl]indol-5-yl]hexahydropyrimidine-2,4-dioneHCO2H

[0540] Intermediate 3i (2.7 g, 5.30 mmol) in FA (20 mL, 521.46 mmol) was stirred at r.t. for Ih. Purification by RPC (gradient: 5-30% MeCN in water with 0.1% FA) gave the title compound in the form of a formate salt (1.60 g, 66 %) as a white solid, m / z (ES+) [M+H]+= 410.2.Example 3l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2- methyl-benzoyl]-4-piperidyl]methyl]-4-piperidyl]indol-5-yl]hexahydropyrimidine-2, 4-dione

[0541] Intermediate 3j (40 mg, 0.10 mmol) was added to Intermediate 3e (42.1 mg, 0.10 mmol), PyBOP (50.8 mg, 0.10 mmol) and DIPEA (51.2 pL, 0.29 mmol) in DMF (1 mL) at r.t. The resulting mixture was stirred at r.t. for Ih. Purification by RP-HPLC (gradient: 16-26% MeCN in water with 0.1% FA) gave the title compound in the form of a formate salt (16 mg, 21 %) as white solid. ’HNMR (DMSO-e / 6): 5 0.92 - 1.16 (2H, m), 1.57 - 1.92 (4H, m), 1.92 - 2.11 (6H, m), 2.10 - 2.28 (6H, m), 2.29 - 2.47 (3H, m), 2.69 -2.76 (2H, m), 2.90 - 3.13 (4H, m), 3.15 - 3.31 (4H, m), 3.77 (2H, t), 4.32 - 4.67 (4H, m), 5.97 (2H, s), 6.47 (IH, d), 6.71 - 6.91 (4H, m), 6.93 - 7.01 (IH, m), 7.08 (IH, dd), 7.19 - 7.31 (IH, m), 7.43 - 7.61 (4H, m), 7.85 - 7.99 (IH, m), 10.28 (IH, s), 14.07 (IH, br s); m / z (ES+) [M+H]+= 823.4.EXAMPLE 4Intermediate 4a:tert- Butyl 4-(5 -bromo-3 -methyl -indol- 1 -yl)piperidine- 1 -carboxylateMe

[0542] Cs₂CO₃ (16.20 g, 49.72 mmol) was added to a stirred solution of tert-butyl 4-methylsulfonyloxypiperidine-1 -carboxylate (13.90 g, 49.74 mmol) and 5 -bromo-3 -methyl- IH-indolc (5.50 g, 26.18 mmol) in DMF (30 mL) under N2 at r.t. The resulting mixture was stirred at 95°C for 8.5h. The mixture was cooled to r.t. then additional tert-butyl 4-methylsulfonyloxypiperidine-l -carboxylate (14.00 g, 50.10 mmol) and Cs2CO3(16.00 g, 49.11 mmol) were added under N2. The resulting mixture was stirred at95 °C for 14h then cooled to r.t. and diluted with EtOAc (200 mL). The mixture was washed with water (2 x 50 mL) and brine (2 x 50 mL). The organic layer was dried (Na2SO4) and concentrated. Purification by LSC (gradient: 0-40% DCM in hexanes then 0-30% EtOAc in hexanes) gave the title compound (5.85 g, 57 %) as a white foam. 'H NMR (CDCh): 5 1.50 (9H, s), 1.81-1.95 (2H, m), 2.00-2.07 (2H, m), 2.28 (3H, d), 2.82-2.99 (2H, m), 4.21-4.40 (3H, m), 6.95 (1H, s), 7.16-7.24 (1H, m), 7.28-7.30 (1H, m), 7.69 (1H, d); m / z (ES+) [M-Bu+2H] = 336.8.Intermediate 4b:tert-Butyl 4-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-indol-1-yl]piperidine-1-carboxylateMe\ Vy°to"'7Bo 0c /

[0543] 1,4 -Dioxane (100 mL) was added to a degassed flask Intermediate 4a (4.20 g, 10.68 mmol), Cs₂CO₃ (6.96 g, 21.36 mmol), Pd2(dba)s (0.885 g, 0.97 mmol), EPhos (1.028 g, 1.92 mmol) and hexahydropyrimidine-2, 4-dione (3.66 g, 32.03 mmol) at r.t. under argon. The mixture was sparged with argon for 5 min then stirred at 100°C for 14h. The mixture was cooled to r.t., diluted with EtOAc (100 mL), and filtered through celite. The filtrate was then concentrated. Purification by FSC (gradient: 0-100% EtOAc in hexanes) gave the title compound (3.06 g, 67 %) as an off-white solid. ’HNMR (CDCL): 5 1.52 (9H, s), 1.85-1.97 (2H, m), 2.02-2.09 (2H, m), 2.32 (3H, d), 2.85-2.97 (4H, m), 3.93 (2H, t), 4.26-4.40 (3H, m), 7.02 (1H, s), 7.13 (1H, dd), 7.37 (1H, d), 7.40 (1H, s), 7.48 (1H, s); m / z (ES+) [M+Na]+= 449.2.Intermediate 4c:l-[3-Methyl-l-(4-piperidyl)indol-5-yl]hexahydropyrimidine-2, 4-dioneQ / ™

[0544] TFA (0.289 mL, 3.75 mmol) was added to a solution of Intermediate 4b (80 mg, 0.19 mmol) in DCM (1.0 mL) at r.t. After Ih the mixture was concentrated. Diethyl ether (2 mL) was added and the resulting mixture was sonicated to yield a solid precipitate. The supernatant was removed and the solid dried under reduced pressure to give the title compound in the form of a trifluoroacetate salt (83 mg, 100 %) as a light pink solid, m / z (ES+) [M+H]+= 326.9.Intermediate 4d:tert-Butyl 4-[[4-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-indol-1-yl]-1-piperidyl]methyl]-4-fluoro-piperidine-1-carboxylate

[0545] A mixture of tert-butyl 4-fluoro-4-formyl -piperidine- 1 -carboxylate (37 mg, 0.16 mmol), sodium acetate (33 mg, 0.40 mmol), and Intermediate 4c (35 mg, 0.08 mmol) in THF (1.0 mb) was stirred at 60°C for 25 min and then NaBH(OAc)3(34 mg, 0.16 mmol) was added. After 0.5h additional tert-butyl 4-fluoro-4-formyl-piperidine-1-carboxylate (37 mg, 0.16 mmol) was added and then after stirring for ten min additional NaBH(OAc)3(20 mg, 0.09 mmol) was added. The mixture was cooled to r.t. and then diluted with DCM (5 mb) and saturated aq. Na₂CO₃ solution (1 mL). The organic layer was separated and the aqueous layer extracted with DCM (2 × 5 mL). The combined organic solutions were dried (Na2SO4) and concentrated. Purification by FSC (gradient: 0-100% EtOAc in hexanes then 0-15% MeOH in DCM) gave the title compound (26 mg, 60 %) as a white solid. ’HNMR (DMSO-d6): δ 1.40 (9H, s), 1.50-1.67 (2H, m), 1.77-1.88 (4H, m), 1.88-1.98 (2H, m), 2.22 (3H, d), 2.32-2.41 (2H, m), 2.61 (2H, d), 2.71 (2H, t), 2.95-3.09 (4H, m), 3.67-3.81 (4H, m), 4.21-4.29 (1H, m), 7.03 (1H, dd), 7.30 (1H, s), 7.38 (1H, d), 7.45 (1H, d), 10.22 (1H, s); m / z (ES+) [M+H]+= 542.1.Intermediate 4e:1 -[ 1 -[ 1 -[(4-Fluoro-4-piperidyl)methyl] -4-piperidyl] -3 -methyl -indol-5-yl]hexahydro-pyrimidine-2, 4-dioneMe

[0546] TFA (0.111 mb, 1.44 mmol) was added to a solution of Intermediate 4d (39 mg, 0.07 mmol) in DCM (0.50 mb) at r.t. After 2h the mixture was concentrated. Diethyl ether (2 mb) was added and the resulting mixture was sonicated to yield a solid precipitate. The solids were filtered off, dried under reduced pressure to give the title compound in the form of a bis-trifluoroacetate salt (48 mg, 100 %) as a light pink solid, m / z (ES+) [M+H]+= 442.0.Example 4l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2- methyl-benzoyl]-4-fluoro-4-piperidyl]methyl]-4-piperidyl]-3-methyl-indol-5-yl]hexahydro-pyrimidine- 2,4-dioneMe

[0547] Prepared in an analogous method to EXAMPLE 1 starting from Intermediate 3e (18 mg, 0.04 mmol), Intermediate 4e (32 mg, 0.05 mmol). Purification by RP-HPLC (gradient: 20-40% MeCN in water with 0.1% FA) gave the title compound in the form of a formate salt (7.5 mg, 20 %) as a white solid. ’H NMR (DMSO-d6): 5 1.49-2.02 (10H, m), 2.10-2.25 (8H, m), 2.34-2.42 (2H, m), 2.60 (2H, d), 2.71 (2H, brt), 3.01 (2H, br d), 3.09 (2H, br d), 3.13-3.22 (2H, m), 3.26-3.29 (2H, m), 3.72-3.78 (2H, m), 4.02-4.40 (3H, m), 4.42-4.49 (2H, m), 5.93 (2H, s), 6.72-6.91 (4H, m), 7.02 (2H, br t), 7.17-7.25 (1H, m), 7.28 (1H, s), 7.38 (1H, s), 7.41-7.50 (2H, m), 7.90 (1H, br d), 10.22 (1H, s), 14.11 (1H, br s);19F NMR (DMS0-< ): 5 -158.29 (IF, s); m / z (ES+) [M+H]+= 855.4.EXAMPLE 5Intermediate 5a:tert- Butyl 4-(4-bromoindol- 1 -yl)piperidine- 1 -carboxylate

[0548] 2-(Tributyl-λ5-phosphanylidene)acetonitrile (92.0 g, 382.56 mmol) was added to a stirred solution of tert-butyl 4-hydroxypiperidine-l -carboxylate (77.0 g, 382.56 mmol) and 4-bromo-1H-indole (50.0 g, 255.04 mmol) in toluene (500 mL) under N2 at r.t. The resulting mixture was stirred at 100°C for 18h and then cooled to r.t. and concentrated under reduced pressure. Purification by RPC (gradient: 0-70% MeCN in water with 0.4% NH4HCO3) gave the title compound (20.0 g, 21 %) as a yellow solid. 'H NMR (DMSO-d6): 5 1.44 (9H, s), 1.76-2.00 (4H, m), 2.98 (2H, m), 4.13 (2H, d), 4.60 (1H, m), 6.42 (1H, d), 7.08 (1H, t), 7.23-7.28 (1H, m), 7.58-7.74 (2H, m); m / z (ES+) [M+H]+= 379.1.Intermediate 5b:tert-Butyl 4-[4-(2,4-dioxohexahydropyrimidin- 1 -yl)indol- 1 -yl]piperidine- 1 -carboxylate

[0549] Prepared in an analogous method to Intermediate 3g starting from Intermediate 5a (1.25 g, 2.64 mmol). Purification by FSC (gradient: 0-60% EtOAc in petroleum ether) gave the title compound (0.65 g, 60 %) as apale yellow solid. ’HNMR^DCL): 5 1.52 (9H, s), 1.86-2.01 (2H, m), 2.06-2.14 (2H, m), 2.86-3.00 (4H, m), 3.95 (2H, t), 4.23-4.50 (3H, m), 6.42 (1H, d), 7.06 (1H, d), 7.22-7.27 (2H, m), 7.38 (1H, d), 7.55 (1H, s); m / z (ES+) [M+Na]+= 435.2.Intermediate 5c:1 -[ 1 -(4-Piperidyl)indol-4-yl]hexahydropyrimidine-2, 4-dione

[0550] Intermediate 5b (7.0 g, 16.97 mmol) was added to AcOH (20 mL). The resulting mixture was stirred at 100°C for 72h and then cooled to r.t. and concentrated under reduced pressure. Purification by RPC (gradient: 0-60% MeCN in water with 0.4% HC1) gave the title compound in the form of a hydrochloride salt (4.50 g, 85 %) as a red solid.1H NMR (DMSO-d6): δ 1.89-2.30 (4H, m), 2.47-2.50 (2H,m), 2.75 (2H, t), 2.99-3.14 (2H, m), 3.76 (2H, t), 4.60-4.77 (1H, m), 6.44 (1H, d), 6.97 (1H, d), 7.16 (1H, t), 7.39 (1H, d), 7.57 (1H, d), 10.33 (1H, s) (NH protons not observed); m / z (ES+) [M+H]+= 313.2.Intermediate 5d:tert-Butyl 4-[4-[4-(2,4-dioxohexahydropyrimidin- 1 -yl)indol- 1 -yl]- 1 -piperidyl] -piperidine- 1 -carboxylate

[0551] AcOH (27.5 pL, 0.48 mmol) was added to a mixture of Intermediate 5c (75 mg, 0.24 mmol) and tert-butyl 4-oxopiperidine-l -carboxylate (96 mg, 0.48 mmol) in DCE (3 mL). NaBH(OAc)3(153 mg, 0.72 mmol) was then added. The mixture was stirred at 70°C for 4h. The mixture was cooled to r.t. and then diluted with sat. aq. NaHCOs (5 mL) and DCM (20 mL). The layers were separated, and the aqueous portion was extracted with DCM (3 * 10 mL). The combined organic solutions were dried (Na2SO4) and concentrated. Purification by FSC (gradient: 0-8% MeOH in DCM) gave the title compound (0.070 g, 59 %) as an off-white solid.1H NMR (CD2Cl2): δ 1.44 (9H, s), 1.79 (2H, br d), 1.97-2.13 (6H, m), 2.40-2.55 (3H, m), 2.71 (2H, br s), 2.85 (2H, t), 3.08 (2H, br d), 3.89 (2H, t), 4.04-4.18 (2H, m), 4.18-4.29 (1H, m), 6.39 (1H, d), 7.00 (1H, d), 7.22 (1H, t), 7.32 (1H, d), 7.40 (1H, d), 7.62 (1H, s); m / z (ES+) [M+H]+= 495.9.Intermediate 5e:1 -[ 1 -[ 1 -(4-Piperidyl)-4-piperidyl] indol-4-yl]hexahydropyrimidine-2, 4-dione

[0552] Prepared in an analogous method to Intermediate 5c starting from Intermediate 5d (70 mg, 0.14 mmol). Concentration gave the title compound in the form of a hydrochloride salt (0.049 g, 74 %) as a white solid, m / z (ES+) [M+H]+= 396.3.Example 5l-[l-[l-[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8- yl]benzoyl]-4-piperidyl]-4-piperidyl]indol-4-yl]hexahydropyrimidine-2, 4-dione

[0553] Prepared in an analogous method to EXAMPLE 1 starting from Intermediate Ij (0.015 g, 0.03 mmol) and Intermediate 5e (0.014 g, 0.03 mmol). Purification by RPC (gradient: 15-50% MeCN in water with 0.1% FA) gave the title compound in the form of a formate salt (7.8 mg, 33 %) as a white solid. ’H NMR(DMSO-d6): δ 0.97 (2H, brd), 1.45 (2H, brs), 1.79 (2H, brd), 1.89-2.02 (6H, m), 2.02-2.22 (2H, m), 2.54-2.57 (2H, m), 2.57-2.65 (2H, m), 2.73-2.78 (2H, m), 2.82-2.95 (2H, m), 2.98-3.05 (2H, m), 3.06-3.12 (2H, m), 3.76 (2H, t), 4.12-4.26 (1H, m), 4.30-4.40 (1H, m), 4.49, (2H, br s), 5.94 (2H, s), 6.40 (1H, br s), 6.80-6.87 (2H, m), 6.90-6.95 (3H, m), 7.12 (1H, t), 7.21 (1H, t), 7.28 (2H, br d), 7.45-7.50 (2H, m), 7.50-7.53, (1H, m), 7.90 (1H, d), 10.30 (1H, s), 14.04-14.20 (1H, m); m / z (ES+) [M+H]+= 795.5.EXAMPLE 6Intermediate 6a:Benzyl 4-(4-bromo-5 -methyl -indol- 1 -yl)piperidine- 1 -carboxylateBr

[0554] Cs₂CO₃ (4.65 g, 14.28 mmol) was added to stirred solution of benzyl 4-methylsulfonyloxypiperidine-1 -carboxylate (4.48 g, 14.28 mmol) and 4-bromo-5-methyl-lH-indole (1.0 g, 4.76 mmol) in DMF (19 mL). The mixture was stirred at 100°C for 22h, cooled to r.t., then diluted with water (100 mL) and EtOAc (100 mL). The layers were separated and the aqueous layer extracted with EtOAc (2 × 100 mL). The organic layers were combined, dried (Na2SO4), filtered and concentrated. Purification by FSC (0-100% EtOAc in hexanes) gave the title compound (0.992 g, 49 %) as a light peach solid. ’HNMR (DMSO-d6): 5 1.82-2.02 (4H, m), 2.43 (3H, s), 3.07 (2H, br s), 4.20 (2H, br d), 4.61 (1H, br t), 5.12 (2H, br s), 6.37 (1H, br s), 7.11 (1H, br d), 7.27-7.37 (1H, m), 7.40 (4H, br d), 7.53 (1H, br d), 7.58 (1H, d); m / z (ES+) [M+H]+= 429.1.Intermediate 6b:Benzyl 4-[4-(tert-butoxycarbonylamino)-5-methyl -indol- 1 -yl]piperidine- 1 -carboxylateNHBoc

[0555] 1,4-Dioxane (4 mL) was added to a mixture of Intermediate 6a (0.299 g, 0.7 mmol), tert-butyl carbamate (0.246 g, 2.10 mmol), Pd Xphos G3 (0.059 g, 0.07 mmol) and Cs2CO3(0.570 g, 1.75 mmol) under N2. The mixture was sparged with N2. The resulting slurry was stirred at 100°C for 16h then cooled to r.t. The mixture was filtered and then the filtrate was concentrated. Purification by FSC (gradient: 0-100% EtOAc in hexanes) gave the title compound (0.323 g, 99 %) as a yellow solid, m / z (ES+) [M+H]+= 464.3.Intermediate 6c:Benzyl 4-(4-amino-5 -methyl -indol- 1 -yl)piperidine- 1 -carboxylateNH2bbz

[0556] 4M HC1 in 1,4-dioxane (1.740 mL, 6.96 mmol) was added to Intermediate 6b (322.6 mg, 0.70 mmol). The resulting solution was stirred at r.t, for Ih then concentrated under reduced pressure to give the title compound in the form of a hydrochloride salt (0.253 g, 100%) as a pink solid, m / z (ES+) [M+H]+= 365.4.Intermediate 6d:Benzyl 4-[4-(2,4-dioxohexahydropyrimidin- 1 -yl)-5 -methyl -indol- 1 -yl]piperidine- 1-carboxylate obbz

[0557] Acrylic acid (0.137 mL, 2.00 mmol) and Intermediate 6c (0.182 g, 0.5 mmol) were added to a scintillation vial. The mixture was allowed to stir at 100°C for 3h. The mixture was then cooled to r.t. and AcOH (3 mL) was added. The mixture was stirred at 120°C for 10 min. Urea (0.180 g, 3.00 mmol) was added and the resulting solution was stirred at 120°C for 16h. The mixture was cooled to r.t. and concentrated. Purification by FSC (gradient: 0-100% EtOAc in hexanes) gave the title compound (0.141 g, 61 %) as a yellow solid, m / z (ES+) [M+H]+= 461.2.Intermediate 6e:1 -[5-Methyl- 1 -(4-piperidyl)indol-4-yl]hexahydropyrimidine-2, 4-dioneo

[0558] Pd / C (32.7 mg, 0.03 mmol) was added to a stirred solution of Intermediate 6d (141.4 mg, 0.31 mmol) in MeOH (3 mL). The flask was then purged with H2. The resulting suspension was stirred at 40°Cunder H2 for 16h then cooled to r.t. The mixture was purged with N2 then filtered through celite. The filtrate was concentrated to give the title compound (0.100 g, 100 %) as a colourless oil. m / z (ES+) [M+H]+= 327.1.Intermediate 6f:tert-Butyl 4-[[4-[4-(2,4-dioxohexahydropyrimidin-1-yl)-5-methyl-indol-1-yl]-1-piperidyl]methyl]piperidine-1-carboxylateo

[0559] Prepared in an analogous method to Intermediate 1c starting from Intermediate 6e (100 mg, 0.31 mmol). Purification by FSC (gradient: 0-100% EtOAc in hexanes) gave the title compound (0.083 g, 51 %) as a colorless oil. m / z (ES+) [M+H]+= 524.5.Intermediate 6g:1-[5-Methyl-1-[1-(4-piperidylmethyl)-4-piperidyl]indol-4-yl]hexahydropyrimidine-2,4-dioneo

[0560] Prepared in an analogous method to Intermediate le starting from Intermediate 6f (82.7 mg, 0.16 mmol) The solution was concentrated under reduced pressure to give the title compound (0.067 g, 100%) as a black oil. m / z (ES+) [M+H]+= 424.3.Example 6l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8- yl]benzoyl]-4-piperidyl]methyl]-4-piperidyl]-5-methyl-indol-4-yl]hexahydropyrimidine-2, 4-dione

[0561] Prepared in an analogous method to EXAMPLE 1 starting from Intermediate Ij (33 mg, 0.08 mmol) and Intermediate 6g (34 mg, 0.08 mmol). Purification by RPC (0-40% MeCN in water with 0.1% FA) gave the title compound in the form of a formate salt (29 mg, 44 %) as a yellow solid. ’HNMR (DMSO-d6): 5 1.01 - 1.34 (4H, m), 1.73 - 1.84 (2H, m), 1.89 - 2.04 (4H, m), 2.11 - 2.37 (10H, m), 2.73 - 2.87 (2H, m), 2.88 - 3.01 (2H, m), 3.07 - 3.13 (2H, m), 3.52 - 3.62 (1H, m), 3.66 - 3.81 (2H, m), 4.03 - 4.30 (2H, m), 4.52 (2H, br s), 5.98 (2H, br s), 6.34 - 6.49 (1H, m), 6.83 - 6.90 (2H, m), 6.94 (2H, br d), 7.01 - 7.14 (1H, m), 7.20 - 7.26 (1H, m), 7.29 (2H, br d), 7.35 - 7.54 (3H, m), 7.91 (1H, br d), 10.32 (1H, s), 14.13 (1H, br s) (four protons are unresolved); m / z (ES+) [M+H]+= 823.5.EXAMPLE 7Intermediate 7a:tert-Butyl 4-[[4-[4-(2,4-dioxohexahydropyrimidin- 1 -yl)indol- 1 -yl] - 1 -piperidyl]methyl] -piperidine- 1 - carboxylate

[0562] Prepared in an analogous method to Intermediate 1c starting from Intermediate 5c (4.00 g, 12.81 mmol). Purification by FSC (gradient: 0-8% MeOH in DCM) gave the title compound (4.80 g, 74 %) as a yellow oil.1H NMR (DMSO-d6): δ 0.88-1.07 (2H, m), 1.40 (9H, s), 1.72 (3H, d), 1.90-2.09 (4H, m), 2.10-2.27 (4H, m), 2.50-2.77 (4H, m), 2.98 (2H, d), 3.78 (2H, m), 3.94 (2H, d), 4.33-4.50 (1H, m), 6.42 (1H, d), 6.97 (1H, d), 7.15 (1H, m), 7.44-7.59 (2H, m), 10.34 (1H, s); m / z (ES+) [M+H]+= 510.3.Intermediate 7b:1 -[ 1 -[ 1 -(4-Piperidylmethyl)-4-piperidyl]indol-4-yl]hexahydropyrimidine-2, 4-dione

[0563] Prepared in an analogous method to Intermediate 3j starting from Intermediate 7a (4.80 g, 9.42 mmol). Purification by RPC (gradient: 0-100% MeCN in water with 0.4% FA) gave the title compound in the form of a bis-formate salt (3.78 g, 74 %) as a yellow solid.1H NMR (DMSO-d6): δ 1.13 - 1.32 (2H, m),1.77 - 1.88 (3H, m), 1.89 - 2.03 (4H, m), 2.10 - 2.27 (4H, m), 2.69 - 2.85 (4H, m), 2.94 - 3.04 (2H, m), 3.16 - 3.27 (2H, m), 3.76 (2H, t), 4.28 - 4.43 (1H, m), 6.40 (1H, d), 6.95 (1H, d), 7.09 - 7.18 (1H, m), 7.46 - 7.54 (2H, m), 10.32 (1H, br s) (NH protons not observed); m / z (ES+) [M+H]+= 410.3.Example 7l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8- yl]benzoyl]-4-piperidyl]methyl]-4-piperidyl]indol-4-yl]hexahydropyrimidine-2, 4-dione

[0564] Prepared in an analogous method to EXAMPLE 1 starting from Intermediate Ij (24 mg, 0.05 mmol) and Intermediate 7b (25 mg, 0.05 mmol). Purification by RPC (gradient: 5-20% MeCN in water with 0.1% FA) gave the title compound in the form of a formate salt (20 mg, 45 %) as a white solid. ’H NMR (DMSO-d6): 5 1.02 - 1.15 (2H, m), 1.73 - 1.86 (3H, m), 1.90 - 2.04 (6H, m), 2.13 - 2.23 (4H, m), 2.23 -2.29 (2H, m), 2.72 - 2.82 (2H, m), 2.84 - 2.95 (2H, m), 2.95 - 3.04 (2H, m), 3.06 - 3.15 (2H, m), 3.74 - 3.82 (2H, m), 3.97 - 4.24 (2H, m), 4.32 - 4.41 (1H, m), 4.45 - 4.56 (2H, m), 5.97 (2H, br s), 6.42 (1H, br s), 6.83 - 6.91 (2H, m), 6.95 (3H, br dd), 7.10 - 7.18 (1H, m), 7.23 (1H, br t), 7.28 (2H, br d), 7.45 - 7.58 (3H, m), 7.84 - 8.00 (1H, m), 10.32 (1H, s), 14.09 (1H, br s); m / z (ES+) [M+H]+= 809.4.EXAMPLE 8Intermediate 8a:tert-Bv yl 4-(4-bromo-7 -fluoro-indol- 1 -yl)piperidine- 1 -carboxylateBr

[0565] 4-Bromo-7-fluoro-1H-indole (0.257 g, 1.2 mmol) was added to a stirred mixture of tert-butyl 4-((methyl-sulfonyl)oxy)piperidine-l -carboxylate (0.670 g, 2.40 mmol) and KOH (0.471 g, 8.40 mmol) in DMSO (2 mL) under N2. The mixture was stirred at 80°C for 16h then cooled to r.t. The mixture was then diluted with water (25 mL) and EtOAc (15 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated. Purification by FSC (gradient: 0-80% DCM in hexanes) gave the title compound (0.383 g, 80 %) as a yellow oil. m / z (ES+) [M+H]+= 397.0.Intermediate 8b:4-Bromo-7 -fluoro- 1 -(4-piperidyl)indole

[0566] Prepared in an analogous method to Intermediate lb starting from Intermediate 8a (383.3 mg, 0.96 mmol). The solution was concentrated to give the title compound in the form of a hydrochloride salt (0.287 g, 100 %) as a pink solid, m / z (ES+) [M+H]+= 297.0.Intermediate 8c:tert-butyl 4-[[4-(4-Bromo-7-fluoro-indol- 1 -yl)- 1 -piperidyl]methyl]piperidine- 1 -carboxylate

[0567] Prepared in an analogous method to Intermediate 1c starting from Intermediate 8b (0.285 g, 0.96 mmol). Purification by FSC (gradient: 0-100% EtOAc in hexanes) gave the title compound (0.123 g, 26 %) as a colorless oil. m / z (ES+) [M+H]+= 496.2.Intermediate 8d:tert-Butyl 4-[ [4-[4-(2,4-dioxohexahydropyrimidin- 1 -yl)-7 -fluoro-indol- 1 -yl] - 1 - piperidyl]methyl]piperidine- 1 -carboxylate

[0568] Prepared in an analogous method to Intermediate Id starting from Intermediate 8c (123 mg, 0.25 mmol), Purification by FSC (gradient: 0-100% EtOAc in hexanes and then 0-10% MeOH in EtOAc) gave the title compound (0.021 g, 16 %) as a yellow solid, m / z (ES+) [M+H]+= 528.3.Intermediate 8e:1 -[7-Fluoro- 1 -[ 1 -(4-piperidylmethyl)-4-piperidyl]indol-4-yl]hexahydropyrimidine-2, 4-dioneo

[0569] Prepared in an analogous method to Intermediate le starting from Intermediate 8d (21.4 mg, 0.04 mmol). The solution was concentrated to give the title compound (17 mg, 100%) as a dark oil. m / z (ES+) [M+H]+= 428.3.Example 8l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8- yl]benzoyl]-4-piperidyl]methyl]-4-piperidyl]-7-fluoro-indol-4-yl]hexahydropyrimidine-2, 4-dione

[0570] Prepared in an analogous method to EXAMPLE 1 starting from Intermediate Ij (0.017 g, 0.04 mmol) and Intermediate 8e. Purification by RPC (gradient: 0-40% MeCN in water with 0.1% FA) gave the title compound (9.7 mg, 29 %) as a yellow solid.1H NMR (DMSO-d6): δ 1.04 - 1.23 (2H, m), 1.68 - 1.94 (3H, m), 1.94 - 2.07 (4H, m), 2.08 - 2.32 (6H, m), 2.73 - 2.82 (2H, m), 2.85 - 3.18 (6H, m), 3.71 - 3.80 (2H, m), 3.97 - 4.30 (2H, m), 4.41 - 4.65 (3H, m), 5.98 (2H, br s), 6.46 - 6.61 (1H, m), 6.82 - 6.89 (2H, m), 6.90 - 7.04 (4H, m), 7.20 - 7.26 (1H, m), 7.29 (2H, br d), 7.44 - 7.64 (2H, m), 7.91 (1H, br d), 10.35 (1H, s), 14.14 (1H, br s) (four protons are unresolved); m / z (ES+) [M+H]+= 827.3.EXAMPLE 9Intermediate 9a:tert-Butyl 4-[[4-[4-(2,4-dioxohexahydropyrimidin-1-yl)indol-1-yl]-1-piperidyl]methyl]-4-methyl-piperidine-1-carboxylate

[0571] Prepared in an analogous method to Intermediate 1c starting from Intermediate 5c (137 mg, 0.44 mmol) and tert-butyl 4-formyl-4-methylpiperidine-l -carboxylate (100 mg, 0.44 mmol). Purification by RPC (gradient 0-80% MeCN in water with 0.4% NH4HCO3) gave the title compound (25 mg, 11 %) as abrown solid.1H NMR (DMSO-d6): δ 0.93 (3H, s), 1.17 - 1.24 (2H, m), 1.37 - 1.45 (11H, m), 1.83 - 1.90 (2H, m), 1.94 - 2.04 (2H, m), 2.21 (2H, s), 2.75 (2H, t), 2.84 - 2.91 (2H, m), 2.99 - 3.14 (2H, m), 3.50 - 3.61 (2H, m), 3.76 (2H, t), 4.27 - 4.39 (1H, m), 6.40 (1H, d), 6.94 (1H, d), 7.09 - 7.16 (1H, m), 7.42 - 7.54 (2H, m), 10.30 (1H, s) (two protons are unresolved); m / z (ES+) [M+H]+=524.3.Intermediate 9b:1 -[ 1 -[ 1 -[(4-Methyl-4-piperidyl)methyl]-4-piperidyl]indol-4-yl]hexahydropyrimidine-2, 4-dione o

[0572] Prepared in an analogous method to Intermediate 3j starting from Intermediate 9a (20 mg, 0.04 mmol). The solution was concentrated to give the title compound in the form of a formate salt (16 mg, 100 %) as a white solid, m / z (ES+) [M+H]+=424.2.Example 9l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8- yl]benzoyl]-4-methyl-4-piperidyl]methyl]-4-piperidyl]indol-4-yl]hexahydropyrimidine-2, 4-dione

[0573] Prepared in an analogous method to EXAMPLE 3 starting from Intermediate Ij (15 mg, 0.04 mmol) and Intermediate 9b (15 mg, 0.04 mmol). Purification by RP-HPLC (gradient: 10-22% MeCN in water with 0.1% FA) gave the title compound in the form of a formate salt (4.5 mg, 15 %) as a white solid.1H NMR (DMSO-6): 5 1.00 (3H, s), 1.29 (2H, d), 1.40-1.55 (2H, m), 1.81-1.92 (2H, m), 1.93-2.10 (4H, m), 2.13- 2.21 (2H, m), 2.22-2.31 (2H, m), 2.59 (1H, m), 2.71-2.80 (2H, m), 2.81-2.95 (2H, m), 3.07-3.12 (2H, m), 3.24-3.31 (5H, m), 3.68-3.85 (4H, m), 4.19-4.41 (1H, m), 4.50 (2H, s), 5.96 (2H, s), 6.31-6.58 (1H, m), 6.79-7.02 (5H, m), 7.03-7.37 (4H, m), 7.38-7.60 (3H, m), 7.78-7.93 (1H, m), 10.32 (1H, s) (-OH not observed); m / z (ES+) [M+H]+=823.5.EXAMPLE 10Intermediate 10a:tert- Butyl 4-(4-bromo-6-methyl-indol- 1 -yl)piperidine- 1 -carboxylate

[0574] Prepared in an analogous method to Intermediate 8a starting from 4-bromo-6-methyl- 1 H-indole (0.252 g, 1.2 mmol). Purification by FSC (gradient: 0-80% DCM in hexanes) gave the title compound (0.344 g, 73 %) as a yellow oil. m / z (ES+) [M+H]+= 393.1.Intermediate 10b:4-Bromo-6-methyl- 1 -(4-piperidyl)indole

[0575] Prepared in an analogous method to Intermediate lb starting from Intermediate 10a (344.2 mg, 0.88 mmol). The solution was concentrated to give the title compound in the form of a hydrochloride salt (0.245 g, 100 %) as a pink solid, m / z (ES+) [M+H]+= 292.8.Intermediate 10c:tert-Butyl 4-[[4-(4-bromo-6-methyl-indol-1-yl)-1-piperidyl]methyl]piperidine-1-carboxylate

[0576] Prepared in an analogous method to Intermediate 1c starting from Intermediate 10b (0.258 g, 0.88 mmol). Purification by FSC (gradient: 0-100% EtOAc in hexanes) gave the title compound (0.132 g, 31 %) as a colorless oil. m / z (ES+) [M+H]+= 490.2.Intermediate lOd:tert-Butyl 4-[ [4-[4-(2,4-dioxohexahydropyrimidin- 1 -yl)-6-methyl-indol- 1 -yl] - 1 - piperidyl]methyl]piperidine- 1 -carboxylate

[0577] Prepared in an analogous method to Intermediate Id starting from Intermediate 10c (132 mg, 0.27 mmol). Purification by FSC (gradient: 0-100% EtOAc in hexanes and then 0-10% MeOH in EtOAc) gave the title compound (56 mg, 39 %) as a yellow solid, m / z (ES+) [M+H]+= 524.4.Intermediate lOe:1 -[6-Methyl- 1 -[ 1 -(4-piperidylmethyl)-4-piperidyl]indol-4-yl]hexahydropyrimidine-2, 4-dione

[0578] Prepared in an analogous method to Intermediate le starting from Intermediate lOd (55.5 mg, 0.11 mmol). The solution was concentrated to give the title compound (0.045 g, 100%) as a dark oil. m / z (ES+) [M+H]+= 424.3.Example 10l-[l-[l-[[l-[4-[3-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8- yl]benzoyl]-4-piperidyl]methyl]-4-piperidyl]-6-methyl-indol-4-yl]hexahydropyrimidine-2, 4-dione

[0579] Prepared in an analogous method to EXAMPLE 1 starting from Intermediate Ij (23 mg, 0.055 mmol) and Intermediate lOe (23 mg, 0.06 mmol). Purification by RPC (C18, gradient: 0-40% MeCN in water with 0.1% FA) gave the title compound in the form of a formate salt (19 mg, 42 %) as a yellow solid.1H NMR (DMSO-d6): δ 1.15-1.27 (2H, m), 1.70-2.33 (13H, m), 2.42 (3H, s), 2.74 (2H, t), 2.81-3.13 (6H, m), 3.27-3.29 (2H, m), 3.74 (2H, t), 3.92-4.24 (2H, m), 4.50 (2H, br s), 5.96 (2H, br s), 6.27-6.46 (1H, m), 6.77-6.89 (3H, m), 6.92 (2H, br d), 7.18-7.51 (6H, m), 7.89 (1H, br d), 10.30 (1H, br s), 14.12 (1H, br s) (three protons are unresolved with water or DMSO signals); m / z (ES+) [M+H]+= 823.5.EXAMPLE 11Intermediate Ila:6-Bromo-3-(4-piperidyl)-lH-indole

[0580] A slurry of piperidin-4-one hydrochloride salt (3.98 g, 29.33 mmol) in toluene (10 mL) was added to a stirred solution of 6-bromo-1H-indole (5 g, 25.50 mmol), triethylsilane (12.22 mL, 76.51 mmol) and methanesulfonic acid (2.484 mL, 38.26 mmol) in toluene (50 mL) at r.t. The resulting mixture was stirred at 70°C for 2h then cooled to r.t. and concentrated. Purification by RPC (gradient: 0-20% MeCN in water with 0.05% HC1) gave the title compound (2.400 g, 34 %) in the form of a hydrochloride salt as a yellow solid, m / z (ES+) [M+H]+= 279.1.Intermediate 11b:tert-Butyl 4-(6-bromo-1H-indol-3-yl)piperidine-1-carboxylate

[0581] Di-tert-butyl dicarbonate (2.74 mL, 11.82 mmol) was added to Intermediate 1 la (2.20 g, 7.88 mmol) and DIPEA (4.13 mL, 23.64 mmol) in DCM (50 mL) at r.t. The resulting mixture was stirred at r.t. for Ih then concentrated. Purification by FSC (gradient: 0-30% EtOAc in petroleum ether) gave the title compound (1.30 g, 43 %) as a white solid. ’HNMR (DMSO-r / 6): 5 1.40 (9H, s), 1.44 - 1.55 (2H, m), 1.85 - 1.95 (2H, m), 2.77 - 2.98 (3H, m), 3.98 - 4.07 (2H, m), 7.05 - 7.10 (IH, m), 7.14 (IH, d), 7.48 - 7.54 (2H, m), 10.94 (IH, br s); m / z (ES+) [M+H]+= 379.3.Intermediate 11c:tert-Butyl 6-bromo-3-( 1 -tert-butoxycarbonyl-4-piperidyl)indole- 1 -carboxylate

[0582] Di -tert-butyl dicarbonate (0.918 mL, 3.95 mmol) was added to Intermediate 11b (1.00 g, 2.64 mmol), DIPEA (1.38 mL, 7.91 mmol) and DMAP (0.032 g, 0.26 mmol) in DCM (30 mL) at r.t. The resulting mixture was stirred at r.t. for 16h then concentrated. Purification by FSC (gradient: 0-15% EtOAc in petroleum ether) gave the title compound ( 1.13 g, 89 %) as a white solid. ’H NMR (CDCL): 5 1.51 (9H, s), 1.59 - 1.69 (2H, m), 1.69 (9H, s), 1.97 - 2.09 (2H, m), 2.90 (3H, t), 4.27 (2H, d), 7.30 (IH, s), 7.37 (IH, dd), 7.42 (IH, d), 8.37 (IH, s); m / z (ES+) [M+Na]+= 501.2.Intermediate 11d:tert-Butyl 3 -( 1 -tert-butoxy carbonyl -4-piperidyl)-6-(2,4-dioxohexahydropyrimidin- 1 -yl)indole- 1 - carboxylate

[0583] Prepared in an analogous method to intermediate 3g starting from Intermediate 11c (1.10 g, 2.29 mmol). Purification by FSC (gradient: 0-5% MeOH in DCM) gave the title compound (1.03 g, 88 %) as a pale yellow solid. ¹H NMR (DMSO-d6): δ 1.41 (9H, s), 1.44 - 1.54 (2H, m), 1.60 (9H, s), 1.86 - 1.97 (2H, m), 2.73 (2H, t), 2.82 - 3.02 (3H, m), 3.82 (2H, t), 4.02 - 4.12 (2H, m), 7.21 (1H, dd), 7.42 (1H, s), 7.66 (1H, d), 8.01 (1H, d), 10.35 (1H, s); m / z (ES+) [M+Na]+= 535.3.Intermediate 11e:1-[3-(4-Piperidyl)-1H-indol-6-yl]hexahydropyrimidine-2,4-dione

[0584] Intermediate 11d (1.00 g, 1.95 mmol) was dissolved in trifluoroethanol (8 mL) and sealed into a microwave tube. The mixture was heated to 150°C for lOh in the microwave reactor then cooled to r.t. and concentrated under reduced pressure. Purification by RPC (gradient: 5-15% MeCN in water with 0.1% FA) gave the title compound (0.480 g, 69 %) in the form of a formate salt as a white solid. ’H NMR: 1.74 -1.89 (2H, m), 1.97 - 2.06 (2H, m), 2.71 (2H, t), 2.89 - 3.06 (3H, m), 3.24 - 3.30 (2H, m), 3.77 (2H, t), 6.92 (1H, dd), 7.15 (1H, d), 7.27 (1H, d), 7.59 (1H, d), 10.25 (1H, br s), 10.93 (1H, s) (piperidine NH protons not observed); m / z (ES+) [M+H]+= 313.0.Intermediate Ilf:tert-Butyl 4-[[4-[6-(2,4-dioxohexahydropyrimidin-1-yl)-1H-indol-3-yl]-1-piperidyl]methyl]piperidine-1-carboxylate

[0585] Sodium acetate (39.9 mg, 0.49 mmol) was added to a stirred slurry of Intermediate 11e (30.35 mg, 0.10 mmol) in DCM (3 mL) and / PrOH (1 mL). tert-Butyl 4-formylpiperidine-l-carboxylate (41.4 mg, 0.19 mmol) was then added. The mixture was stirred at r.t. for 20 min before NaBH(OAc)3 (61.8 mg, 0.29 mmol) was added. The resulting slurry was stirred at r.t for 16h then concentrated. Purification by FSC (gradient: 0-20% MeOH in DCM) gave the title compound (49 mg, 99 %) as a white solid, m / z (ES+) [M+H]+= 511.2.Intermediate 11g:1-[3-[1-(4-Piperidylmethyl)-4-piperidyl]-1H-indol-6-yl]hexahydropyrimidine-2,4-dione

[0586] Prepared in an analogous method to Intermediate lb starting from Intermediate 11f (0.049 g, 0.10 mmol). The solution was concentrated under reduced pressure to give the title compound in the form of a bis-hydrochloride salt (0.042 g, 98 %) as a white solid, m / z (ES+) [M+H]+= 410.3.Example 111-[3-[1-[[1-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8-yl]benzoyl]-4-piperidyl]methyl]-4-piperidyl]-1H-indol-6-yl]hexahydropyrimidine-2,4-dione

[0587] Prepared in an analogous method to EXAMPLE 1 starting from Intermediate Ij (0.042 g, 0.1 mmol) and Intermediate 11g (0.041 g, 0.10 mmol). Purification by RPC (gradient: 0-40% MeCN in water with 0.1% FA) gave the title compound in the form of a formate salt (0.044 g, 54 %) as a white solid. ’H NMR (DMSO-d6): 5 1.01-1.15 (2H, m), 1.65-1.81 (4H, m), 1.82-2.01 (5H, m), 2.11-2.37 (6H, m), 2.71 (2H, t), 2.77-2.93 (3H, m), 3.00-3.12 (4H, m), 3.24-3.28 (2H, m), 3.76 (2H, t), 3.92-4.26 (2H, m), 4.49 (2H, br s), 5.95 (2H, s), 6.80-6.95 (5H, m), 7.13 (1H, d), 7.18-7.29 (4H, m), 7.46 (1H, s), 7.52 (1H, d), 7.86-7.92 (1H, m), 10.24 (1H, s), 10.84 (1H, br s), 14.00 (1H, br s); m / z (ES+) [M+H]+= 809.4.Example 12Intermediate 12a:tert-Butyl 8-(3-fluoro-4-methoxycarbonyl-phenyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylateBoc—Me

[0588] Prepared in an analogous method to Intermediate 3a starting from methyl 4-bromo-2-fluorobenzoate (2.00 g, 8.58 mmol). Purification by FSC (gradient: 0-20% EtOAc in petroleum ether) gave the title compound (2.54 g, 81 %) as an off-white solid. ’H NMR (CDCh): 5 1.46 (9H, s), 1.85-1.95 (2H, m), 2.02-2.08 (2H, m), 3.19 (2H, dd), 3.55-3.72 (1H, m), 3.77-3.89 (1H, m), 3.89 (3H, s), 4.20-4.25 (2H, m), 6.42 (1H, dd), 6.52 (1H, dd), 7.84 (1H, t); m / z (ES+) [M+H]+= 365.2.Intermediate 12b:Methyl 4-(3,8-diazabicyclo[3.2. l]octan-8-yl)-2 -fluoro-benzoate

[0589] Prepared in an analogous method to Intermediate 3b starting from Intermediate 12a (2.5 g, 6.86 mmol). Concentration under reduced pressure gave the title compound in the form of a hydrochloride salt (1.70 g, 94 %) as a white solid, m / z (ES+) [M+H]+= 265.1.Intermediate 12c:Methyl 4-[3-(3-amino-6-chloro-pyridazin-4-yl)-3, 8-diazabicyclo[3.2. l]octan-8-yl]-2 -fluoro-benzoate

[0590] A mixture of Intermediate 12b (1.20 g, 4.54 mmol), 4-bromo-6-chloropyridazin-3-amine (0.946 g, 4.54 mmol), DIPEA (3.2 mL, 18.16 mmol) and DMA (6.0 mL) was heated to 120°C for 3h under N2. After cooling to r.t. the mixture was diluted with water (30 mL) and the resulting solid was collected by filtration. The solid was suspended in MeOH (10 mL), gently warmed with stirring, then cooled to r.t. The solid was then collected by filtration and washed with ice cold MeOH. The solid was dried under reduced pressure to give the title compound (1.39 g, 78 %) as a tan solid. ’H NMR (DMSO-t / 6): 5 1.89-2.00 (2H, m), 2.11-2.20 (2H, m), 2.88 (2H, brd), 3.19 (2H, br d), 3.75 (3H, s), 4.48-4.56 (2H, m), 5.84 (2H, s), 6.72-6.77 (2H, m), 6.88 (1H, s), 7.66-7.72 (1H, m);19F NMR (DMSO-d6): δ -107.62 (1F, s); m / z (ES+) [M+H]+= 391.8.Intermediate 12d:Methyl 4-[3-[3-amino-6-(2 -hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2. l]-octan-8-yl]-2 -fluorobenzoateNH2F

[0591] Intermediate 12c (2.00 g, 5.10 mmol) was added to 2-hydroxyphenylboronic acid (0.845 g, 6.13 mmol) and Cs₂CO₃ (3.33 g, 10.21 mmol), and Pd(dppf)Cl₂ (0.373 g, 0.51 mmol) in 1,4-dioxane (40 mL) and water (4.0 mL). The resulting mixture was stirred at 100°C for 2h then cooled to r.t. and diluted with EtOAc (300 mL). The mixture was washed with brine (150 mL). The organic layer was dried (Na₂SO₄) and concentrated. Purification by FSC (gradient: 0-20% MeOH in DCM) gave the title compound (2.00 g, 87 %) as a red oil. m / z (ES+) [M+H]+= 450.2.Intermediate 12e:4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-fluoro-benzoic acidNH2F

[0592] Prepared in an analogous method to Intermediate Ij starting from Intermediate 12d (2.00 g, 4.45 mmol). Purification by FSC (gradient: 0-100% MeCN in water with 0.1% FA) gave the title compound (1.50 g, 77 %) as agrey solid. ¹H NMR (DMSO-d6): δ 1.92-2.07 (2H, m), 2.14-2.26 (2H, m), 3.04 (2H, br d), 3.24-3.28 (2H, m), 4.51-4.59 (2H, m), 5.97 (2H, s), 6.70-6.79 (2H, m), 6.79-6.90 (2H, m), 7.18-7.24 (1H, m), 7.49 (1H, s), 7.66-7.73 (1H, m), 7.89 (1H, br d), 12.51 (1H, s), 13.90 (1H, s); m / z (ES+) [M+H]+= 436.1.Example 121-[1-[1-[[1-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8-yl]-2-fluoro-benzoyl]-4-piperidyl]methyl]-4-piperidyl]indol-5-yl]hexahydropyrimidine-2,4-dione

[0593] Prepared in an analogous method to EXAMPLE 3 starting from Intermediate 12e (21 mg, 0.05 mmol) and Intermediate 3j (20 mg, 0.05 mmol). Purification by RP-HPLC (gradient: 13-23% MeCN in water with 0.1% FA) gave the title compound in the form of a formate salt (6.9 mg, 17 %) as a white solid.¹H NMR (DMSO-d6): δ 0.92-1.14 (2H, m), 1.62-2.06 (9H, m), 2.11-2.34 (6H, m), 2.66-2.85 (3H, m), 2.94-3.14 (5H, m), 3.22-3.28 (2H, m), 3.49-3.63 (1H, m), 3.77 (2H, t), 4.27-4.58 (4H, m), 5.99 (2H, s), 6.46 (1H, d), 6.74-6.91 (4H, m), 7.07 (1H, dd), 7.15-7.29 (2H, m), 7.46 (1H, d), 7.49-7.59 (3H, m), 7.93 (1H, dd), 10.27 (1H, s), 14.10 (1H, s); m / z (ES+) [M+H]+= 827.5.EXAMPLE 13Intermediate 13a:tert-Butyl 8-(3-chloro-4-methoxycarbonyl-phenyl)-3,8-diazabicyclo[3.2.1] octane -3 -carboxylateCl

[0594] Prepared in an analogous method to Intermediate If starting from methyl 4-bromo-2-chlorobenzoate (3 g, 12.02 mmol). Purification by FSC (gradient: 0-30% EtOAc in petroleum ether) gave the title compound (2.80 g, 61 %) as a yellow solid. ’H NMR (DMSO-t / 6): 5 1.39 (9H, s), 1.70 (2H, d), 1.84-2.03 (2H, m), 2.94 (1H, d), 3.11 (1H, t), 3.63 (2H, d), 3.76 (3H, s), 4.44 (2H, s), 6.82-6.90 (1H, m), 6.97 (1H, d), 7.74 (1H, d); m / z (ES+) [M+H]+= 381.2.Intermediate 13b:Methyl 2-chloro-4-(3,8-diazabicyclo[3.2. l]octan-8-yl)benzoateClHC1©'1-C5- - ' L.

[0595] Prepared in an analogous method to Intermediate 3b starting from Intermediate 13a (2.90 g, 7.61 mmol). Concentration under reduced pressure gave the title compound in the form of a hydrochloride salt (1.60 g, 75 %) as a white solid, m / z (ES+) [M+H]+= 281.5.Intermediate 13c:Methyl 4-[3 -(3 -amino-6-chloro-pyridazin-4-yl)-3, 8 -diazabicyclo [3.2.1 ]octan-8-yl] -2 -chloro-benzoate NH2CI

[0596] Prepared in an analogous method to Intermediate Ih starting from Intermediate 13b (1.8 g, 6.41 mmol) to give the title compound (1.200 g, 46 %) as a yellow solid. ’H NMR (DMSO-t / 6): 5 1.89-2.07 (2H, m), 2.16 (2H, d), 2.89 (2H, d), 3.20 (2H, d), 3.71 (s, 3H), 4.55 (2H, d), 5.85 (2H, s), 6.83-7.05 (3H, m), 7.75 (IH, d); m / z (ES+) [M+H]+= 409.2, 410.0.Intermediate 13d:Methyl 4-[3 -[3 -amino-6-(2-hydroxyphenyl)pyridazin-4-yl] -3, 8 -diazabicyclo [3.2.1] -octan-8-yl] -2 -chlorobenzoate

[0597] Intermediate 13c (400 mg, 0.98 mmol) was added to 2-hydroxyphenylboronic acid (0.853 g, 6.19 mmol), sodium acetate (241 mg, 2.94 mmol) and Pd(dppf)Cl2(0.717 g, 0.10 mmol) in 1,4-dioxane (2.0 mL) and water (0.2 mL). The mixture was stirred at 100°C for 4h and then cooled to r.t. The mixture was diluted with EtOAc (10 mb) and then filtered through celite. The filtrate was concentrated. Purification by RPC (gradient: 0-100% MeCN in water) gave the title compound (0.170 g, 37 %) as a white solid. ’H NMR (DMSO-d6): 5 2.04 (2H, m), 2.20 (2H, m), 3.04 (2H, d), 3.30-3.30 (m, 5H), 4.57 (2H, s), 5.98 (2H, s), 6.80-6.94 (3H, m), 6.98 (IH, d), 7.16-7.28 (lH, m), 7.50 (IH, s), 7.77 (IH, d), 7.91 (IH, d) (-OH proton not observed); m / z (ES+) [M+H]+= 466.3.Intermediate 13e:4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-chloro-benzoic acid

[0598] Prepared in an analogous method to Intermediate Ij starting from Intermediate 13d (160 mg, 0.34 mmol) to give the title compound (75 mg, 48 %) as a white solid. ’H NMR (DMSO-t / 6): 5 1.97-2.0 (2H, m), 2.07 (1H, s), 2.12-2.22 (2H, m), 3.04 (2H, d), 3.26 (1H, s), 3.30 (2H, s), 5.99 (2H, s), 6.79-7.09 (4H, m), 7.22 (1H, t), 7.50 (1H, s), 7.76 (1H, d), 7.90 (1H, d), 14.13 (1H, s) (-CO2H proton not observed); m / z (ES+) [M+H]+= 452.3.Example 131-[1-[1-[[1-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8-yl]-2-chloro-benzoyl]-4-piperidyl]methyl]-4-piperidyl]indol-5-yl]hexahydropyrimidine-2,4-dione

[0599] Prepared in an analogous method to EXAMPLE 3 starting from Intermediate 13e (22 mg, 0.05 mmol) and Intermediate 3j (20 mg, 0.05 mmol). Purification by RP-HPLC gradient: 12-23% MeCN in water with 0.1% FA) gave the title compound (7.6 mg, 17 %) in the form of a formate salt as a white solid. ’H NMR (DMSO-d6): 50.89 - 1.25 (2H, m), 1.60 - 2.05 (10H, m), 2.08 - 2.25 (6H, m), 2.69 - 2.76 (3H, m), 2.95 - 3.10 (5H, m), 3.26 - 3.31 (2H, m), 3.77 (2H, t), 4.27 - 4.43 (1H, m), 4.43 - 4.59 (3H, m), 5.98 (2H, s), 6.45 (1H, d), 6.82 - 6.93 (3H, m), 6.98 - 7.03 (1H, m), 7.04 - 7.18 (2H, m), 7.23 (1H, s), 7.46 (1H, d), 7.50 - 7.57 (3H, m), 7.93 (1H, d), 10.27 (1H, s) (-OH proton not observed); m / z (ES+) [M+H]+= 843.4.EXAMPLE 14Intermediate 14a:tert- Butyl 4-(4-bromo-3 -methyl -indol- 1 -yl)piperidine- 1 -carboxylateMe BrBod

[0600] Prepared in an analogous method to Intermediate 1 a starting from 4-bromo-3-methyl-1H-indole (0.599 g, 2.85 mmol). Purification by FSC (gradient: 0-35% EtOAc in hexanes) gave the title compound (0.314 g, 28 %) as an off-white foam. ¹H NMR (DMSO-d6): δ 1.42 (9H, s), 1.71-1.81 (2H, m), 1.84-1.91(2H, m), 2.44 (3H, d), 2.80-3.08 (2H, m), 4.06-4.17 (2H, m), 4.47-4.55 (1H, m), 6.95-7.02 (1H, m), 7.15 (1H, d), 7.39 (1H, s), 7.53 (1H, d); m / z (ES+) [M-tBu+2H]+= 336.6.Intermediate 14b:tert-Butyl 4-[4-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-indol-1-yl]piperidine-1-carboxylate oBod

[0601] Prepared in an analogous method to Intermediate 4b starting from Intermediate 14a. Purification by FSC (gradient: 0-100% EtOAc in hexanes) gave the title compound (15 mg, 4 %) as an off-white solid. ¹H NMR (DMSO-d6): δ 1.42 (9H, s), 1.73-1.84 (2H, m), 1.84-1.95 (2H, m), 2.20 (3H, d), 2.75 (2H, t), 2.86-3.06 (2H, m), 3.57-3.63 (1H, m), 3.76-3.85 (1H, m), 4.02-4.16 (2H, m), 4.49-4.56 (1H, m), 6.90 (1H, d), 7.09-7.15 (1H, m), 7.28 (1H, s), 7.49 (1H, d), 10.33 (1H, s); m / z (ES+) [M-tBu+2H]+= 370.8.Intermediate 14c:1 -[3-Methyl- 1 -(4-piperidyl)indol-4-yl]hexahydropyrimidine-2, 4-dioneoTFA

[0602] Prepared in an analogous method to Intermediate 4c starting from Intermediate 14b (15 mg, 0.04 mmol) to give the title compound in the form of a trifluoroacetate salt (15 mg, 100 %) as a light pink solid after trituration with diethyl ether, m / z (ES+) [M+H]+= 326.8.Intermediate 14d:tert-Butyl 4-[[4-[4-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-indol-1-yl]-1-piperidyl]methyl]-4-fluoro-piperidine-1-carboxylateo

[0603] A mixture of tert-butyl 4-fluoro-4-formyl -piperidine- 1 -carboxylate (16 mg, 0.07 mmol), sodium acetate (14 mg, 0.17 mmol), and Intermediate 14c (15 mg, 0.03 mmol) in THF (0.80 mb) was stirred at 60°C for 10 min and then NaBH(OAc)₃ (14 mg, 0.07 mmol) was added. After 20 min additional tertbutyl 4-fluoro-4-formyl -piperidine- 1 -carboxylate (18 mg, 0.08 mmol) was added and then after stirring for 15 min additional NaBH(OAc)₃ (18 mg, 0.09 mmol) was added. After 0.5h the mixture was cooled to r.t. and then diluted with DCM (5 mb) and saturated aq. Na₂CO₃ solution (1 mL). The organic layer was separated and the aqueous layer extracted with DCM (2 × 5 mL). The combined organic solutions were dried (Na₂SO₄) and concentrated. Purification by FSC (gradient: 0-100% EtOAc in hexanes then 0-15% MeOH in DCM) gave the title compound (13 mg, 71 %) as a white solid. ¹H NMR (DMSO-d6): δ 1.40 (9H, s), 1.51-1.66 (2H, m), 1.78-2.00 (6H, m), 2.21 (3H, s), 2.34-2.43 (2H, m), 2.60 (2H, d), 2.75 (2H, t), 2.95-3.12 (4H, m), 3.56-3.64 (1H, m), 3.67-3.76 (2H, m), 3.76-3.88 (1H, m), 4.24-4.34 (1H, m), 6.89 (1H, d), 7.07-7.14 (1H, m), 7.27 (1H, s), 7.45 (1H, d), 10.33 (1H, s);19F NMR (DMSO-d6): δ -157.98 (1F, s); m / z (ES+) [M+H]+= 542.0.Intermediate 14e:1-[1-[1-[(4-Fluoro-4-piperidyl)methyl]-4-piperidyl]-3-methyl-indol-4-yl]hexahydro-pyrimidine-2,4-dione

[0604] Prepared in an analogous method to Intermediate 4e starting from Intermediate 14d (12 mg, 0.02 mmol) to give the title compound in the form of a bis-trifluoroacetate salt (15 mg, 100 %) as a light pink solid after trituration with diethyl ether, m / z (ES+) [M+H]+= 442.0.Example 141-[1-[1-[[1-[4-[3-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8-yl]benzoyl]-4-fluoro-4-piperidyl]methyl]-4-piperidyl]-3-methyl-indol-4-yl]hexahydro-pyrimidine-2,4-dione

[0605] Prepared in an analogous method to Example 1 starting from Intermediate Ij (8.2 mg, 0.02 mmol), Intermediate 14e (15 mg, 0.02 mmol). Purification by RPC (gradient: 5-25% MeCN in water with0.1% FA) gave the title compound in the form of a formate salt (6.9 mg, 41 %) as a white solid. ’H NMR (DMSO-d6): 5 1.62-1.78 (2H, m), 1.81-2.01 (8H, m), 2.14-2.24 (5H, m), 2.32-2.44 (2H, m), 2.61 (2H, d), 2.75 (2H, t), 2.98-3.05 (2H, m), 3.08 (2H, br d), 3.17-3.23 (2H, m), 3.24-3.28 (2H, m), 3.55-3.64 (1H, m), 3.76-3.85 (1H, m), 3.85-4.03 (2H, m), 4.20-4.35 (1H, m), 4.46-4.54 (2H, m), 5.95 (2H, s), 6.81-6.91 (3H, m), 6.93 (2H, d), 7.06-7.14 (1H, m), 7.19-7.24 (1H, m), 7.26 (1H, s), 7.30 (2H, d), 7.43-7.47 (2H, m), 7.89 (1H, dd), 10.33 (1H, s), 14.11 (1H, br s);19F NMR (DMSO-d6): δ -157.62 (1F, s); m / z (ES+) [M+H]+= 841.4.EXAMPLE 15Intermediate 15a:tert-Butyl 4-[2-[4-[4-(2,4-dioxohexahydropyrimidin-1-yl)indol-1-yl]-1-piperidyl]-ethyl]piperidine-1-carboxylate

[0606] To a solution of Intermediate 5c (2.00 g, 6.40 mmol), tert-butyl 4-(2-oxoethyl)piperidine-l-carboxylate (1.892 g, 8.32 mmol) and AcOH (1.100 mL, 19.21 mmol) in DCM (60 mL) was added NaBH(OAc)₃ (5.43 g, 25.61 mmol). The mixture was stirred at r.t. for 3h then diluted with sat. aq. NaHCO₃ (100 mL) and DCM (300 mL). The organic layer was separated, sequentially with water (2 × 100 mL) and brine (50 mL), and then dried over Na₂SO₄ and concentrated. Purification by FSC (0-4% MeOH in DCM) gave the title compound (2.00 g, 60 %) as a white solid. ’H NMR (DMSO-c / 6): 5 1.01 (2H, m), 1.40 (9H, s), 1.43 (3H, d), 1.59-1.70 (2H, m), 1.89-2.07 (4H, m), 2.15 (2H, s), 2.39 (2H, s), 2.77 (4H,t), 3.02 (2H, d), 3.78 (2H, m), 3.93 (2H, d), 4.36 (1H, d), 6.42 (1H, d), 6.97 (1H, d), 7.15 (1H, m), 7.46-7.59 (2H, m), 10.34 (1H, s); m / z (ES+) [M+Na]+= 546.4.Intermediate 15b:1-[1-[1-[2-(4-Piperidyl)ethyl]-4-piperidyl]indol-4-yl]hexahydropyrimidine-2,4-dione

[0607] Intermediate 15a (1.90 g, 3.63 mmol) was stirred in FA (50 mL) at 50°C for 4h then cooled to r.t. The solvent was removed under reduced pressure. The residue was basified with saturated aq. NaHCOs and then concentrated under reduced pressure. Purification by RPC (gradient: 0-25% MeCN in water) gave the title compound (0.671 g, 44 %) as a white solid. ’H NMR (DMSO-d6): δ 1.04 (2H, m), 1.38 (3H, s), 1.61 (2H, d), 1.95 (4H, m), 2.13 (2H, m), 2.30-2.48 (4H, m), 2.76 (2H, m), 2.91 (1H, d), 3.00 (2H, d), 3.77 (2H, m), 3.93 (1H, s), 4.36 (1H, m), 6.41 (1H, d), 6.95 (1H, d), 7.14 (1H, m), 7.47-7.55 (2H, m), 10.32 (1H, s) (-NH proton not observed); m / z (ES+) [M+H]+= 424.2.EXAMPLE 15l-[l-[l-[2-[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8- yl]benzoyl]-4-piperidyl]ethyl]-4-piperidyl]indol-4-yl]hexahydropyrimidine-2, 4-dione

[0608] Prepared in an analogous method to EXAMPLE 1 starting from Intermediate Ij (9.86 mg, 0.02 mmol) and Intermediate 15b (10 mg, 0.02 mmol) Purification by RPC (gradient: 10-50% MeCN in water with 0.1% FA) gave the title compound in the form of a formate salt (8.8 mg, 45 %) as a yellow solid. ’H NMR (DMSO-d6): δ 1.06-1.18 (2H, m), 1.40-1.47 (2H, m), 1.48-1.55 (1H, m), 1.67-1.75 (2H, m), 1.93-2.02 (7H, m), 2.19 (5H, m), 2.39-2.44 (2H, m), 2.74-2.79 (3H, m), 3.02-3.05 (2H, m), 3.08-3.12 (2H, m), 3.28-3.31 (2H, m), 3.75-3.80 (3H, m), 4.36-4.41 (1H, m), 4.47-4.53 (2H, m), 5.89-6.02 (2H, m), 6.40-6.43 (1H, m), 6.83-6.88 (2H, m), 6.91-6.95 (2H, m), 6.95-6.98 (1H, m), 7.13-7.17 (1H, m), 7.20-7.24 (1H, m), 7.25-7.30 (2H, m), 7.46-7.55 (4H, m), 10.29-10.35 (1H, m), 12.87-14.71 (1H, m); m / z (ES+) [M+H]+= 823.5.EXAMPLE 16Intermediate 16a: / / 7- Butyl 6-[[4-[4-(2,4-dioxohexahydropyrimidin- 1 -yl)indol- 1 -yl]- 1 -piperidyl] -methyl] -2- azaspiro[3.3]heptane-2 -carboxylate

[0609] NaBH(OAc)3 (678 mg, 3.20 mmol) was added to tert-butyl 6-formyl-2-azaspiro[3.3]heptane-2-carboxylate (361 mg, 1.60 mmol) and Intermediate 5c (250 mg, 0.80 mmol) in THF (4 mL). The resulting mixture was stirred at r.t. for Ih. The mixture was diluted with DCM (100 mL), and washed sequentially with water (40 mL) and brine (40 mL). The organic layer was separated and dried (Na2SO4) andconcentrated. Purification by FSC (gradient: 0-20% MeOH in DCM) gave the title compound (0.300 g, 72 %) as a yellow oil. 'HNMR (DMSO-d6): δ 1.37 (9H, s), 1.83-1.89 (7H, m), 2.10-2.16 (8H, m), 2.68-2.75 (2H, m), 3.75-3.81 (4H, m), 4.46-4.53 (3H, m), 6.45 (1H, d), 7.05-7.11 (1H, m), 7.45 (1H, d), 7.51-7.58 (2H, m), 10.27 (1H, s); m / z (ES+) [M+H]+= 522.4.Intermediate 16b:l-[l-[l-(2-Azaspiro[3.3]heptan-6-ylmethyl)-4-piperidyl]indol-4-yl]hexahydro-pyrimidine-2, 4-dione

[0610] Prepared in an analogous method to Intermediate 3j starting from Intermediate 16a (290 mg, 0.56 mmol. Purification by RPC (gradient: 0-100% MeCN in water with 0.4% ammonium formate) gave the title compound (0.200 g, 77 %) as a yellow oil. m / z (ES+) [M+H]+= 422.4.EXAMPLE 16l-[l-[l-[[2-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8- yl]benzoyl]-2-azaspiro[3.3]heptan-6-yl]methyl]-4-piperidyl]indol-4-yl]hexahydropyrimidine-2, 4-dione

[0611] Prepared in an analogous method to Example 1 starting from Intermediate Ij (69 mg, 0.17 mmol) and Intermediate 16b (100 mg, 0.24 mmol). Purification by RP-HPLC (gradient: 11-22% MeCN in water with 0.1% FA) gave the title compound (20 mg, 10 %) in the form of a formate salt as a white solid. 'HNMR (DMSO-d6): δ 1.87-2.02 (8H, m), 2.06-2.23 (4H, m), 2.29-2.33 (4H, m), 2.73-2.79 (2H, m), 3.00-3.09 (4H, m), 3.23-3.27 (3H, m), 3.75-3.81 (2H, m), 3.91-4.06 (2H, m), 4.24 (1H, s), 4.35-4.45 (2H, m), 4.53 (2H, d), 5.98 (2H, s), 6.38-6.44 (1H, m), 6.81-6.99 (5H, m), 7.13-7.25 (2H, m), 7.45-7.57 (5H, m), 7.86-7.93 (1H, m), 10.34 (1H, s) (-OH proton not observed); m / z (ES+) [M+H]+= 821.4.EXAMPLE 17Intermediate 17a:(5-Bromo-3-cyclopropyl-lH-indol-2-yl)-trimethyl-silane

[0612] 4-Bromo-2 -iodoaniline (0.4 g, 1.34 mmol), 2-cyclopropylethynyl(trimethyl)silane (0.371 g, 2.69 mmol), NaHCO3(0.356 g, 3.36 mmol), LiCl (0.063 g, 1.48 mmol), and bis(triphenylphosphine)palladium(II) dichloride (0.094 g, 0.13 mmol) in DMF (4 mL) were degassed at r.t.with N2. The mixture was stirred at 100°C for lOh then cooled to r.t. and concentrated. Purification by FSC (gradient: 0-30% EtOAc in hexanes) gave the title compound (0.310 g, 75 %) as an off-white solid. ’H NMR (CD2CI2): 50.41-0.46 (9H, m), 0.70-0.77 (2H, m), 0.90-0.99 (2H, m), 1.85-1.93 (1H, m), 7.17-7.25 (2H, m), 7.80-7.85 (1H, m), 7.96-8.12 (1H, m); m / z (ES+) [M+H]+= 308.1.Intermediate 17b:5-Bromo-3-cyclopropyl-1H-indole

[0613] 1.0 M tetra-w-butylammonium fluoride in THF (1.343 mL, 1.34 mmol) was added to a stirred solution of Intermediate 17a (0.310 g, 1.06) in THF (3 mL). The mixture was stirred at 70°C for 3h then cooled to r.t. and concentrated. Purification by FSC (gradient: 0-30% EtOAc in hexanes) gave the title compound (0.210 g, 66 %) as a white solid. ¹H NMR (CD2Cl2): δ 0.56-0.65 (2H, m), 0.80-0.98 (2H, m), 1.81-1.92 (1H, m), 6.93 (1H, dd), 7.24 (2H, s), 7.85 (1H, s), 8.04 (1H, br s); m / z (ES ) [M-H]’ = 233.9.Intermediate 17c: / / 7- Butyl 4-(5 -bromo-3 -cyclopropyl -indol- 1 -yl)piperidine- 1 -carboxylate

[0614] Prepared in an analogous method to Intermediate la starting from Intermediate 17b (0.248 g, 0.89 mmol). Purification by FSC (gradient: 10-100% DCM in hexanes) gave the title compound (0.140 g, 37 %) as a white solid. ¹H NMR (CD2Cl2): δ 0.55-0.62 (2H, m), 0.84-0.91 (2H,m), 1.47 (9H, s), 1.80-1.91 (3H, m), 1.94-2.03 (2H, m), 2.88 (2H, br s), 4.28 (3H, ddt), 6.91 (1H, s), 7.1-7.28 (2H, m), 7.82 (1H, d); m / z (ES+) [M-Boc+2H]+= 319.1.Intermediate 17d:tert-Butyl 4 - [ 3 -cyclopropyl-5 -(2,4-dioxohexahydropyrimidin- 1 -yl)indol- 1 -yl] -piperidine- 1 -carboxylate

[0615] Prepared in an analogous method to Intermediate 2b starting from Intermediate 17c (0.140 g, 0.33 mmol). Purification by FSC (gradient: 0-10% MeOH in DCM) gave the title compound (0.112 g, 74 %)asapale yellow solid. ’HNMR (CD2C12): 50.60 (2H,brd), 0.86-0.90 (2H,m), 1.50-1.55 (9H, m), 1.86-1.93 (3H, m), 1.97-2.01 (2H, m), 2.81-2.85 (2H, m), 2.85-2.98 (2H, m), 3.88 (2H, t), 4.23-4.38 (3H, m),6.95 ( 1H, s), 7.10 (1H, br d), 7.34-7.38 (1H, m), 7.42 (1H, br s), 7.58 (1H, s); m / z (ES+) [M-Bu+2H] = 397.2.Intermediate 17e:l-[3-Cyclopropyl-l-(4-piperidyl)indol-5-yl]hexahydropyrimidine-2, 4-dioneH7FA H

[0616] Prepared in an analogous method to Intermediate 4c starting from Intermediate 17d (140 mg, 0.31 mmol). Concentration under reduced pressure gave the title compound in the form of a trifluoroacetate salt (0.120 g, 83 %) as a pale yellow solid, m / z (ES+) [M+H]+= 353.3.Intermediate 17f: / - Butyl 4-[[4-[3-cyclopropyl-5-(2,4-dioxohexahydropyrimidin-l-yl)indol-l-yl]-l-piperidyl]methyl]-4- fluoro-piperidine- 1 -carboxylate

[0617] Intermediate 17e (0.047 g, 0.1 mmol) and tert-butyl 4-fhioro-4-formylpiperidine-l -carboxylate (0.046 g, 0.20 mmol) in DCM (2 mL) and DMF (0.2 mL) were stirred at r.t. for 2h. NaBH(OAc)3(0.032 g, 0.15 mmol) was added in one portion and the mixture was stirred at r.t. for 16h, then concentrated. Purification by FSC (gradient: 0-10% MeOH in DCM) gave the title compound (0.03 g, 53 %) as a pale yellow solid, m / z (ES+) [M+H]+=568.3.Intermediate 17g:l-[3-Cyclopropyl-l-[l-[(4-fhioro-4-piperidyl)methyl]-4-piperidyl]indol-5-yl]-hexahydropyrimidine-2,4- dione

[0618] Prepared in an analogous method to Intermediate 4e starting from Intermediate 17f (0.028 g, 0.05 mmol). Concentration under reduced pressure gave the title compound in the form of a bis-trifluoroacetate salt (0.031 g, 89 %) as a pale yellow solid, m / z (ES+) [M+H]+=468.2.EXAMPLE 17l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8- yl]benzoyl]-4-fhioro-4-piperidyl]methyl]-4-piperidyl]-3-cyclopropyl-indol-5-yl]hexahydro-pyrimidine- 2,4-dione

[0619] Prepared in an analogous method to EXAMPLE 1 starting from Intermediate Ij (13 mg, 0.03 mmol) and Intermediate 17g (0.021 g, 0.03 mmol). Purification by RPC (gradient: 5-30% MeCN in water with 0.1% FA) gave the title compound in the form of a formate salt (13 mg, 50 %) as a white solid. ’H NMR (DMSO-d6): δ 0.56-0.61 (2H, m), 0.82 (2H, s), 1.64-1.77 (2H, m), 1.79-2.01 (10H, m), 2.15-2.21 (2H, m), 2.33-2.38 (2H, m), 2.42-2.46 (2H, m), 2.58-2.65 (2H, m), 2.70-2.74 (2H, m), 2.98-3.03 (2H, m), 3.07-3.12 (2H, m), 3.12-3.21 (2H, m), 3.32-3.39 (1H, m), 3.76 (2H, t), 4.20-4.29 (1H, m), 4.47-4.54 (2H, m), 5.95 (2H, s), 6.81-6.89 (2H, m), 6.93 (2H, d), 7.00-7.07 (1H, m), 7.17-7.25 (2H, m), 7.30 (2H, d), 7.42-7.51 (3H, m), 7.90 (1H, s), 10.22 (1H, s), 13.84-14.69 (1H, m); m / z (ES+) [M+H]+= 867.4.EXAMPLE 18l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8- yl]benzoyl]-4-fhioro-4-piperidyl]methyl]-4-piperidyl]-3-methyl-indol-5-yl]hexahydro-pyrimidine-2,4- dioneMe

[0620] Prepared in an analogous method to EXAMPLE 1 starting from Intermediate Ij (18 mg, 0.04 mmol) and Intermediate 4e (35 mg, 0.05 mmol). Purification by RPC (gradient: 5-25% MeCN in water with 0.1% FA) gave the title compound in the form of a formate salt (14 mg, 39 %) as a white solid. ’H NMR (DMSO-d6): δ 1.61-1.80 (2H, m), 1.82-2.01 (8H, m), 2.13-2.20 (2H, m), 2.21 (3H, s), 2.32-2.42 (2H, m), 2.60 (2H, d), 2.71 (2H, t), 2.98-3.05 (2H, m), 3.08 (2H, br d), 3.15-3.23 (2H, m), 3.28 (2H, br d), 3.75 (2H, t), 3.79-4.07 (2H, m), 4.20-4.29 (1H, m), 4.44-4.54 (2H, m), 5.95 (2H, s), 6.80-6.89 (2H, m), 6.93 (2H, d),7.03 (1H, dd), 7.16-7.26 (1H, m), 7.27-7.32 (3H, m), 7.38 (1H, d), 7.45 (1H, d), 7.47 (1H, s), 7.89 (1H, dd), 10.23 (1H, s), 14.11 (1H, br s);19F NMR (DMSO-d6): δ -157.59 (IF, s); m / z (ES+) [M+H]+= 841.4.EXAMPLE 19l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8-yl]-2- fluoro-benzoyl]-4-fluoro-4-piperidyl]methyl]-4-piperidyl]-3-methyl-indol-5-yl]hexahydro-pyrimidine- 2,4-dione

[0621] Prepared in an analogous method to EXAMPLE 1 starting from Intermediate 12e (27 mg, 0.06 mmol) and Intermediate 4e (48 mg, 0.07 mmol). Purification by RPC (gradient: 5-30% MeCN in water with 0.1% FA) gave the title compound in the form of a formate salt (25 mg, 46 %) as a white solid. ’H NMR (DMSO-d6): 5 1.54-1.75 (2H, m), 1.80-2.00 (8H, m), 2.16-2.20 (2H, m), 2.21 (3H, s), 2.32-2.42 (2H, m), 2.61 (2H, d), 2.71 (2H, t), 2.98-3.14 (5H, m), 3.21-3.29 (3H, m), 3.38-3.49 (1H, m), 3.75 (2H, t), 4.15-4.31 (2H, m), 4.44-4.55 (2H, m), 5.95 (2H, s), 6.75-6.89 (4H, m), 7.03 (1H, dd), 7.17-7.25 (2H, m), 7.29 (1H, s), 7.38 (1H, d), 7.45 (1H, d), 7.49 (1H, s), 7.90 (1H, dd), 10.22 (1H, s), 14.09 (1H, br s);19F NMR (DMSO-d6): -158.08 (IF, s), -113.88 (IF, s); m / z (ES+) [M+H]+= 859.4EXAMPLE 20Intermediate 20a: / / 7- Butyl 4-[ [4 - [ 3 -cyclopropyl-5 -(2,4-dioxohexahydropyrimidin- 1 -yl)indol- 1 -yl] - 1 - piperidyl]methyl]piperidine- 1 -carboxylate

[0622] Prepared in an analogous method to Intermediate 17f starting from Intermediate 17e (0.047 g, 0.1 mmol). Purification on FSC (gradient: 0-8% MeOH in DCM) gave the title compound (0.041 g, 75 %) as a white solid, m / z (ES+) [M+H]+= 550.5.Intermediate 20b:l-[3-Cyclopropyl-l-[l-(4-piperidyhnethyl)-4-piperidyl]indol-5-yl]hexahydro-pyrimidine-2, 4-dione2TFA

[0623] Prepared in an analogous method to Intermediate 4e starting from Intermediate 20a (41 mg, 0.07 mmol). Concentration under reduced pressure gave the title compound in the form of a bis-trifluoroacetate salt (0.048 g, 95 %) as a pale yellow solid, m / z (ES+) [M+H]+= 450.4.Example 20l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8- yl]benzoyl] -4-piperidyl]methyl] -4-piperidyl] -3 -cyclopropyl -indol-5 -yl]hexahydropyrimidine-2, 4-dione

[0624] Prepared in an analogous method to Example 1 starting from Intermediate 20b (13 mg, 0.03 mmol) and Intermediate Ij (20 mg, 0.03 mmol). Purification by RPC (gradient: 10-40% MeCN in water with 0.1% FA) gave the title compound in the form of a formate salt (15 mg, 59 %) as a white solid. ’H NMR (DMSO-d6): δ 0.53-0.62 (2H, m), 0.79-0.88 (2H, m), 1.03-1.27 (3H, m), 1.67-2.38 (16H, m), 2.41-2.47 (3H, m), 2.72 (2H, t), 2.84-3.00 (3H, m), 3.06-3.11 (2H, m), 3.21-3.25 (2H, m), 3.75-3.80 (2H, m), 4.47-4.52 (2H, m), 5.91-6.00 (2H, m), 6.81-6.88 (2H, m), 6.92 (2H, d), 7.02-7.24 (3H, m), 7.25-7.30 (2H, m), 7.42-7.56 (3H, m), 7.86-7.92 (1H, m), 10.18-10.27 (1H, m), 13.92-14.26 (1H, m); m / z (ES+) [M+H]+= 849.4.EXAMPLE 21Intermediate 21a:tert-Bv yl rac-(37?,47?)-4-(5 -bromoindol- 1 -yl)-3 -methyl -piperidine- 1 -carboxylate

[0625] Prepared in an analogous method to Intermediate 5a starting from tert-butyl rac-(3 / ?.4. S)-4-hydroxy-3-methyl-piperidine-l-carboxylate (0.440 g, 2.04 mmol) and 5-bromo-lH-indole (0.440 g, 2.24 mmol). Purification by FSC (gradient: 0-50% DCM in hexanes then 0-40% EtOAc in hexanes) gave the title compound (0.174 g, 22 %) as a viscous oil. ’HNMR (CDCh): 50.67 (3H, d), 1.51 (9H, s), 1.86-2.04(2H, m), 2.07-2.18 (1H, m), 2.43-2.69 (1H, m), 2.78-3.05 (1H, m), 3.78-4.01 (1H, m), 4.18-4.48 (2H, m), 6.51 (1H, d), 7.14 (1H, d), 7.23-7.26 (1H, m), 7.28-7.31 (1H, m), 7.72-7.82 (1H, m); m / z (ES+) | M- / Bu+2H| = 336.6.Intermediate 21b:tert-Butyl-(3R,4R)-4-(5-bromoindol-l-yl)-3 -methyl -piperidine- 1 -carboxylate (ISOMER 1)and / c / 7- Butyl -(3. S',4. S')-4-(5-bromoindol- 1 -yl)-3-methyl-piperidine- 1 -carboxylate (ISOMER 2)Bo / Bo /

[0626] tert-Butyl rac-(3R,4S)-4-hydroxy-3 -methyl -piperidine- 1 -carboxylate (0.340 g, 0.86 mmol) was purified by preparative SFC (Chiralpak IJ, 5 pm, 21 mm diameter, 250 mm length, 40°C column temperature, 100 bar outlet pressure, 70 mL / min flow rate, eluting with 15% MeOH containing 0.2% NH4OH in CO2), to give ISOMER 1 which eluted first from the column (0.169 g, 50%) and ISOMER 2 which eluted second from the column (0.110 g, 32 %) as viscous oils.Intermediate 21c:to -Buty I -(3 / ?.4 / ?)-4-| 5 -(2,4-dioxohexahydropyrimidin- 1 -yl)indol- 1 -yl] -3 -methyl-piperidine- 1 - carboxylateorto7-Butyl-(3. S\4. S)-4-| 5-(2.4-dioxohcxahydropyrimidin- 1 -yl)indol- 1 -yl |-3-mcthyl-pipcridinc- 1 -carboxylateBo< / Bo< /

[0627] Prepared in an analogous method to Intermediate 4b starting from Intermediate 21b ISOMER 1 (0.168 g, 0.43 mmol). Purification by FSC (gradient: 0-100% EtOAc in hexanes) gave the title compound (0.134 g, 67 %) as a white solid. 'H NMR (CDCh): 50.70 (3H, d), 1.51 (9H, s), 1.89-2.01 (2H, m), 2.08-2.18 (1H, m), 2.51-2.62 (1H, m), 2.83-2.94 (3H, m), 3.85-3.98 (3H, m), 4.23-4.39 (2H, m), 6.57 (1H, d), 7.13 (1H, dd), 7.19 (1H, d), 7.36-7.44 (2H, m), 7.53 (1H, d); m / z (ES+) [M-tBu+2H]+= 370.8.Intermediate 21d:tert-Bv yl 4-fluoro-4-(trifluoromethylsulfonyloxymethyl)piperidine- 1 -carboxylate

[0628] To a solution of tert-butyl 4-fluoro-4-(hydroxymethyl)piperidine-l -carboxylate (0.100 g, 0.43 mmol) and 2,6-lutidine (0.060 mL, 0.51 mmol) in DCM (0.72 mL) at -5°C was added trifluoromethanesulfonic anhydride (0.076 mL, 0.45 mmol) over 3 min. The mixture was stirred at -5°C for 50 min then quenched with 1.0 M aq. sodium bisulfate (5 mL) and diluted with DCM (20 mL). The layers were separated. The organic layer was washed with 1.0 M aq. sodium bisulfate (5 mL), then saturated aq. NaHCOs (10 mL). The organic layer was dried (Na2SO4) and concentrated to give the title compound (0.142 g, 91 %) as a light brown oil. ’HNMR (DMSO-d6): δ 1.37-1.45 (9H, m), 1.56-1.76 (2H, m), 1.76-1.90 (2H, m), 2.99 (2H, br s), 3.65-3.96 (2H, m), 4.81-4.96 (2H, m); m / z (ES+) [M-Bu+2H] = 309.8.Intermediate 21e: / / 7- Butyl 4-fl uoro-4-| -(3 / ?.4 / ?)-4-| 5 -(2,4-dioxohexahydropyrimidin- 1 -yl)indol- 1 -yl] -3 -methyl- 1 - piperidyl]methyl]piperidine- 1 -carboxylateortert- Butyl 4-fl uoro-4-| -(3. S',4. S')-4-| 5 -(2,4-dioxohexahydropyrimidin- 1 -yl)indol- 1 -yl] -3 -methyl- 1 - piperidyl]methyl]piperidine- 1 -carboxylate

[0629] TFA (0.235 mL, 3.05 mmol) was added to a solution of Intermediate 21d (130 mg, 0.30 mmol) in DCM (0.80 mL) at r.t. After 0.5 h the mixture was quenched with saturated aq. NaHCO3(0.5 mL). The aqueous layer was extracted with DCM (2 x 15 mL). The combined organic solutions were dried (Na2SO4) and then concentrated. Intermediate 21e (0.122 g, 0.33 mmol) was added to the residue, and then 1,4-dioxane (1.0 mL) and DIPEA (0.159 mL, 0.91 mmol) were added under N2 at r.t. The mixture was stirred at 80°C for 16.5h and then cooled to r.t. and concentrated. Purification by FSC (gradient: 0-100% EtOAc in hexanes) gave the title compound (74 mg, 45 %) as a white solid. ’H NMR (DMSO-d6): δ 0.53 (3H, d), 1.40 (9H, s), 1.51-1.69 (2H, m), 1.75-1.88 (3H, m), 1.93-2.05 (1H, m), 2.05-2.14 (1H, m), 2.14-2.29 (1H, m), 2.37-2.42 (1H, m), 2.58 (2H, d), 2.71 (2H, t), 2.93-3.11 (4H, m), 3.67-3.80 (4H, m), 3.89-4.00 (1H, m), 6.47 (1H, d), 7.05 (1H, dd), 7.44 (1H, d), 7.49-7.57 (2H, m), 10.23 (1H, s);19F NMR (DMSO-d6): -157.98 (IF, s); m / z (ES+) [M+H]+= 542.2.Intermediate 2 If:l-| l-|-(3 / ?.4 / ?)-l-|(4-Fluoro-4-pipcridyl)mcthyl |-3-mcthyl-4-pipcridyl |indol-5-yl |hcxahydropyrimidinc- 2,4-dioneor1 -[ 1 -[-(35,45)- 1 -[(4-Fluoro-4-piperidyl)methyl] -3-methyl-4-piperidyl]indol-5-yl]hexahydropyrimidine- 2, 4-dione

[0630] Prepared in an analogous method to Intermediate 4e starting from Intermediate 2 If (72 mg, 0.13 mmol) to give the title compound in the form of a bis-trifluoroacetate salt (89 mg, 100 %) as a light pink solid after trituration with diethyl ether, m / z (ES+) [M+H]+= 442.0.Example 21l-[l-[-(37?,47?)-l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]benzoyl]-4-fhioro-4-piperidyl]methyl]-3-methyl-4-piperidyl]indol-5-yl]hexahydropyrimidine-2, 4-dione orl-[l-[-(3S,4S)-l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]benzoyl]-4-fluoro-4-piperidyl]methyl]-3-methyl-4-piperidyl]indol-5-yl]hexahydropyrimidine-2, 4-dioneNW or NW Ki II KJ II HO JL HO J.M U

[0631] Prepared in an analogous method to EXAMPLE 1 starting from Intermediate Ij (29 mg, 0.07 mmol) and Intermediate 21g (63 mg, 0.09 mmol). Purification by RPC (gradient: 5-30% MeCN in water with 0.1% FA) gave the title compound in the form of a formate salt (19 mg, 33 %) as a white solid. ’H NMR(DMSO-J6): 50.53 (3H, d), 1.61-1.82 (3H,m), 1.84-2.03 (5H, m), 2.03-2.24 (4H, m), 2.34-2.44 (1H, m), 2.61 (2H, d), 2.71 (2H, t), 2.95-3.05 (2H, m), 3.08 (2H, br d), 3.16-3.25 (2H, m), 3.28 (2H, br d), 3.76 (2H, t), 3.83-4.07 (3H, m), 4.44-4.56 (2H, m), 5.95 (2H, s), 6.47 (1H, d), 6.81-6.90 (2H, m), 6.93 (2H, d), 7.04 (1H, dd), 7.18-7.24 (1H, m), 7.31 (2H, d), 7.44 (1H, d), 7.47 (1H, s), 7.49-7.55 (2H, m), 7.89 (1H, dd), 10.24 (1H, s), 14.12 (1H, br s);19F NMR (DMSO-d6): -157.64 (IF, s); m / z (ES+) [M+H]+= 841.4.EXAMPLE 22Intermediate 22a:Intermediate 22a: Benzyl 4-(5-bromo-4-methyl-indol-l-yl)piperidine-l-carboxylate

[0632] Prepared in an analogous method to Intermediate 6a starting from 5-bromo-4-methyl- 1 H-indole (1.00 g, 4.76 mmol). Purification by FSC (gradient: 0-100% EtOAc in hexanes) gave the title compound (0.89 g, 44 %) as a pale orange sticky foam. ¹H NMR (DMSO-d6): δ 1.79-1.98 (4H, m), 2.50 (3H, s), 3.07(2H, br s), 4.20 (2H, br d), 4.60 (1H, tt), 5.12 (2H, s), 6.55 (1H, d), 7.28 (1H, d), 7.31-7.42 (6H, m), 7.54 (1H, d); m / z (ES+) [M+H]+= 429.1.Intermediate 22b:Benzyl 4-(5 -((tert-butoxycarbonyl)amino)-4-methyl- 1 H-indol - 1 -yl)piperidine- 1 -carboxylate

[0633] Prepared in an analogous method to Intermediate 6b starting from Intermediate 22a (0.886 g, 2.07 mmol). The reaction mixture was filtered through a pad of Celite. The filter cake was rinsed with EtOAc (3 x 10 mL), then DCM (3 x 10 mL), and concentrated to give the title compound (0.961 g, 100 %) (assumed theoretical yield) as a brown foam, m / z (ES+) [M+Na]+= 486.3.Intermediate 22c:Benzyl 4-(5 -amino-4-methyl-indol- 1 -yl)piperidine- 1 -carboxylate

[0634] Intermediate 22b (0.486 g, 4.15 mmol) was stirred in 4M HC1 in 1,4-dioxane (7.77 mL, 31.1 mmol) at r.t. for 2h then quenched with saturated aq. NaHCOs (40 mL). The aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic solutions were dried (Na2SO4) and concentrated. Purification by FSC (gradient: 0-75% 3: 1 EtOAc: EtOH in hexanes with 10% DCM) gave the title compound (0.542 g, 72 %) as a golden brown foam. ’HNMR (DMSO-d6): 5 1.81 (2H, qd), 1.93 (2H, br d), 2.18 (3H, s), 3.05 (2H, br s), 4.18 (2H, br d), 4.29 (2H, br s), 4.42 (1H, tt), 5.12 (2H, s), 6.25 (1H, d), 6.59 (1H, d), 7.09 (1H, d), 7.26 (1H, d), 7.30-7.47 (5H, m); m / z (ES+) [M+Na]+= 386.2.Intermediate 22d:3 -[ [ 1 -( 1 -Benzyloxy carbonyl -4-piperidyl)-4-methyl-indol-5 -yl] amino] propanoic acid

[0635] To a solution of Intermediate 22c (0.542 g, 1.49 mmol) in toluene (4.9 mL) at r.t. was added acrylic acid (0.124 mL, 1.79 mmol). The mixture was stirred at 110°C for 20h then cooled to r.t. Purification by FSC (gradient: 0-20% MeOH in DCM) gave the title compound (0.233 g, 36 %) as a brown foam. ’H NMR (DMSO-d6): 5 1.72-1.87 (2H, m), 1.87-2.00 (2H, m), 2.19 (3H, s), 2.52 (1H, br s), 3.04 (2H, br dd), 3.16 (1H, s), 3.30 (4H, br s), 4.17 (2H, br d), 4.44 (1H, brt), 5.10 (2H s), 6.28 (1H, br s), 6.62 (1H, d), 7.21 (1H, d), 7.25-7.49 (6H, m); m / z (ES+) [M+H]+= 436.4.Intermediate 22e:Benzyl 4-[5-(2,4-dioxohexahydropyrimidin- 1 -yl)-4-methyl-indol- 1 -yl]piperidine- 1-carboxylate

[0636] To a solution of Intermediate 22d (0.233 g, 0.53 mmol) in AcOH (1.8 mL) at r.t. was added urea (0.096 g, 1.6 mmol). The mixture was stirred at 120°C for 9h, then cooled to r.t and concentrated. Purification by FSC (gradient: 0-20% MeOH in DCM) gave the title compound (0.210 g, 85 %) as a brown foam.1H NMR (DMSO-6): 5 1.94 (4H, br s), 2.31 (3H, s), 2.68-2.84 (2H, m), 3.08 (2H, br s), 3.55 (1H, dt), 3.75 (1H, ddd), 4.21 (2H, br d), 4.58-4.65 (1H, m), 5.12 (2H, br s), 6.54 (1H, d), 7.03 (1H, d), 7.31-7.40 (5H, m), 7.42-7.45 (1H, m), 7.54 (1H, d), 12.00 (1H, br d); m / z (ES+) [M+H]+= 461.2.Intermediate 22f:1 -[4-Methyl- 1 -(4-piperidyl)indol-5-yl]hexahydropyrimidine-2, 4-dione

[0637] Prepared in an analogous method to Intermediate 6e starting from Intermediate 22e (0.210 g, 0.46 mmol). Purification by RPC (gradient: 0-40% MeCN in water with 0.1% NH4OH) gave the title compound (0.056 g, 38 %) as an off-white solid. ’HNMR (DMSO-d6): 5 1.76-1.93 (4H, m), 2.32 (3H, s), 2.66-2.84 (4H, m), 3.08 (2H, br d), 3.55 (1H, dt), 3.75 (1H, ddd), 4.32-4.48 (1H, m), 6.53 (1H, d), 7.01 (1H, d), 7.41 (1H, d), 7.49 (1H, d), 10.24 (1H, br s); m / z (ES-) [M-H]-= 325.2.Intermediate 22g:tert-Butyl 4-[[4-[5-(2,4-dioxohexahydropyrimidin-1-yl)-4-methyl-indol-1-yl]-1-piperidyl]methyl]-4-fluoro-piperidine-1-carboxylate

[0638] To a solution of Intermediate 22f (0.020 g, 0.06 mmol) and Intermediate 21d (0.025 g, 0.07 mmol) in 1,4-dioxane (0.581 mL) was added DIPEA (0.032 mL, 0.18 mmol). The mixture was stirred at 80°C for 15h, then cooled to r.t. and concentrated under reduced pressure. Purification by FSC (gradient: 0-20% MeOH in DCM) gave the title compound (0.030 g, 90 %) as a peach solid, m / z (ES+) [M+H]+= 542.3.Intermediate 22h:1 -[ 1 -[ 1 -[(4-Fluoro-4-piperidyl)methyl] -4-piperidyl] -4-methyl-indol-5-yl]hexa-hydropyrimidine-2, 4-dione

[0639] To Intermediate 22g (0.030 g, 0.06 mmol) at r.t. was added TFA (0.212 mL, 2.77 mmol). The mixture was stirred at r.t. for 45 min, then concentrated. The crude product was precipitated with Et2O (2mL) and collected by filtration. The precipitate was washed with Et2O (3 x 2 mL), and dried to give the title compound in the form of a bis-trifluoroacetate salt (0.030 g, 81 %) as an off-white solid. ’H NMR (DMSO-d6): 5 1.72-2.23 (8H, m), 2.33 (3H, s), 2.68-2.85 (2H, m), 3.07 (2H, br d), 3.25 (8H, br d), 3.55 (2H, dt), 3.75 (1H, ddd), 6.58 (1H, br s), 6.92-7.15 (1H, m), 7.44 (2H, br s), 10.26 (1H, s); NH proton not observed; m / z (ES+) [M+H]+= 442.3.Example 22l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8- yl]benzoyl]-4-fluoro-4-piperidyl]methyl]-4-piperidyl]-4-methyl-indol-5-yl]hexahydro-pyrimidine-2,4- dione

[0640] Prepared in an analogous method to EXAMPLE 1 starting from Intermediate Ij (0.019 g, 0.04 mmol) and Intermediate 22h (0.030 g, 0.04 mmol). Purification by RPC (gradient: 0-65% MeCN in water with 0.1% NH4OH) gave the title compound (0.016 g, 43 %) as a white solid. 'H NMR (DMSO-t / 6): 51.63-1.80 (2H, m), 1.85-1.95 (4H, m), 1.95-2.04 (4H, m), 2.16-2.24 (2H, m), 2.31 (3H, s), 2.42 (2H, brt), 2.58-2.68 (2H, m), 2.68-2.83 (2H, m), 3.05 (2H, br d), 3.10 (2H, br d), 3.16-3.29 (4H, m), 3.54 (1H, dt), 3.74 (1H, ddd), 3.94 (2H, br d), 4.26-4.39 (1H, m), 4.52 (2H, br s), 5.96 (2H, s), 6.53 (1H, d), 6.82-6.90 (2H, m), 6.95 (2H, d), 7.01 (1H, d), 7.19-7.25 (1H, m), 7.32 (2H, d), 7.39 (1H, d), 7.49 (1H, s), 7.53 (1H, d), 7.91 (1H, dd), 10.24 (1H, br s), 13.55-14.71 (1H, m); m / z (ES+) [M+H]+= 841.4.EXAMPLE 23Intermediate 23a:tert- Butyl 4-(5 -bromo-7 -methyl -indol- 1 -yl)piperidine- 1 -carboxylate

[0641] To a mixture of 5 -bromo-7 -methyl- 1 / / -indole (800 mg, 3.81 mmol) in tert-amyl alcohol (20.0 mL) at 95°C was added tert-butyl 4-((methylsulfonyl)oxy)piperidine-l -carboxylate (2.66 g, 9.52 mmol) alongside potassium tert-butoxide (1.28 g, 11.4 mmol) in 5 equal potions every 0.5h. The mixture was stirred at 95°C for 3h, then cooled to r.t. The mixture was diluted with MTBE (10 mL), saturated aq. NH4CI solution (10 mL) and water (10 mL). The layers were separated, and the aqueous layer was extracted with MTBE (10 mL). The organic layers were combined, washed with brine (10 mL), dried (Na2SO4), and concentrated. Purification by FSC (gradient: 0-100% DCM in heptane), followed by RPC (gradient: 0-100% MeCN in water with 0.1%NH4OH) gave the title compound (0.373 g, 25 %) as a pale brown solid.1H NMR (DMSO-6): 5 1.49 (9H, s), 1.74-1.95 (2H, m), 2.07 (2H, d), 2.69 (3H, s), 2.86 (2H, q), 4.32 (2H, s), 4.77 (1H, tt), 6.45 (1H, d), 6.98-7.06 (1H, m), 7.17 (1H, d), 7.58 (1H, d); m / z (ES+) [M-tBu+2H]+= 337.3.Intermediate 23b:tert-Butyl 4-[5-(2,4-dioxohexahydropyrimidin-1-yl)-7-methyl-indol-1-yl]piperidine-1-carboxylate

[0642] Prepared in an analogous method to Intermediate 4b starting from Intermediate 23a (1.05 g, 2.67 mmol). Purification by FSC (gradient: 0-100% EtOAc in heptane) gave the title compound (0.550 g, 48 %) as a pale yellow solid. ’HNMR (DMSO-d6): 5 1.43 (9H, s), 1.83 (2H, qd), 1.97 (2H, s), 2.66-2.75 (5H, m), 2.96 (2H, s), 3.74 (2H, t), 4.11 (2H, d), 4.85 (1H, ddd), 6.45 (1H, d), 6.77-6.87 (1H, m), 7.28 (1H, d), 7.53 (1H, d), 10.23 (1H, s); m / z (ES+) [M-tBu+2H]+= 371.5.Intermediate 23c:l-[7-Methyl-l-(4-piperidyl)indol-5-yl]hexahydropyrimidine-2, 4-dione

[0643] 4.0 M HC1 in 1,4-dioxane (0.35 mL, 1.4 mmol) was added to Intermediate 23b (30 mg, 0.07 mmol) in 1,4-dioxane (0.176 mL) at r.t. The mixture was stirred at r.t. for 8h, then concentrated. The crude residue was dissolved in DCM (2 mL) with few drops of MeOH, then quenched with sat. aq. NaHCOs (2 mL). The mixture was stirred at r.t. for 0.5h, and the layers were separated. The aqueous layer was extracted with DCM (2 x 25 mL). The organic layers were combined, dried (Na2SO4), and concentrated to give the title compound (23 mg, 100 %) as a pale golden yellow film, m / z (ES+) [M+H]+= 326.9.Intermediate 23d:tert-Butyl 4-[[4-[5-(2,4-dioxohexahydropyrimidin-1-yl)-7-methyl-indol-1-yl]-1-piperidyl]methyl]-4-fluoro-piperidine-1-carboxylate

[0644] Prepared in an analogous method to Intermediate 22g starting from Intermediate 23c (0.026 g, 0.07 mmol) and Intermediate 21d (0.029 g, 0.08 mmol). Purification by FSC (gradient: 0-20% MeOH in DCM) gave the title compound (0.033 g, 84 %) as a sticky golden yellow solid. ’H NMR (DMSO-t / 6): 5 1.36-1.42 (9H, m), 1.56-1.67 (2H, m), 1.79-1.89 (2H, m), 1.89-2.04 (4H, m), 2.32-2.40 (2H, m), 2.61-2.71 (5H, m), 3.04 (2H, br d), 3.28 (2H, br s), 3.72-3.76 (2H, m), 4.65 (1H, br t), 6.45 (2H, br s), 6.82 (2H, br s), 7.21-7.31 (1H, m), 7.54 (2H, br s), 10.24 (2H, s); m / z (ES+) [M+H]+= 542.3.Intermediate 23e:1 -[ 1 -[ 1 -[(4-Fluoro-4-piperidyl)methyl] -4-piperidyl] -7-methyl-indol-5-yl]hexahydro-pyrimidine-2, 4-dione■2HCI

[0645] Prepared in an analogous method to Intermediate lb starting from Intermediate 23d (32 mg, 0.060 mmol). The solution was concentrated to give the title compound in the form of a bis -hydrochloride salt (30 mg, 100 %) as a lavender solid, m / z (ES+) [M+H]+= 442.4.Example 23l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8- yl]benzoyl]-4-fhioro-4-piperidyl]methyl]-4-piperidyl]-7-methyl-indol-5-yl]hexahydro-pyrimidine-2,4- dione

[0646] Prepared in an analogous method to EXAMPLE 1 starting from Intermediate Ij (25 mg, 0.06 mmol) and Intermediate 23e (31 mg, 0.06 mmol). Purification by RPC (gradient: 0-40% MeCN in water with 0.1% FA) gave the title compound in the form of a formate salt (15 mg, 29 %) as an off-white solid. 'H NMR (DMSO-d6): 5 1.64-1.79 (2H, m), 1.85-2.02 (8H, m), 2.19 (2H, br d), 2.31-2.40 (2H, m), 2.64-2.72 (6H, m), 3.01-3.13 (4H, m), 3.14-3.23 (2H, m), 3.28 (2H, br s), 3.59-3.68 (1H, m), 3.73 (2H, t), 3.84-4.04 (2H, m), 4.51 (2H, br s), 4.57-4.70 (1H, m), 5.96 (2H, s), 6.44 (1H, d), 6.80-6.89 (3H, m), 6.94 (2H, br d), 7.18-7.25 (1H, m), 7.26-7.34 (3H, m), 7.47 (1H, s), 7.52 (1H, d), 7.90 (1H, dd), 10.23 (1H, s), 14.13 (1H, br s); m / z (ES+) [M+H]+= 841.4.EXAMPLE 24Intermediate 24a:tert-Butyl 4-[[4-[4-(2,4-dioxohexahydropyrimidin-1-yl)indol-1-yl]-1-piperidyl]methyl]-4-fluoro-piperidine-1-carboxylate

[0647] Intermediate 5c (190mg, 0.61 mmol) and tert-butyl 4-fluoro-4-formylpiperidine-1-carboxylate (200mg, 0.86 mmol) in THF (6 mL) was added tetraisopropoxytitanium (346 mg, 1.22 mmol). The reaction was stirred at r.t overnight. Then NaBH(OAc)3(258 mg, 1.22 mmol) was added and the reaction was stirred at r.t for 2h. The reaction was concentrated and purified by FSC (gradient: 0-6% MeOH in DCM) to givetitle compound (200 mg, 62 %) as a white solid. 'H NMR (DMSO-t / 6): 5 1.41 (9H, s), 1.52-1.71 (2H, m), 1.79-1.89 (2H, m), 1.90-1.93 (2H, m), 1.96-2.09 (2H, m), 2.34-2.45 (2H, m), 2.56-2.63 (2H, m), 2.76 (2H, m), 2.93-3.16 (4H, m), 3.67-3.85 (4H, m), 4.30-4.43 (1H, m), 6.42 (1H, d), 6.96 (1H, d), 7.15 (1H, s), 7.45-7.61 (2H, m), 10.20-10.42 (1H, m); m / z (ES+) [M+H]+= 528.4.Intermediate 24b:l-[l-[l-[(4-Fluoro-4-piperidyl)methyl]-4-piperidyl]indol-4-yl]hexahydropyrimidine-2, 4-dione

[0648] Prepared in an analogous method to Intermediate 3j starting from Intermediate 24a (175 mg, 0.33 mmol). Purification by RPC (gradient: 20-35% MeCN in water with 0.1% ammonium formate) gave the title compound (80 mg, 56 %) as a white solid, m / z (ES+) [M+H]+= 428.3.Example 24l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8- yl]benzoyl]-4-fluoro-4-piperidyl]methyl]-4-piperidyl]indol-4-yl]hexahydropyrimidine-2, 4-dione

[0649] Prepared in an analogous method to EXAMPLE 1 starting from Intermediate Ij (75 mg, 0.18 mmol) and Intermediate 24b (75 mg, 0.18 mmol). Purification by RP-HPLC (gradient: 47-65% MeCN in water with 0.1% NH4OH) gave the title compound (13 mg, 9 %) as a white solid. ’H NMR (DMSO-d6): 5 1.51 - 1.81 (2H, m), 1.81 - 2.08 (8H, m), 2.12 - 2.22 (2H, m), 2.35 - 2.45 (2H, m), 2.56 - 2.68 (2H, m), 2.71 - 2.79 (2H, m), 2.96 - 3.12 (4H, m), 3.13 - 3.31 (4H, m), 3.76 (2H, t), 3.82 - 4.03 (2H, m), 4.27 - 4.42 (1H, m), 4.45 - 4.56 (2H, m), 5.96 (2H, s), 6.40 (1H, d), 6.78 - 6.89 (2H, m), 6.89 - 6.98 (3H, m), 7.07 - 7.16 (1H, m), 7.17 - 7.25 (1H, m), 7.30 (2H, d), 7.43 - 7.62 (3H, m), 7.90 (1H, dd), 10.32 (1H, s), 14.14 (1H, s); m / z (ES+) [M+H]+= 827.6.EXAMPLE 25Intermediate 25a:tert-Butyl 4-cyano-4-[[4-[5-(2,4-dioxohexahydropyrimidin-1-yl)indol-1-yl]-1-piperidyl]methyl]piperidine-1-carboxylate

[0650] Prepared in an analogous method to Intermediate 1c starting from Intermediate 3h (100 mg, 0.32 mmol) and tert-butyl 4-cyano-4-formylpiperidine-l -carboxylate (114 mg, 0.48 mmol). Purification by RPC (gradient: 0-100% MeCN in water with 0.4% NH4HCO3) gave the title compound (80 mg, 47 %) as a white solid, m / z (ES+) [M-tBu+2H]+= 435.2.Intermediate 25b:4-[ [4 - [ 5 -(2,4-Dioxohexahydropyrimidin- 1 -yl)indol- 1 -yl] - 1 -piperidyl] methyl] -piperidine-4-carbonitrile

[0651] Prepared in an analogous method to Intermediate 3j starting from Intermediate 25a (75 mg, 0.14 mmol). Purification by RPC (gradient: 0-100% MeCN in water with 0.4% NH4HCO3) gave the title compound (20 mg, 33 %) as a white solid. 'H NMR (DMSO-d6): 5 1.32 - 1.49 (2H, m), 1.82 - 2.03 (6H, m), 2.53 - 2.77 (8H, m), 2.87 - 2.98 (2H, m), 2.99 - 3.10 (2H, m), 3.75 (2H, t), 4.24 - 4.43 (1H, m), 6.44 (1H, d), 7.06 (1H, dd), 7.44 (1H, d), 7.50 - 7.58 (2H, m), 10.25 (1H, s); NH proton not observed; m / z (ES+) [M+H]+= 435.4.Example 25l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]benzoyl]-4-[[4- [5 -(2,4-dioxohexahydropyrimidin- 1 -yl)indol- 1 -yl] - 1 -piperidyl]methyl]piperidine-4-carbonitrilNH2

[0652] PyBOP (29.9 mg, 0.06 mmol) was added to DIPEA (30.1 pL, 0.17 mmol), Intermediate Ij (24 mg, 0.06 mmol) and Intermediate 25b (25 mg, 0.06 mmol) in DMF (2 mL) at 40°C. The resulting mixture was stirred at 40°C for Ih then cooled to r.t. Purification by RP-HPLC (gradient: 18-28% MeCN in water with 0.1% FA) gave the title compound in the form of a formate salt (10 mg, 20 %) as a yellow solid. ’H NMR (DMSO-d6): 5 1.50 - 1.63 (2H, m), 1.85 - 2.02 (8H, m), 2.13 - 2.22 (2H, m), 2.55 - 2.63 (2H, m), 2.65 - 2.76 (4H, m), 2.98 - 3.13 (6H, m), 3.75 (2H, t), 4.08 - 4.25 (2H, m), 4.31 - 4.41 (IH, m), 4.46 - 4.56 (2H, m), 5.94 - 6.13 (2H, m), 6.44 (IH, d), 6.80 - 6.89 (2H, m), 6.93 (2H, d), 7.06 (IH, dd), 7.18 - 7.25 (IH,m), 7.31 (2H, d), 7.44 - 7.48 (2H, m), 7.50 - 7.59 (2H, m), 7.82 - 7.91 (1H, m), 10.25 (1H, s); two protons are unresolved; -OH not observed; m / z (ES+) [M+H]+= 834.0.EXAMPLE 26Intermediate 26a:l-[3-Iodo-l-(4-piperidyl)indol-5-yl]hexahydropyrimidine-2, 4-dioneH

[0653] A mixture of Intermediate 3h in the form of a trifluoroacetate salt (0.640 g, 1.5 mmol) and A-iodosuccinimide (0.371 g, 1.65 mmol) in DMSO (3.0 mL) was stirred in the dark at r.t. for 1,5h. Purification by RPC (gradient: 5-60% MeCN in water with 0.1% NH4OH) gave the title compound (0.532 g, 81 %) as a white solid. 'H NMR (DMSO-d6): δ 1.80-1.92 (4H, m), 2.64-2.78 (4H, m), 3.07 (2H, br d), 3.80 (2H, t), 4.41-4.50 (1H, m), 7.16 (1H, dd), 7.21 (1H, d), 7.63 (1H, d), 7.73 (1H, s), 10.32 (1H, br s) (piperidine N-H not observed); m / z (ES+) [M+H]+= 439.2.Intermediate 26b:tert-Butyl 4-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-iodo-indol-1-yl]piperidine-1-carboxylate

[0654] A mixture of Intermediate 26a (0.698 g, 1.59 mmol), di-tert-butyl dicarbonate (0.452 g, 2.07 mmol), and DIPEA (0.834 mL, 4.78 mmol) in DCM (8 mL) was stirred at r.t. for 20h then quenched with water (5 mL). The organic solution was separated, and the aqueous was extracted with DCM (3 x 5 mL). The combined organic solutions were dried (Na2SO4) and concentrated under reduced pressure. Purification by FSC (gradient: 0-100% EtOAc in hexanes) gave the title compound (0.809 g, 94 %) as a white solid. ’H NMR (DMSO-d6): 5 1.42-1.47 (9H, s), 1.86 (2H, br d), 1.90-1.96 (2H, m), 2.75 (2H, br t), 2.97 (2H, br s), 3.80 (2H, br t), 4.13 (2H, br s), 4.63 (1H, br t), 7.18 (1H, br d), 7.22 (1H, s), 7.64 (1H, br d), 7.82 (1H, s), 10.32 (1H, s); m / z (ES+) [M+Na]+= 561.3.Intermediate 26c:tert-Butyl 4-[5-(2,4-dioxohexahydropyrimidin- 1 -yl)-3-(2-pyridyl)indol- 1 -yl] -piperidine- 1 -carboxylate

[0655] DMF (2.0 mL) was added to a degassed flask containing Intermediate 26b (0.108 g, 0.2 mmol), tetrakis(triphenylphosphine)palladium(0) (0.023 g, 0.02 mmol), Cui (0.046 g, 0.24 mmol), and tributyl(2-pyridyl) stannane (0.071 mL, 0.22 mmol) at r.t. under N2. The mixture was sparged with N2 for 10 minhen stirred at 100°C for 2h. The mixture was cooled to r.t., diluted with EtOAc (10 mL), filtered through celite and concentrated. Purification by RPC (gradient: 5-60% MeCN in water with 0.1% NH4OH) gave the title compound (0.041 g, 42 %) as a white solid. ’HNMR (DMSO-t / 6): 51.44-1.48 (9H, s), 1.89-2.04 (4H, m), 2.71-2.81 (2H, m), 3.02 (2H, br s), 3.76-3.85 (2H, m), 4.17 (2H, br s), 4.64-4.71 (1H, m), 7.13 (1H, t), 7.18 (1H, dd), 7.67 (1H, d), 7.71-7.78 (1H, m), 7.88 (1H, d), 8.37 (1H, s), 8.42 (1H, d), 8.58 (1H, d), 10.28 (1H, s); m / z (ES+) [M+H]+= 490.5.Intermediate 26d:l-[l-(4-Piperidyl)-3-(2-pyridyl)indol-5-yl]hexahydropyrimidine-2, 4-dione

[0656] Prepared in an analogous method to Intermediate 4c starting from Intermediate 26c (30 mg, 0.06 mmol). Concentration under reduced pressure gave the title compound in the form of a bis-trifluoroacetate salt (38 mg, 100 %) as a pink solid, m / z (ES+) [M+H]+= 390.3.Intermediate 26e:tert-Butyl 4-[[4-[5-(2,4-dioxohexahydropyrimidin- 1 -yl)-3-(2-pyridyl)indol- 1 -yl]- 1 -piperidyl]methyl] -4- fluoro-piperidine- 1 -carboxylateH CL N X3Boc^

[0657] Prepared in an analogous method to Intermediate 22g starting from Intermediate 26d (22.5 mg, 0.04 mmol) and Intermediate 21d (15 mg, 0.04 mmol). Purification by RPC (gradient: 5-100% MeCN inwater with 0.1% NH4OH) gave the title compound (14 mg, 62 %) as a white solid. ’H NMR (CD3OD): 5 1.49 (9H, s), 1.60-1.76 (2H, m), 1.96 (2H, br t), 2.09 (2H, br s), 2.14-2.26 (2H, m), 2.50 (2H, br s), 2.61-2.69 (2H, m), 2.84-2.91 (2H, m), 3.09-3.26 (4H, m), 3.88-3.98 (4H, m), 4.42 (1H, br s), 7.18-7.26 (2H, m), 7.57-7.64 (1H, m), 7.82 (2H, br s), 8.05 (1H, s), 8.22 (1H, s), 8.56 (1H, d) (N-H not observed); m / z (ES+) [M+H]+= 605.6.Intermediate 26f:l-[l-[l-[(4-Fluoro-4-piperidyl)methyl]-4-piperidyl]-3-(2-pyridyl)indol-5-yl]hexa-hydropyrimidine-2,4- dione

[0658] Prepared in an analogous method to Intermediate 4e starting from Intermediate 26e (14 mg, 0.02 mmol). Concentration under reduced pressure gave the title compound in the form of a bis-trifluoroacetate salt (15 mg, 94 %) as a pink solid, m / z (ES+) [M+H]+= 505.6.Example 26l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8- yl]benzoyl]-4-fhioro-4-piperidyl]methyl]-4-piperidyl]-3-(2-pyridyl)indol-5-yl]hexahydro-pyrimidine-2,4- dione

[0659] Prepared in an analogous method to EXAMPLE 1 starting from Intermediate 26f (15 mg, 0.02 mmol) and Intermediate Ij (9.1 mg, 0.02 mmol). Purification by RPC (gradient: 5-100% MeCN in water with 0.1% NH4OH) gave the title compound (14 mg, 71 %) as a white solid. ’H NMR (DMSO-t / 6) 5 1.66-1.82 (2H, m), 1.90-2.03 (6H, m), 2.05-2.16 (2H, m), 2.20 (2H, br d), 2.43-2.49 (3H, m), 2.61-2.71 (2H, m), 2.76 (2H, t), 3.04-3.14 (4H, m), 3.16-3.31 (4H, m), 3.81 (2H, t), 3.95 (1H, br s), 4.43 (1H, br t), 4.52 (2H, br s), 5.97 (2H, s), 6.82-6.90 (2H, m), 6.91-6.99 (2H, m), 7.10-7.18 (2H, m), 7.19-7.25 (1H, m), 7.30-7.36(2H, m), 7.49 (1H, s), 7.63 (1H, d), 7.74 (1H, t), 7.87-7.93 (2H, m), 8.35 (1H, s), 8.41 (1H, d), 8.58 (1H, d), 10.28 (1H, s), 14.14 (1H, s); m / z (ES+) [M+H]+= 904.9.EXAMPLE 27Intermediate 27a:Benzyl 4-(5 -bromo-6-methyl-indol- 1 -yl)piperidine- 1 -carboxylateN—#- V- BrCbzz

[0660] Prepared in an analogous method to Intermediate 6a starting from 5-bromo-6-methyl-1H-indole (1.00 g, 4.76 mmol). Purification by FSC (gradient: 0-100% EtOAc in hexanes) gave the title compound (0.869 g, 43 %) as a pale pink sticky foam. 'H NMR (DMSO-d6): 5 1.81-1.97 (4H, m), 2.45 (3H, s), 3.07 (2H, br s), 4.20 (2H, br d), 4.59 (1H, tt), 5.12 (2H, br s), 6.40 (1H, d), 7.30-7.41 (5H, m), 7.49 (1H, d), 7.60 (1H, s), 7.76 (1H, s); m / z (ES+) [M+H]+= 427.1.Intermediate 27b:Benzyl 4-[5-(tert-butoxycarbonylamino)-6-methyl-indol- 1 -yl]piperidine- 1 -carboxylateCbzz

[0661] Prepared in an analogous method to Intermediate 6b starting from Intermediate 27a (0.869 g, 2.03 mmol). The mixture was filtered through a pad of celite. The filter cake was rinsed with EtOAc (3 x 10 mL), then DCM (3 x 10 mL), and concentrated to give the title compound (0.943 g, 100 %) (assumed theoretical yield) as a brown foam, m / z (ES+) [M+Na]+= 486.3.Intermediate 27c:Benzyl 4-(5 -amino-6-m ethyl -indol- 1 -yl)piperidine- 1 -carboxylateCbz'

[0662] Prepared in an analogous method to Intermediate 22c starting from Intermediate 27b (0.943 g, 2.03 mmol). Purification by FSC (gradient: 0-75% 3:1 EtOAc: EtOH in hexanes with 10% DCM) gave the title compound (0.296 g, 40 %) as a golden brown foam. ’H NMR (DMSO-t / 6): 5 1.80 (2H, qd), 1.93 (2H, br d), 2.19 (3H, s), 3.06 (2H, br s), 4.19 (2H, br d), 4.30 (2H, br s), 4.42 (1H, tt), 5.12 (2H, s), 6.12 (1H, d), 6.75 (1H, s), 7.15 (1H, s), 7.19 (1H, d), 7.28-7.45 (5H, m); m / z (ES+) [M+Na]+= 386.1.Intermediate 27d:3 -[ [ 1 -( 1 -Benzyloxy carbonyl -4-piperidyl)-6-methyl-indol-5 -yl] amino] propanoic acidCbzz

[0663] Prepared in an analogous method to Intermediate 22d starting from Intermediate 27c (0.296 g, 0.81 mmol). Purification by FSC (gradient: 0-20% MeOH in DCM) gave the title compound (0.166 g, 47 %) as a brown foam, m / z (ES+) [M+H]+= 436.3.Intermediate 27e:Benzyl 4-[5-(2,4-dioxohexahydropyrimidin- 1 -yl)-6-methyl-indol- 1 -yl]piperidine- 1-carboxylate

[0664] Prepared in an analogous method to Intermediate 22e starting from Intermediate 27d (0.166 g, 0.38 mmol). Purification by FSC (gradient: 0-20% MeOH in DCM) gave the title compound (0.125 g, 71 %) as a brown foam. 'H NMR (DMSO-d6): 5 1.87-1.97 (6H, m), 2.26-2.32 (3H, m), 2.68-2.84 (2H, m), 3.03-3.12 (2H, m), 3.76 (1H, ddd), 4.21 (2H, br d), 5.12 (2H, br s), 6.41 (1H, d), 7.28-7.40 (6H, m), 7.45-7.50 (2H, m), 11.76-12.69 (1H, m); m / z (ES+) [M+H]+= 461.3.Intermediate 27f:1 -[6-Methyl- 1 -(4-piperidyl)indol-5-yl]hexahydropyrimidine-2, 4-dione

[0665] Prepared in an analogous method to Intermediate 6e starting from Intermediate 27e (0.125 g, 0.27 mmol). Purification by RPC (gradient: 0-40% MeCN in water with 0.1% NH4OH) gave the title compound (0.027 g, 30 %) as an off-white solid. ’HNMR (DMSO-d6): 5 1.78-1.94 (4H, m), 2.29 (3H, s), 2.66-2.82 (4H, m), 3.10 (2H, br d), 3.55 (1H, dt), 3.76 (1H, ddd), 4.20-4.61 (1H, m), 6.41 (1H, d), 7.34-7.50 (3H, m), 10.25 (1H, br s) (NH not observed); m / z (ES+) [M+H]+= 327.2.Intermediate 27g:tert-Butyl 4-[[4-[5-(2,4-dioxohexahydropyrimidin-1-yl)-6-methyl-indol-1-yl]-1-piperidyl]methyl]-4-fluoro-piperidine-1-carboxylate

[0666] Prepared in an analogous method to Intermediate 22g starting from Intermediate 27f (12 mg, 0.04 mmol) and Intermediate 21d (15 mg, 0.04 mmol). Purification by FSC (gradient: 0-20% MeOH in DCM) gave the title compound (13 mg, 65 %) as a golden brown film, m / z (ES+) [M+H]+= 542.3.Intermediate 27h:1 -[ 1 -[ 1 -[(4-Fluoro-4-piperidyl)methyl] -4-piperidyl] -6-methyl-indol-5-yl]hexahydro-pyrimidine-2, 4-dione2TFA

[0667] Prepared in an analogous method to Intermediate 22h starting from Intermediate 27g (13 mg, 0.02 mmol) to give the title compound in the form of a bis-trifluoroacetate salt (14 mg, 87%) as a light pink solid after trituration with diethyl ether, m / z (ES+) [M+H]+= 442.3.Example 27l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8- yl]benzoyl]-4-fhioro-4-piperidyl]methyl]-4-piperidyl]-6-methyl-indol-5-yl]hexahydro-pyrimidine-2,4- dione

[0668] Prepared in an analogous method to EXAMPLE 1 starting from Intermediate Ij (8.7 mg, 0.02 mmol) and Intermediate 27h (13 mg, 0.02 mmol). Purification by RPC (gradient: 0-65% MeCN in water with 0.1% NH4OH) gave the title compound (3.5 mg, 20 %) as a white solid. ’H NMR (DMSO-t / 6): 51.62-1.79 (2H, m), 1.84-2.05 (8H, m), 2.18-2.23 (2H, m), 2.28 (3H, s), 2.39-2.46 (2H, m), 2.61 (1H, br s), 2.63-2.67 (1H, m), 2.69-2.81 (2H, m), 3.05 (2H, br d), 3.10 (2H, br d), 3.16-3.25 (2H, m), 3.27-3.30 (2H, m), 3.55 (1H, dt), 3.76 (1H, ddd), 3.82-4.06 (2H, m), 4.18-4.41 (1H, m), 4.52 (2H, br s), 5.96 (2H, s), 6.40 (1H, d), 6.82-6.90 (2H, m), 6.95 (2H, d), 7.18-7.26 (1H, m), 7.29-7.36 (2H, m), 7.40-7.44 (2H, m), 7.45-7.51 (2H, m), 7.91 (1H, dd), 10.25 (1H, s), 14.14 (1H, br s); m / z (ES+) [M+H]+= 841.4.EXAMPLE 28Intermediate 28a:tert-Butyl 4-[[4-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-methyl-indol-1-yl]-1-piperidyl]methyl]piperidine-1-carboxylate

[0669] A mixture of tert-butyl 4-formyl -piperidine- 1 -carboxylate (32 mg, 0.15 mmol), sodium acetate (40 mg, 0.49 mmol, and Intermediate 4c (40 mg, 0.09 mmol) in THF (1.0 mb) was stirred at 60°C for 20min and then NaBH(OAc)3(58 mg, 0.28 mmol) was added. After 0.5h the mixture was cooled to r.t. and then diluted with DCM (5 mL) and saturated aq. NaHCO3solution (1.0 mL). The organic layer was separated and the aqueous layer extracted with DCM (2 x 5 mL). The combined organic solutions were dried (Na2SO4) and concentrated. Purification by FSC (gradient: 0-100% EtOAc in hexanes then 0-15% MeOH in DCM) gave the title compound (42 mg, 87 %) as a white solid. 'HNMR: 50.89-1.02 (2H, m), 1.38 (9H, s), 1.63- 1.74 (3H, m), 1.82-1.96 (4H, m), 2.09-2.20 (4H, m), 2.22 (3H, d), 2.63-2.78 (4H, m), 2.90-2.99 (2H, m), 3.75 (2H, t), 3.86-3.96 (2H, m), 4.22-4.30 (1H, m), 7.03 (1H, dd), 7.30 (1H, s), 7.38 (1H, d), 7.45 (1H, d), 10.22 (1H, s); m / z (ES+) [M+H]+= 524.1.Intermediate 28b:l-[3-Methyl-l-[l-(4-piperidylmethyl)-4-piperidyl]indol-5-yl]hexahydropyrimidine-2, 4-dioneMe

[0670] Prepared in an analogous method to Intermediate 4e starting from Intermediate 28a (40 mg, 0.08 mmol) to give the title compound in the form of a bis-trifluoroacetate salt (50 mg, 100 %) as a light pink solid after trituration with diethyl ether, m / z (ES+) [M+H]+= 424.0.Example 28l-[l-[l-[[l-[4-[3-[3-amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8- yl]benzoyl] -4-piperidyl]methyl] -4-piperidyl] -3 -methyl -indol-5 -yl]hexahydropyrimidine-2, 4-dioneNH2N

[0671] Prepared in an analogous method to Example 1 starting from Intermediate Ij (17 mg, 0.04 mmol) and Intermediate 28b (31 mg, 0.05 mmol). Purification by RPC (gradient: 5-25% MeCN in water with 0.1% FA) gave the title compound in the form of a formate salt (11.6 mg, 35 %) as a white solid. ’H NMR (DMSO-d6): 5 1.00-1.12 (2H, m), 1.69-1.84 (3H, m), 1.84-2.00 (6H, m), 2.06-2.25 (9H, m), 2.68- 2.76 (2H, m), 2.88 (2H, br d), 2.96 (2H, br d), 3.08 (2H, br d), 3.24-3.28 (2H, m), 3.75 (2H, t), 3.95-4.22 (2H, m), 4.21-4.31 (1H, m), 4.49 (2H, br s), 5.94 (2H, s), 6.81-6.89 (2H, m), 6.92 (2H, d), 7.03 (1H, dd), 7.19-7.24 (1H, m), 7.24-7.30 (3H, m), 7.38 (1H, d), 7.45 (1H, d), 7.47 (1H, s), 7.90 (1H, dd), 10.22 (1H, s), 14.12 (1H, br s); m / z (ES+) [M+H]+= 823.3.EXAMPLE 29Intermediate 29a:tert-Butyl 4-[4-[5-(2,4-dioxohexahydropyrimidin- 1 -yl)indol- 1 -yl] - 1 -piperidyl]piperidine- 1 -carboxylate

[0672] Prepared in an analogous method to Intermediate 5d starting from Intermediate 3h (50 mg, 0.16 mmol). Purification by FSC (0-10% MeOH in DCM with 1% NH4OH) gave the title compound (0.030 g, 38 %) as white solid. 'HNMR (CD2C12): 5 1.40-1.45 (9H, m), 1.46-1.52 (2H, m), 1.77-1.83 (2H, m), 2.06-2.12 (4H, m), 2.44-2.51 (2H, m), 2.53-2.60 (1H, m), 2.68-2.77 (2H, m), 2.81-2.85 (2H, m), 3.10 (2H, br d), 3.86 (2H, t), 4.15 (2H, br s), 4.23 (1H, dt), 6.52 (1H, d), 7.10 (1H, dd), 7.33 (1H, d), 7.42 (1H, d), 7.49 (1H, d), 7.78 (1H, s); m / z (ES+) [M+H]+= 495.9.Intermediate 29b:1 -[ 1 -[ 1 -(4-Piperidyl)-4-piperidyl]indol-5-yl]hexahydropyrimidine-2, 4-dione2HCI

[0673] Prepared in an analogous method to Intermediate lb starting from Intermediate 29a (30 mg, 0.06 mmol). The solution was concentrated to give the title compound in the form of a bis-hydrochloride salt (0.028 g, 99 %) as pink solid, m / z (ES+) [M+H]+= 396.3.Example 29I-[I-[I-[I-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8- yl]benzoyl]-4-piperidyl]-4-piperidyl]indol-5-yl]hexahydropyrimidine-2, 4-dione

[0674] Prepared in an analogous method to EXAMPLE 1 starting from Intermediate Ij (10.56 mg, 0.03 mmol) and Intermediate 29b (10 mg, 0.03 mmol). Purification by RPC (gradient: 10-50% MeCN in water with 0.1% FA) gave the title compound in the form of a formate salt (8.70 mg, 43 %) as a yellow solid. ’H NMR (DMSO-d6): 5 1.38-1.49 (2H, m), 1.78-1.86 (2H, m), 1.92-2.03 (6H, m), 2.15-2.22 (2H, m), 2.40-2.46 (2H, m), 2.57-2.66 (1H, m), 2.70-2.76 (2H, m), 2.98-3.05 (2H, m), 3.07-3.12 (2H, m), 3.27-3.33 (4H, m), 3.77 (1H, s), 3.77 (1H, br d), 4.00-4.28 (2H, m), 4.29-4.38 (1H, m), 4.51 (2H, br s), 5.92-6.01 (2H, m), 6.42-6.49 (1H, m), 6.82-6.89 (2H, m), 6.90-6.97 (2H, m), 7.03-7.10 (1H, m), 7.19-7.26 (1H, m), 7.28-7.32(2H, m), 7.43-7.50 (2H, m), 7.50-7.57 (2H, m), 7.84-7.99 (1H, m), 10.25 (1H, s), 13.60-14.54 (1H, m); m / z (ES+) [M+H]+= 795.5.Example 30l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8- yl]benzoyl]-4-piperidyl]methyl]-4-piperidyl]indol-5-yl]hexahydropyrimidine-2, 4-dione

[0675] Prepared in an analogous method to Example 1 starting from Intermediate Ij (0.024 g, 0.05 mmol) and Intermediate 3j (0.025 g, 0.05 mmol). Purification by RPC (gradient: 5-25% MeCN in water with 0.1% FA) gave the title compound in the form of a formate salt (0.015 g, 34 %) as a white solid. ’H NMR (DMSO-d6): 5 1.04-1.16 (2H, m), 1.74-1.87 (3H, m), 1.90-2.02 (6H, m), 2.12-2.22 (4H, m), 2.22-2.28 (2H, m), 2.70-2.76 (2H, m), 2.86-2.92 (1H, m), 2.96-3.02 (2H, m), 3.07-3.12 (2H, m), 3.29 (3H, br s), 3.73-3.80 (2H, m), 3.96-4.22 (2H, m), 4.31-4.41 (1H, m), 4.46-4.55 (2H, m), 5.93-5.99 (2H, m), 6.42-6.47 (1H, m), 6.82-6.91 (2H, m), 6.91-6.97 (2H, m), 7.05-7.10 (1H, m), 7.21-7.26 (1H, m), 7.26-7.30 (2H, m), 7.43-7.50 (2H, m), 7.50-7.57 (2H, m), 7.88-7.95 (1H, m), 10.17-10.32 (1H, m), 13.84-14.42 (1H, m); m / z (ES+) [M+H]+= 809.4.EXAMPLE 31Intermediate 3 la:tert-Butyl 4-[[4-[4-(2,4-dioxohexahydropyrimidin-l-yl)pyrrolo[2,3-c]pyridin-l-yl]-l-piperidyl]methyl]-4- fluoro-piperidine- 1 -carboxylate

[0676] Prepared in an analogous method to Intermediate 22g starting from Intermediate 2c (25 mg, 0.08 mmol) and Intermediate 21d (32 mg, 0.09 mmol). Purification by FSC (gradient: 0-20% MeOH in DCM) gave the title compound (9.0 mg, 21 %) as a pale yellow solid, m / z (ES ) [M-H]-= 527.3.Intermediate 31b:l-[l-[l-[(4-Fluoro-4-piperidyl)methyl]-4-piperidyl]pyrrolo[2,3-c]pyridin-4-yl]hexa-hydropyrimidine-2,4- dione2TFA

[0677] Prepared in an analogous method to Intermediate 22h starting from Intermediate 3 la (9.0 mg, 0.02 mmol) to give the title compound in the form of a bis-trifluoroacetate salt (8.0 mg, 72 %) as an off-white solid after trituration with diethyl ether, m / z (ES+) [M+H]+= 429.1.Example 31l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8- yl]benzoyl]-4-fhioro-4-piperidyl]methyl]-4-piperidyl]pyrrolo[2,3-c]pyridin-4-yl]hexahydro-pyrimidine- 2,4-dione

[0678] Prepared in an analogous method to EXAMPLE 1 starting from Intermediate Ij (5.0 mg, 0.01 mmol) and Intermediate 31b (8.0 mg, 0.01 mmol). Purification by RPC (gradient: 0-60% MeCN in water with 0.1% NH4OH) gave the title compound (4.1 mg, 40 %) as a white solid. 'HNMR (DMSO-t / 6) 5 1.63-1.81 (2H, m), 1.88-2.11 (7H, m), 2.16-2.24 (2H, m), 2.40-2.48 (3H, m), 2.53-2.59 (4H, m), 2.61-2.67 (2H, m), 2.79 (2H, t), 3.01-3.14 (4H, m), 3.16-3.25 (2H, m), 3.83 (1H, t), 3.89-4.03 (1H, m), 4.48-4.59 (3H, m), 5.96 (2H, s), 6.52 (1H, d), 6.82-6.91 (2H, m), 6.95 (2H, d), 7.19-7.26 (1H, m), 7.32 (2H, d), 7.48 (1H, s), 7.80 (1H, d), 7.91 (1H, dd), 8.09 (1H, s), 8.89 (1H, s), 10.43 (1H, s), 14.14 (1H, s). m / z (ES+) [M+H]+= 828.3.EXAMPLE 32Intermediate 32a:tert-Butyl rel-(3S,4S)-4-[5-(2,4-dioxohexahydropyrimidin-1-yl)indol-1-yl]-3-methyl-piperidine-1-carboxylateortert-Butyl rel-(3R,4R)-4-[5-(2,4-dioxohexahydropyrimidin-1-yl)indol-1-yl]-3-methyl-piperidine-1-carboxylate

[0679] Prepared in an analogous method to Intermediate 4b starting from Intermediate 21b ISOMER 2 (0.108 g, 0.27 mmol). Purification by FSC (gradient: 0-100% EtOAc in hexanes) gave the title compound (0.052 g, 42 %) as a white solid. 'H NMR (CDCh): 50.70 (3H, d), 1.51 (9H, s), 1.90-2.01 (2H, m), 2.09-2.19 (1H, m), 2.52-2.63 (1H, m), 2.84-2.94 (3H, m), 3.88-3.96 (3H, m), 4.23-4.40 (2H, m), 6.57 (1H, d), 7.13 (1H, dd), 7.19 (1H, d), 7.38-7.42 (2H, m), 7.53 (1H, d); m / z (ES+) [M-tBu+2H]+= 370.9.Intermediate 32b:tert-Butyl 4-fluoro-4-[[rel-(3S,4S)-4-[5-(2,4-dioxohexahydropyrimidin-1-yl)indol-1-yl]-3-methyl-1-piperidyl]methyl]piperidine-1-carboxylateortert-Butyl 4-fluoro-4-[[rel-(3R,4R)-4-[5-(2,4-dioxohexahydropyrimidin-1-yl)indol-1-yl]-3-methyl-1-piperidyl]methyl]piperidine-1-carboxylate

[0680] Prepared in an analogous method to Intermediate 21e starting from Intermediate 32a (50 mg, 0.12 mmol) and Intermediate 21d (47 mg, 0.13 mmol). Purification by FSC (gradient: 0-100% EtOAc in hexanes) gave the title compound (26 mg, 41 %) as a white solid. ’H NMR (DMSO-c / 6): 50.53 (3H, d), 1.40 (9H, s), 1.51-1.70 (2H, m), 1.74-1.89 (3H, m), 1.93-2.05 (1H, m), 2.06-2.14 (1H, m), 2.15-2.29 (1H, m), 2.36-2.41 (1H, m), 2.58 (2H, d), 2.71 (2H, t), 2.93-3.12 (4H, m), 3.67-3.81 (4H, m), 3.90-4.01 (1H, m), 6.48 (1H, d), 7.05 (1H, dd), 7.44 (1H, d), 7.49-7.60 (2H, m), 10.23 (1H, s);19F NMR (DMSO-d6): -157.98 (IF, s); m / z (ES+) [M+H]+= 542.1.Intermediate 32c:l-[l-[re / -(3S,4S)-l-[(4-Fluoro-4-piperidyl)methyl]-3-methyl-4-piperidyl]indol-5-yl]hexahydropyrimidine- 2,4-dioneorl-[l-[re / -(3R,4R)-l-[(4-Fluoro-4-piperidyl)methyl]-3-methyl-4-piperidyl]indol-5- yl]hexahydropyrimidine-2, 4-dione2TFA 2TFA

[0681] Prepared in an analogous method to Intermediate 4e starting from Intermediate 32b (25 mg, 0.05 mmol) to give the title compound in the form of a bis-trifluoroacetate salt (30 mg, 100 %) as a light pink solid after trituration with diethyl ether, m / z (ES+) [M+H]+= 442.0.Example 32l-[l-[-(3S,4S)-l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]benzoyl]-4-fluoro-4-piperidyl]methyl]-3-methyl-4-piperidyl]indol-5-yl]hexahydropyrimidine-2, 4-dione orl-[l-[-(37?,47?)-l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]benzoyl]-4-fluoro-4-piperidyl]methyl]-3-methyl-4-piperidyl]indol-5-yl]hexahydropyrimidine-2, 4-dione

[0682] Prepared in an analogous method to Example 1 starting from Intermediate Ij (16 mg, 0.04 mmol) and Intermediate 32c (30 mg, 0.05 mmol). Purification by RPC (gradient: 5-30% MeCN in water with 0.1% FA) gave the title compound in the form of a formate salt (16 mg, 49 %) as a white solid. ’H NMR(DMSO-d6): 50.53 (3H, d), 1.63-1.83 (3H,m), 1.86-1.94 (2H,m), 1.94-2.05 (3H, m), 2.06-2.24 (4H, m), 2.34-2.44 (1H, m), 2.61 (2H, d), 2.71 (2H, t), 2.98-3.04 (2H, m), 3.08 (2H, br d), 3.17-3.24 (2H, m), 3.27-3.28 (2H, m), 3.76 (2H, t), 3.83-4.04 (3H, m), 4.46-4.54 (2H, m), 5.95 (2H, s), 6.47 (1H, d), 6.79-6.89 (2H, m), 6.90-6.96 (2H, m), 7.04 (1H, dd), 7.18-7.24 (1H, m), 7.27-7.33 (2H, m), 7.44 (1H, d), 7.47 (1H, s), 7.49-7.55 (2H, m), 7.89 (1H, dd), 10.23 (1H, s), 14.12 (1H, br s);19F NMR (DMSO-6): -157.56 (IF, s); m / z (ES+) [M+H]+= 841.4.EXAMPLE 33Intermediate 33a:tert-Butyl 4-(5-bromo-3-cyano-indol-1-yl)piperidine-1-carboxylateNBod

[0683] Prepared in an analogous method to Intermediate la starting from 5-bromo-lH-indole-3-carbonitrile (0.884 g, 4 mmol). Diethyl ether was added to residue and the resulting mixture was sonicated. The solid was collected by filtration and dried to give the title compound (1.020 g, 63 %) as a white solid. 'HNMR (CD2CI2): 1.45-1.49 (9H, m), 1.81-2.00 (2H, m), 2.10 (2H, br d), 2.91 (2H, br s), 4.24-4.43 (3H, m), 7.35-7.43 (1H, m), 7.43-7.47 (1H, m), 7.70-7.73 (1H, m), 7.91 (1H, d); m / z (ES+) [M+H]+=404.0.Intermediate 33b:tert-Butyl 4-[3-cyano-5-(2,4-dioxohexahydropyrimidin-1-yl)indol-1-yl]piperidine-1-carboxylateBod

[0684] Prepared in an analogous method to Intermediate 4b starting from Intermediate 33a (0.150 g, 0.37 mmol). Purification by FSC (gradient: 0-100% EtOAc in hexanes) gave the title compound (0.051 g, 31 %) as an off-white solid. ’HNMR (DMSO-d6): 5 1.43 (9H, s), 1.70-1.90 (2H, m), 1.93-2.05 (2H, m), 2.73 (2H, t), 2.80-3.13 (2H, m), 3.82 (2H, t), 4.04-4.20 (2H, m), 4.64-4.78 (1H, m), 7.19-7.41 (1H, m), 7.59 (1H, d), 7.80 (1H, d), 8.50 (1H, s), 10.33 (1H, s); m / z (ES+) [M-tBu+2H]+ = 381.8.Intermediate 33c:5 -(2,4-Dioxohexahydropyrimidin- 1 -yl)- 1 -(4-piperidyl)indole-3 -carbonitrileTFA

[0685] Prepared in an analogous method to Intermediate 4c starting from Intermediate 33b (50 mg, 0.11 mmol) to give the title compound in the form of a trifluoroacetate salt (52 mg, 100 %) as a light yellow solid after trituration with diethyl ether, m / z (ES+) [M+H]+= 337.8.Intermediate 33d:tert-Butyl 4-[[4-[3-cyano-5-(2,4-dioxohexahydropyrimidin-1-yl)indol-1-yl]-1-piperidyl]methyl]-4-fluoro-piperidine-1-carboxylate

[0686] Prepared in an analogous method to Intermediate 22g starting from Intermediate 21e (0.101 g, 0.28 mmol) and Intermediate 33c (52 mg, 0.12 mmol). Purification by RPC (gradient: 10-50% MeCN in water with 0.1% NH4OH) gave the title compound (34 mg, 53 %) as a white solid. ’H NMR (DMSO-d6): δ 1.40 (9H, s), 1.51-1.68 (2H, m), 1.76-1.89 (2H, m), 1.91-2.04 (4H, m), 2.37-2.42 (2H, m), 2.59 (2H, d), 2.73 (2H, t), 2.96-3.09 (4H, m), 3.68-3.77 (2H, m), 3.81 (2H, t), 4.42-4.50 (1H, m), 7.29 (1H, dd), 7.59 (1H, d), 7.77 (1H, d), 8.49 (1H, s), 10.32 (1H, s);19F NMR (DMSO-6): -158.00 (1F, s); m / z (ES+) [M+H]+= 553.2.Intermediate 33e:5-(2,4-Dioxohexahydropyrimidin- 1 -yl)- 1 -[ 1 -[(4-fluoro-4-piperidyl)methyl]-4-piperidyl]indole-3- carbonitrile

[0687] Prepared in an analogous method to Intermediate 4e starting from Intermediate 33d (33 mg, 0.06 mmol) to give the title compound in the form of a bis-trifluoroacetate salt (41 mg, 100 %) as a light pink solid after trituration with diethyl ether, m / z (ES+) [M+H]+= 453.0.Example 33l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2 -fluorobenzoyl] -4-fluoro-4-piperidyl]methyl] -4-piperidyl] -5 -(2,4-dioxohexahydropyrimidin- 1 -yl)indole-3 - carbonitrileNOHO

[0688] Prepared in an analogous method to EXAMPLE 1 starting from Intermediate 12e (22 mg, 0.05 mmol) and Intermediate 33e (41 mg, 0.06 mmol). Purification by RPC (gradient: 10-60% MeCN in water with 0.1%NH4OH) gave the title compound (21 mg, 49 %) as a white solid. ’HNMR (DMSO-t / 6): 51.56-1.75 (2H, m), 1.80-2.03 (8H, m), 2.12-2.24 (2H, m), 2.36-2.44 (2H, m), 2.62 (2H, d), 2.73 (2H, t), 2.96-3.17 (5H, m), 3.21-3.28 (3H, m), 3.37-3.54 (1H, m), 3.81 (2H, t), 4.13-4.33 (1H, m), 4.42-4.53 (3H, m), 5.95 (2H, s), 6.76-6.81 (2H, m), 6.81-6.89 (2H, m), 7.17-7.24 (2H, m), 7.29 (1H, dd), 7.48 (1H, s), 7.59 (1H, d), 7.77 (1H, d), 7.90 (1H, dd), 8.48 (1H, s), 10.32 (1H, s), 14.11 (1H, br s);19F NMR (DMSO-t / e): -158.20 (1F, br s), -113.84 (1F, s); m / z (ES+) [M+H]+= 870.4.Example 34l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]benzoyl]- 4-fluoro-4-piperidyl]methyl]-4-piperidyl]-5-(2,4-dioxohexahydropyrimidin-l-yl)indole-3-carbonitrile

[0689] Prepared in an analogous method to EXAMPLE 1 starting from Intermediate Ij (13 mg, 0.03 mmol) and Intermediate 33e (20 mg, 0.03 mmol). Purification by RPC (gradient: 5-30% MeCN in water with 0.1% FA) gave the title compound in the form of a formate salt (19 mg, 74 %) as white solid. ’H NMR (DMSO-d6): 51.62-1.81 (2H, m), 1.84-2.08 (9H, m), 2.13-2.22 (2H, m), 2.39-2.46 (2H, m), 2.56-2.62 (1H, m), 2.65 (1H, br s), 2.73 (2H, t), 2.98-3.15 (5H, m), 3.14-3.22 (2H, m), 3.21-3.27 (2H, m), 3.76-3.84 (2H, m), 4.43-4.54 (3H, m), 5.95 (2H, s), 6.81-6.88 (2H, m), 6.93 (2H, d), 7.21 (1H, t), 7.26-7.32 (3H, m), 7.47 (1H, s), 7.59 (1H, d), 7.77 (1H, d), 7.89 (1H, d), 8.49 (1H, s), 10.32 (1H, s), 14.00-14.19 (1H, m); m / z (ES+) [M+H]+= 852.5.Example 35Intermediate 35a:tert-Butyl 4-[2-[4-[5-(2,4-dioxohexahydropyrimidin- 1 -yl)indol- 1 -yl]- 1 -piperidyl]-ethyl]piperidine- 1 - carboxylate

[0690] To a mixture of Intermediate 3h, 2.5 g, 8.00 mmol), sodium acetate (1.31 g, 16.0 mmol), tertbutyl 4-(2-oxoethyl)piperidine-l -carboxylate (2.73 g, 12.0 mmol) and AcOH (0.92 mL, 16 mmol) in DCM (120 mL) and MeOH (15 mL) at 10°C was added NaBH(OAc)3 (5.09 g, 24.0 mmol). The mixture was warmed to r.t. and stirred for 18h, then concentrated. Purification by FSC (gradient: 0- 10% MeOH in DCM) gave the title compound (2.49 g, 59 %) as a pink solid. ’HNMR (DMSO-d6): 5 1.01 (2H, qd), 1.40 (13H, s), 1.66 (2H, d), 1.88-2.10 (7H, m), 2.26 (2H, d), 2.47 (1H, s), 2.71 (2H, s), 2.74 (1H, s), 3.08 (2H, d), 3.93 (2H, d), 4.39 (1H, dt), 6.47 (1H, d), 7.08 (1H, dd), 7.46 (1H, d), 7.51-7.58 (2H, m), 10.28 (1H, s); m / z (ES+) [M+H]+= 524.3.Intermediate 35b:l-[l-[l-[2-(4-Piperidyl)ethyl]-4-piperidyl]indol-5-yl]hexahydropyrimidine-2, 4-dione

[0691] To a mixture of Intermediate 35a (2.49 g, 4.75 mmol) in DCM (75 mL) at r.t. was added tert-butyl-dimethylsilyl trifluoromethanesulfonate (1.89 g, 7.13 mmol). The mixture was stirred at r.t. for 4h then concentrated under reduced pressure. Purification by RPC (gradient: 0-40% MeCN in water with 0.05% HC1) gave the title compound in the form of a bis-hydrochloride salt (1.09 g, 46 %) as a pink solid.1HNMR(DMSO-d6): 51.22-1.41 (2H,m), 1.54-1.73 (3H, m), 1.76-1.90 (2H, m), 2.11-2.23 (2H, m), 2.25-2.43 (2H, m), 2.72 (2H, t), 2.78-2.93 (2H, m), 3.07-3.30 (6H, m), 3.60-3.71 (2H, m), 3.76 (2H, t), 4.58-4.78 (1H, m), 6.51 (1H, d), 7.11 (1H, dd), 7.41 (1H, d), 7.48 (1H, d), 7.61 (1H, d), 8.14-8.43 (1H, m), 8.47-8.63 (1H, m), 9.87-10.11 (1H, m), 10.27 (1H, s); m / z (ES+) [M+H]+= 424.2.Example 35l-[l-[l-[2-[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8- yl]benzoyl]-4-piperidyl]ethyl]-4-piperidyl]indol-5-yl]hexahydropyrimidine-2, 4-dioneo

[0692] Prepared in an analogous method to Example 1 starting from Intermediate Ij (10 mg, 0.02 mmol) and Intermediate 35b (11 mg, 0.02 mmol). Purification by RPC (gradient: 0-30% MeCN in water with 0.1% FA) gave the title compound in the form of a formate salt (4.8 mg, 24 %) as an off-white solid.1HNMR(DMSO-d6): 51.04-1.15 (2H,m), 1.38-1.45 (2H, m), 1.53-1.60 (1H, m), 1.66-1.73 (2H, m), 1.85-2.00 (6H, m), 2.08-2.20 (4H, m), 2.34-2.40 (2H, m), 2.69-2.73 (2H, m), 2.78-2.91 (2H, m), 2.97-3.01 (2H, m), 3.05-3.09 (2H, m), 3.26-3.28 (2H, m), 3.75 (2H, br t), 3.94-4.16 (2H, m), 4.29-4.37 (1H, m), 4.49 (2H, br s), 5.96 (2H, s), 6.43 (1H, d), 6.80-6.87 (2H, m), 6.91 (2H, br d), 7.05 (1H, br d), 7.21 (1H, t), 7.26 (2H, br d), 7.45 (2H, d), 7.50-7.56 (2H, m), 7.90 (1H, br d), 10.25 (1H, s), 14.14 (1H, br s); m / z (ES+) [M+H]+= 823.5.EXAMPLE 36Intermediate 36a:5 -Bromo-3 -isopropyl- 1 / / -indole

[0693] 5-Bromo-lH-indole (2.000 g, 10.2 mmol) and acetone (1.185 g, 20.40 mmol) in toluene (15 mL) was added to a stirred solution of triethylsilane (4.89 mL, 30.60 mmol) and TFA (1.179 mL, 15.30 mmol) in toluene (30 mL). The mixture was stirred at 55°C for 16h then cooled to r.t and quenched with sat. aq. NaHCOs (50 mL). The mixture was extracted with EtOAc (2 x 40 mL), then the combined organic solutions were dried (Na2SO4) and concentrated. Purification by FSC (gradient: 0-30% EtOAc in hexanes) gave the title compound (1.90 g, 78 %) as an off-white solid. ’H NMR (CD2CI2): 1.31-1.40 (6H, m), 3.15 (1H, dtd), 6.98-7.03 (1H, m), 7.18-7.31 (2H, m), 7.74-7.79 (1H, m), 8.08 (1H, br s); m / z (ES+) [M+H]+= 238.1.Intermediate 36b:tert-Butyl 4-(5-bromo-3-isopropyl-indol-1-yl)piperidine-1-carboxylateJb

[0694] Prepared in an analogous method to Intermediate la starting from Intermediate 36a (0.953 g, 4 mmol). Purification by FSC (gradient: 10-100% DCM in hexanes) gave the title compound (0.547 g, 32 %) as a white solid. ’HNMR^DzCh): 1.32 (6H, d), 1.47 (9H, s), 1.81-1.93 (2H,m), 2.01 (2H, br d), 2.89 (2H, br s), 3.08-3.18 (1H, m), 4.30 (3H, ddt), 6.98 (1H, s), 7.24 (2H, s), 7.74 (1H, s); m / z (ES+) [M+H]+= 421.1.Intermediate 36c:tert-Butyl 4 - [ 5 -(2,4-dioxohexahydropyrimidin- 1 -y 1) -3 -isopropyl -indol- 1 -yl]piperidine- 1 -carboxylate

[0695] Prepared in an analogous method to Intermediate 2b starting from Intermediate 36b (0.211 g, 0.5 mmol). Purification by FSC (gradient: 0-10% MeOH in DCM) gave the title compound (0.142 g, 62 %) as awhite solid. 'HNMR (CD2C12): 5 1.33 (6H, dd), 1.46-1.49 (9H, m), 1.83-1.96 (2H, m), 1.96-2.07 (2H, m), 2.79-2.86 (2H, m), 2.86-2.98 (2H, m), 3.13-3.21 (1H, m), 3.86 (2H, td), 4.19-4.38 (3H, m), 7.01-7.05 (1H, m), 7.05-7.12 (1H, m), 7.35-7.40 (1H, m), 7.45-7.55 (2H, m); m / z (ES+) [M-Bu+2H] = 399.2.Intermediate 36d:l-[3-Isopropyl-l-(4-piperidyl)indol-5-yl]hexahydropyrimidine-2, 4-dione

[0696] Prepared in an analogous method to Intermediate 4c starting from Intermediate 36c (161 mg, 0.35 mmol). Concentration under reduced pressure gave the title compound in the form of a trifluoroacetate salt (0.135 g, 82 %) as a light yellow solid, m / z (ES+) [M+H]+= 354.7.Intermediate 36e:tert-Butyl 4-[[4-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-isopropyl-indol-1-yl]-1-piperidyl]methyl]-4-fluoro-piperidine-1-carboxylate

[0697] Intermediate 36d (0.047 g, 0.1 mmol) and tert-butyl 4-fluoro-4-formylpiperidine-l -carboxylate (0.046 g, 0.20 mmol) in DCM (2 mL) were stirred at r.t. for 2h then NaBH(OAc)3(0.064 g, 0.30 mmol) was added. The mixture was stirred at r.t. for 2h then concentrated. Purification by FSC (gradient: 0-8% MeOH in DCM) gave the title compound (0.046 g, 80 %) as a white solid, m / z (ES+) [M+H]+= 569.9.Intermediate 36f:1 -[ 1 -[ 1 -[(4-Fluoro-4-piperidyl)methyl] -4-piperidyl] -3-isopropyl-indol-5-yl]hexa-hydropyrimidine-2,4- dioneo o2TFA

[0698] Prepared in an analogous method to Intermediate 4e starting from Intermediate 36e (57 mg, 0.10 mmol). Concentration under reduced pressure gave the title compound in the form of a bis-trifluoroacetate salt (0.062 g, 89 %) as an off-white solid, m / z (ES+) [M+H]+= 470.0.Example 36l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8- yl]benzoyl]-4-fhioro-4-piperidyl]methyl]-4-piperidyl]-3-isopropyl-indol-5-yl]hexahydro-pyrimidine-2,4- dione

[0699] Prepared in an analogous method to Example 1 starting from Intermediate Ij (13 mg, 0.03 mmol) and Intermediate 36f (21 mg, 0.03 mmol). Purification by RPC (gradient: 5-30% MeCN in water with 0.1% FA) gave the title compound in the form of a formate salt (18 mg, 69 %) as a white solid. ’H NMR(DMSO-d6): 51.27 (6H, d), 1.59 - 1.79 (2H, m), 1.81 - 2.04 (8H, m), 2.14 -2.21 (2H, m), 2.34 -2.43 (2H, m), 2.56 - 2.65 (2H, m), 2.72 (2H, t), 2.97 - 3.12 (5H, m), 3.15 - 3.24 (2H, m), 3.26 - 3.28 (2H, m), 3.76 (2H, t), 3.80 - 4.02 (2H, m), 4.20 - 4.33 (1H, m), 4.46 - 4.54 (2H, m), 5.95 (2H, s), 6.78 - 6.87 (2H, m), 6.93 (2H, d), 7.00 - 7.06 (1H, m), 7.16 - 7.23 (1H, m), 7.26 (1H, s), 7.30 (2H, d), 7.42 - 7.51 (3H, m), 7.84 - 7.96 (1H, m), 10.22 (1H, s), 14.12 (1H, br s); m / z (ES+) [M+H]+= 869.6.EXAMPLE 37Intermediate 37a: / ert- Butyl 4-[[4-[5-(2,4-dioxohexahydropyrimidin- 1 -yl)-3-isopropyl-indol- 1 -yl]- 1 - piperidyl]methyl]piperidine- 1 -carboxylate

[0700] Intermediate 36d (0.047 g, O.lmmol) and tert-butyl 4-formylpiperidine-1-carboxylate (0.023 g, 0.11 mmol) in DCM (21 mL) were stirred at r.t. for 20 min then NaBH(OAc)3(0.064 g, 0.30 mmol) was added. The mixture was stirred at r.t. for Ih then concentrated. Purification by FSC (gradient: 0-8% MeOH in DCM) gave the title compound (0.050 g, 91 %) as a white solid. ’HNMR (CD2Q2): 1.02-1.11 (2H, m), 1.31-1.36 (6H, m), 1.41-1.46 (9H, m), 1.61-1.71 (2H, m), 1.72-1.78 (2H, m), 2.01-2.04 (2H, m), 2.04-2.09 (2H, m), 2.09-2.19 (2H, m), 2.23 (2H, d), 2.61-2.76 (2H, m), 2.82 (2H, t), 3.02 (2H, br d), 3.86 (2H, t), 3.99-4.14 (2H, m), 4.19 (IH, br d), 7.04-7.12 (2H, m), 7.36 (IH, d), 7.41-7.46 (IH, m), 7.49 (IH, s); m / z (ES+) [M+H]+= 551.7.Intermediate 37b:l-[3-Isopropyl-l-[l-(4-piperidyhnethyl)-4-piperidyl]indol-5-yl]hexahydropyrimidine-2, 4-dione2TFA

[0701] Prepared in an analogous method to Intermediate 4e starting from Intermediate 37a (55 mg, 0.10 mmol) in DCM (1 mL). Concentration under reduced pressure gave the title compound in the form of a bis-trifluoroacetate salt (0.052 g, 77 %) as a yellow solid, m / z (ES+) [M+H]+= 452.0.Example 37l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8- yl]benzoyl] -4-piperidyl]methyl] -4-piperidyl] -3 -isopropyl -indol-5 -yl]hexahydropyrimidine-2, 4-dione

[0702] Prepared in an analogous method to EXAMPLE 1 starting from Intermediate Ij (13 mg, 0.03 mmol) and Intermediate 37b (20 mg, 0.03 mmol). Purification by RPC (gradient: 5-30% MeCN in water with 0.1% FA) gave the title compound in the form of a formate salt (20 mg, 78 %) as a white solid. ’H NMR (DMSO-d6): 5 1.02-1.14 (2H, m), 1.25-1.29 (6H, m), 1.70-2.02 (10H, m), 2.10-2.25 (6H, m), 2.65-2.78 (2H, m), 2.80-2.93 (2H, m), 2.94-3.00 (2H, m), 3.07-3.12 (2H, m), 3.23-3.28 (2H, m), 3.76 (2H, t), 3.87-4.22 (2H, m), 4.25-4.32 (1H, m), 4.49 (2H, br s), 5.95 (2H, s), 6.81-6.89 (2H, m), 6.92 (2H, d), 7.00-7.05 (1H, m), 7.18-7.23 (1H, m), 7.24-7.29 (3H, m), 7.43-7.48 (3H, m), 7.90 (1H, d), 10.22 (1H, s), 13.96-14.23 (1H, m); m / z (ES+) [M+H]+= 851.6.EXAMPLE 38Intermediate 38a:Methyl 4-[3-[3-amino-6-(5-fluoro-2-hydroxy-phenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-

[0703] Pd Xphos G3 (90 mg, 0.11 mmol) was added to Intermediate Ih (400 mg, 1.07 mmol), 4-fluoro-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenol (255 mg, 1.07 mmol) and Cs2CO3(1046 mg, 3.21 mmol) in 1,4-dioxane (6 mL) and water (0.6 mL) under N2. The resulting mixture was stirred at 100°C for 2h then cooled to r.t. The mixture was filtered through celite then the solids were washed with EtOAc (50 mL). The filtrate was concentrated. Purification by FSC (gradient: 0-100% EtOAc in petroleum ether) gave the title compound (0.100 g, 21 %) as a brown solid. ’H NMR (DMSO-r / 6): 5 0.83 (2H, d), 1.22 (5H, s), 3.75 (4H, s), 4.56 (2H, s), 6.03 (2H, s), 6.85 (IH, dd), 6.95 (2H, d), 7.04 (IH, s), 7.48 (IH, s), 7.73-7.87 (3H, m), 13.95 (IH, s); m / z (ES+) [M+H]+= 450.2Intermediate 38b:4-[3 -[3 -Amino-6-(5 -fluoro-2-hydroxy-phenyl)pyridazin-4-yl] -3, 8 -diazabicyclo [3.2.1] -octan-8-yl]benzoic

[0704] LiOH (53.3 mg, 2.22 mmol) was added to Intermediate 38a (100 mg, 0.22 mmol) in THF (1.5 mL) and water (1.5 mL). The resulting mixture was stirred at 80°C for Ih. The mixture was cooled to r.t. then acidified with aq. IM HC1 to pH 4. The resulting solid was collected by filtration then washed with water and dried under reduced pressure to give the title compound (70 mg, 72 %) as a brown solid. ’H NMR (DMSO-d6): 5 1.94-2.09 (2H, m), 2.15-2.25 (2H, m), 3.08 (2H, d), 3.29-3.31 (2H, m), 4.50-4.62 (2H, m), 6.05 (2H, s), 6.86 (IH, dd), 6.95 (2H, d), 7.06 (IH, td), 7.49 (IH, s), 7.81 (3H, dd) (-OH and -CO2H not observed); m / z (ES+) [M+H]+= 436.2Intermediate 38c:tert-Butyl 4-[[4-[5-(2,4-dioxohexahydropyrimidin-1-yl)indol-1-yl]-1-piperidyl]methyl]-4-fluoro-piperidine-1-carboxylate

[0705] Intermediate 3h (500 mg, 1.60 mmol) was added to tert-butyl 4-fhroro-4-formylpiperidine-l-carboxylate (370 mg, 1.60 mmol) in DCM (2 mL) and warmed to 40°C for Ih. NaBH(OAc)3 (1357 mg, 6.40 mmol) was then added. The resulting mixture was stirred at r.t. for 2h then cooled to r.t. and concentrated. Purification by FSC (gradient: 10-100% EtOAc in hexanes) gave the title compound (0.380 g, 45 %) as a white solid. ’H NMR (DMSO-r / 6): 5 1.40 (9H, s), 1.51 - 1.67 (2H, m), 1.79 - 1.91 (4H, m),1.92 - 2.03 (2H, m), 2.34 - 2.43 (2H, m), 2.54 - 2.63 (2H, m), 2.71 (2H, t), 2.95 - 3.12 (4H, m), 3.68 - 3.79 (4H, m), 4.26 - 4.39 (1H, m), 6.44 (1H, d), 7.06 (1H, dd), 7.44 (1H, d), 7.49 - 7.55 (2H, m), 10.23 (1H, s); m / z (ES+) [M+H]+= 528.3.Intermediate 38d:l-[l-[l-[(4-Fluoro-4-piperidyl)methyl]-4-piperidyl]indol-5-yl]hexahydropyrimidine-2, 4-dione

[0706] Intermediate 38c (380 mg, 0.72 mmol) was added to formic acid (4 mL). The resulting mixture was stirred at 40 °C for 2h. The solvent was removed under reduced pressure. Purification by RPC (gradient: 3-100% MeCN in water with 0.1% NH4HCO3) gave the title compound (0.220 g, 71 %) as a white solid. m / z (ES+) [M+H]+= 428.2.Example 38l-[l-[l-[[l-[4-[3-[3-Amino-6-(5-fluoro-2-hydroxy-phenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8- yl]benzoyl]-4-fluoro-4-piperidyl]methyl]-4-piperidyl]indol-5-yl]hexahydropyrimidine-2, 4-dione

[0707] Prepared in an analogous method to EXAMPLE 1 starting from Intermediate 38b (20 mg, 0.05 mmol) and Intermediate 38d (20 mg, 0.05 mmol). Purification by RPC (gradient: 15-95% MeCN in water with 0.1% NH4HCO3) gave the title compound (11 mg, 29 %) as a white solid. ’HNMR (DMSO-t / e): 5 1.71 (2H, dt), 1.84-2.06 (8H, m), 2.18 (2H, t), 2.36-2.46 (2H, m), 2.59 (1H, s), 2.65 (1H, s), 2.72 (2H, t), 3.04 (2H, d), 3.11 (2H, d), 3.17-3.23 (2H, m), 3.24-3.28 (2H, s), 3.76 (2H, t), 3.93 (2H, s), 4.25-4.41 (1H, m), 4.51 (2H, s), 6.03 (2H, s), 6.45 (1H, d), 6.86 (1H, dd), 6.94 (2H, d), 7.06 (2H, ddd), 7.31 (2H, d), 7.45 (1H, d), 7.47-7.56 (3H, m), 7.85 (1H, dd), 10.25 (1H, s), 13.99 (1H, s);19F NMR (DMSO-6): -125.719, -157.651; m / z (ES+) [M+H]+= 845.5.EXAMPLE 39Intermediate 39a:tert-Butyl 4-[[4-[4-(2,4-dioxohexahydropyrimidin-1-yl)-5-methyl-indol-1-yl]-1-piperidyl]methyl]-4-fluoro-piperidine-1-carboxylate

[0708] Prepared in an analogous method to Intermediate 22g starting from Intermediate 6e (17 mg, 0.05 mmol) and Intermediate 21e (21 mg, 0.06 mmol). Purification by FSC (gradient: 0-20% MeOH in DCM) gave the title compound (24 mg, 85 %) as a sticky reddish brown solid, m / z (ES+) [M+H]+= 542.3.Intermediate 39b:1 -[ 1 -[ 1 -[(4-Fluoro-4-piperidyl)methyl] -4-piperidyl] -5-methyl-indol-4-yl]hexa-hydropyrimidine-2, 4-dione2TFA

[0709] Prepared in an analogous method to Intermediate 22h starting from Intermediate 39a (23 mg, 0.04 mmol) to give the title compound in the form of a bis-trifluoroacetate salt (25 mg, 88 %) as a light brown solid after trituration with diethyl ether, m / z (ES+) [M+H]+= 442.3.Example 39l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8- yl]benzoyl]-4-fluoro-4-piperidyl]methyl]-4-piperidyl]-5-methyl-indol-4-yl]hexahydro-pyrimidine-2,4- dione

[0710] Prepared in an analogous method to EXAMPLE 1 starting from Intermediate Ij (16 mg, 0.04 mmol) and Intermediate 39b (25 mg, 0.04 mmol). Purification by RPC (gradient: 0-65% MeCN in water with 0.1% NH4OH) gave the title compound (7.5 mg, 24%) as a white solid. ’H NMR (DMSO-t / 6): 51.63-1.81 (2H, m), 1.87-2.03 (7H, m), 2.08 (2H, s), 2.15-2.21 (2H, m), 2.21-2.27 (3H, m), 2.38-2.46 (2H, m), 2.61 (1H, s), 2.63-2.68 (1H, m), 2.70-2.80 (1H, m), 2.80-2.88 (1H, m), 3.04 (2H, br d), 3.10 (2H, br d), 3.21 (1H, br s), 3.29 (2H, br d), 3.58 (1H, ddd), 3.71-3.82 (1H, m), 3.94 (2H, br dd), 4.23-4.42 (1H, m), 4.52 (2H, br s), 5.97 (2H, s), 6.40 (1H, d), 6.82-6.89 (2H, m), 6.95 (2H, d), 7.03 (1H, d), 7.18-7.26 (1H, m), 7.32 (2H, d), 7.44 (1H, d), 7.46-7.55 (2H, m), 7.91 (1H, dd), 10.31 (1H, br s), 14.14 (1H, br s); m / z (ES+) [M+H]+= 841.5.Example 40:Intermediate 40a:tert-Butyl 4-(5 -bromo-3 -iodo-indol- 1 -yl)piperidine- 1 -carboxylateIBoe /

[0711] N-Iodosuccinimide (445 mg, 1.98 mmol) was added to Intermediate 3f (715 mg, 1.89 mmol) in DMSO (3.77 mL). The mixture was stirred at r.t. for 1h then quenched with saturated aq. sodium thiosulfate (10 mL) and extracted with EtOAc (3 x 30 mL). The combined organic solutions were then sequentially washed with saturated aq. sodium thiosulfate (10 mL) and brine (10 mL), then dried (Na2SO4) and concentrated. Purification by FSC (gradient: 10-40% EtOAc in hexanes) gave the title compound (0.822 g, 86 %) as a white solid.1H NMR (DMSO-d6): δ 1.44 (9H, s), 1.77-1.96 (4H, m), 2.84-3.08 (2H, m), 4.06-4.20 (2H, m), 4.50-4.70 (1H, m), 7.28-7.46 (2H, m), 7.58-7.72 (1H, m), 7.79-7.93 (1H, m); m / z (ES+) [M+H]+= 503.1.Intermediate 40b:tert-Butyl 4-[5-bromo-3-(1-methylpyrazol-4-yl)indol-1-yl]piperidine-1-carboxylate

[0712] DMF (3.95 mL) and 2M aq. NaHCO3(1 mL, 2.00 mmol) were added sequentially to a mixture of Intermediate 40a (250 mg, 0.49 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (124 mg, 0.59 mmol) and Pd(dppf)Cl2(36.2 mg, 0.05 mmol) under N2. The mixture was sparged for 5 min then stirred at 90°C for 2h. The mixture was cooled to r.t., diluted with EtOAc (20 mL) and water (20 mL), then extracted with EtOAc (3 x 20 mL). The combined organic solutions were washed with 10% aq. LiCl (3 x 5 mL) and brine (5 mL) then dried (Na2SO4) and concentrated. Purification by FSC (gradient: 10-100% EtOAc in hexanes) gave the title compound (0.132 g, 58 %) as a white solid. ’H NMR (DMSO-d6): 51.45 (9H, s), 1.79-1.90 (2H, m), 1.92-1.99 (2H, m), 3.87-3.90 (3H, m), 3.91-3.94 (2H, m), 4.08-4.19 (2H, m), 4.55-4.64 (1H, m), 7.27-7.31 (1H, m), 7.58-7.62 (1H, m), 7.76-7.78 (1H, m), 7.84-7.86 (1H, m), 7.90-7.92 (1H, m), 8.12-8.15 (1H, m); m / z (ES+) [M+H]+= 459.5.Intermediate 40c:tert-Butyl 4-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-(1-methylpyrazol-4-yl)indol-1-yl]piperidine-1-carboxylate

[0713] A solution of Intermediate 40b (133 mg, 0.29 mmol) in 1,4-dioxane (4.65 mL) was added to a mixture of hexahydropyrimidine-2, 4-dione (99 mg, 0.87 mmol), t-BuBrettPhos Pd G3 (24.74 mg, 0.03 mmol), t-BuBrettPhos (14.03 mg, 0.03 mmol), and Cs2CO3(283 mg, 0.87 mmol) under N2. The mixture was stirred at 90°C for 1.5h. The mixture was then cooled to r.t., diluted with EtOAc and filtered through celite. The filtrate was then concentrated. Purification by FSC (gradient: 0-100%, EtOAc in hexane) gave the title compound (0.059 g, 41 %) as a white solid. ’H NMR (DMSO-r / 6): 5 1.45 (9H, s), 1.82-1.91 (2H, m), 1.94-2.01 (2H, m), 2.72-2.80 (2H, m), 2.92-3.07 (2H, m), 3.78-3.83 (2H, m), 3.89 (3H, s), 4.10-4.20 (2H, m), 4.56-4.65 (1H, m), 7.10-7.16 (1H, m), 7.55-7.64 (1H, m), 7.66-7.73 (1H, m), 7.74-7.81 (1H, m), 7.81-7.86 (1H, m), 8.02-8.10 (1H, m), 10.23-10.30 (1H, m); m / z (ES+) [M+H]+= 493.6.Intermediate 40d:1-[3-(1-Methylpyrazol-4-yl)-1-(4-piperidyl)indol-5-yl]hexahydropyrimidine-2,4-dioner V oXNH

[0714] tert-Butyldimethylsilyl trifluoromethanesulfonate (89 μL, 0.39 mmol) was added to Intermediate 40c (95 mg, 0.19 mmol) in DCM (1.8 mL) at r.t. The mixture was stirred at r.t. for 2h then concentrated to give the title compound (76 mg, 100%) as a white solid, m / z (ES+) [M+H]+= 393.3.Intermediate 40e:tert-Butyl 4-[[4-[5-(2,4-dioxohexahydropyrimidin-1-yl)-3-(1-methylpyrazol-4-yl)indol-1-yl]-1-piperidyl]methyl]-4-fluoro-piperidine-1-carboxylate / yN'N'Me

[0715] Tetraisopropoxytitanium (0.115 mL, 0.38 mmol) was added to a stirred solution of tert-butyl 4-fluoro-4-formyl-piperidine-l-carboxylate (0.088 g, 0.38 mmol) and Intermediate 40d (0.075 g, 0.19 mmol) in THF (1.8 mL) at r.t. The mixture was stirred at r.t. for 3h then NaBH(OAc)3(0.121 g, 0.57 mmol) was added. The mixture was stirred at r.t. for 3h then quenched with sat. aq. NaHC’CF (5 mL) and extracted with 3:1 CHCl3 / iPrOH (3 × 20 mL). The combined organic solutions were then dried (Na2SO4) andconcentrated. Purification by RPC (gradient: 10-100% MeCN in water) gave the title compound (0.017 g, 15 %) as a white solid, m / z (ES+) [M+H]+= 608.4.Intermediate 40f:1-[1-[1-[(4-Fluoro-4-piperidyl)methyl]-4-piperidyl]-3-(1-methylpyrazol-4-yl)indol-5-yl]hexahydropyrimidine-2,4-dione

[0716] Intermediate 40e (70 mg, 0.12 mmol) was stirred in 4M HC1 in 1,4-dioxane (3 mL, 12.00 mmol) at r.t for 0.5h then concentrated to give the title compound as a bis-hydrochloride salt (66 mg, 100 %) as a white solid, m / z (ES+) [M+H]+= 508.6.Example 401-[1-[1-[[1-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8-yl]benzoyl]-4-fluoro-4-piperidyl]methyl]-4-piperidyl]-3-(1-methylpyrazol-4-yl)indol-5-yl]hexahydropyrimidine-2,4-dione

[0717] Prepared in an analogous method to EXAMPLE 1 starting from Intermediate Ij (40 mg, 0.10 mmol) and Intermediate 40f (58 mg, 0.11 mmol). Purification by RPC (gradient: 5-45% MeCN in water with 0.1% FA) gave the title compound in the form of a formate salt (9.4 mg, 11%) as a white solid. ’H NMR (DMSO-d6): 5 1.22-1.33 (1H, m), 1.34-1.46 (1H, m), 1.67-1.81 (2H, m), 1.93 (8H, br d), 2.14-2.26 (2H, m), 2.39-2.48 (2H, m), 2.59-2.69 (2H, m), 2.72-2.81 (2H, m), 3.03-3.15 (4H, m), 3.17-3.25 (2H, m), 3.27-3.29 (1H, m), 3.77-3.85 (2H, m), 3.89 (3H, br s), 3.94-4.09 (1H, m), 4.31-4.41 (1H, m), 4.47-4.56 (2H, m), 5.87-6.03 (2H, m), 6.81-6.90 (2H, m), 6.95 (2H, br d), 7.08-7.15 (1H, m), 7.19-7.25 (1H, m), 7.28-7.36 (2H, m), 7.45-7.52 (1H, m), 7.56 (1H, br d), 7.70 (1H, br s), 7.81 (2H, br d), 7.91 (1H, br d), 8.04-8.11 (1H, m), 10.28 (1H, br s) 14.06 (1H, br s); m / z (ES+) [M+H]+= 907.6.EXAMPLE 41Intermediate 41a:tert-Butyl 6-[[4-[5-(2,4-dioxohexahydropyrimidin-1-yl)indol-1-yl]-1-piperidyl]-methyl]-2-azaspiro[3.3]heptane-2-carboxylate

[0718] NaBH(OAc)3(678 mg, 3.20 mmol) was added to a mixture of tert-butyl 6-formyl-2-azaspiro[3.3]heptane-2-carboxylate (361 mg, 1.60 mmol) and Intermediate 3h (250 mg, 0.80 mmol) in THF (4 mL). The resulting mixture was stirred at r.t for Ih then diluted with DCM (100 mL) and washed sequentially with water (50 mL) and brine (50 mL). The organic layer was separated, dried (Na2SO4) and concentrated. Purification by FSC (gradient: 0-20% MeOH in DCM) gave the title compound (0.300 g, 72 %) as awhite solid. 'HNMR (DMSO-d6): δ 1.37 (9H, s), 1.82-1.97 (7H, m), 2.08-2.21 (5H, m), 2.32-2.39 (3H, m), 2.76 (2H, t), 3.73-3.84 (6H, m), 4.46-4.52 (1H, m), 6.41 (1H, d), 6.92-7.01 (1H, m), 7.11-7.16 (1H, m), 7.47-7.57 (2H, m), 10.34 (1H, s); m / z (ES+) [M+H]+= 522.4.Intermediate 41b:1-[1-[1-(2-Azaspiro[3.3]heptan-6-ylmethyl)-4-piperidyl]indol-5-yl]hexahydro-pyrimidine-2,4-dione

[0719] Prepared in an analogous method to Intermediate 3j starting from Intermediate 41a (290 mg, 0.56 mmol). Purification by RPC (gradient: 5-100% MeCN in water with 0.1% NH4HCO3) gave the title compound (0.200 g, 80 %) as a yellow oil. m / z (ES+) [M+H]+= 422.4.Example 411-[1-[1-[[2-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8-yl]benzoyl]-2-azaspiro[3.3]heptan-6-yl]methyl]-4-piperidyl]indol-5-yl]hexahydropyrimidine-2,4-dione

[0720] Prepared in an analogous method to Example 1 starting from Intermediate Ij (69.3 mg, 0.17 mmol) and Intermediate 41b (100 mg, 0.24 mmol). Purification by RPC (gradient: 0-60% MeCN in water with 0.1% FA) gave the title compound in the form of a formate salt (15 mg, 7.7 %) as a white solid. ’H NMR (DMSO-d6): 5 1.89-2.13 (6H, m), 2.15-2.24 (3H, m), 2.27-2.42 (3H, m), 2.68-2.75 (4H, m), 2.76-2.88 (2H, m), 2.98-3.12 (3H, m), 3.21-3.26 (4H, m), 3.72-3.77 (2H, m), 3.88-4.12 (2H, m), 4.17-4.39 (2H, m), 4.42-4.61 (3H, m), 5.99 (2H, s), 6.45 - 6.58 (1H, m), 6.79-7.01 (4H, m), 7.04-7.16 (1H, m), 7.17-7.25 (1H, m), 7.42-7.71 (6H, m), 7.86-7.93 (1H, m), 10.28 (1H, s), (-OH not observed); m / z (ES+) [M+H]+= 821.4.EXAMPLE 42Intermediate 42a:tert-Butyl 8-(4-(benzylthio)phenyl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate

[0721] A flask containing benzyl(4-bromophenyl)sulfane (3.00 g, 10.74 mmol), tert-butyl 3,8-diazabicyclo[3.2.1]-octane-3-carboxylate (2.28 g, 10.74 mmol), Pd(OAc)2 (0.190 g, 0.85 mmol), BINAP (0.950 g, 1.53 mmol), Cs2CO3(10.2 g, 31.31 mmol) and toluene (40 mL) was purged with N2 for 10 min, then stirred at 110°C for 22h. After cooling to r.t. the mixture was filtered and the filter cake was washed with EtOAc. The filtrate was concentrated under reduced pressure. Purification by FSC (gradient: 0-20% EtOAc in hexanes) gave the title compound (2.74 g, 62 %) as an oil. ’HNMR: (CDCI3) 5 1.46 (9H, s), 1.77-1.95 (2H, m), 1.96-2.04 (2H, m), 3.20 (1H, br d), 3.30 (1H, br d), 3.60 (1H, br d), 3.74 (1H, br d), 3.97 (2H, s), 4.11-4.16 (1H, m), 4.16-4.25 (1H, m), 6.70 (2H, br d), 7.17-7.26 (7H, m); m / z (ES+) [M+H]+= 411.2.Intermediate 42b:8-(4-(Benzylthio)phenyl)-3,8 -diazabicyclo [3.2.1] octane

[0722] Prepared in an analogous method to Intermediate 3b starting from Intermediate 42a (2.73 g, 6.65 mmol). Concentration under reduced pressure gave the title compound in the form of a hydrochloride salt (2.30 g, 95 %) as a white solid.1H NMR (DMSO-d6): δ 2.00-2.12 (4H, m), 2.90-3.05 (4H, m), 4.05 (2H, s), 4.36 (2H, br s), 6.77-6.86 (2H, m), 7.17-7.29 (7H, m), 9.04 (1H, br s), 9.42 (1H, br s); m / z (ES+) [M+H]+= 311.1.Intermediate 42c:4-( 8 -(4-(Benzylthio)phenyl)-3, 8 -diazabicyclo [3.2.1] octan-3 -yl) -6-chloropyridazin-3 -amine

[0723] A mixture of Intermediate 42b (2.30 g, 6.63 mmol), 4-bromo-6-chloropyridazin-3-amine (1.39 g, 6.67 mmol), DIPEA (4.6 mL, 26.34 mmol) and DMA (7 mL) was heated to 120°C for Ih under N2. After cooling to r.t. the mixture was diluted with water (3 mL) and extracted with EtOAc (2 x 30 mL). The combined organic solutions were washed with water, dried (Na2SO4) and concentrated under reduced pressure to give a pale orange solid. The solid was suspended in 10 mL MeOH, gently warmed with stirring, then cooled to r.t. The solid was then collected by filtration and washed with ice cold MeOH. The solid was dried under reduced pressure to give the title compound (1.66 g, 57 %) as a tan solid. ’HNMR: (CDCI3) 5 2.00-2.07 (2H, m), 2.15-2.25 (2H, m), 3.08-3.21 (4H, m), 3.99 (2H, s), 4.33 (2H, br s), 5.00 (2H, br s), 6.67-6.73 (3H, m), 7.19-7.26 (7H, m); m / z (ES+) [M+H]+= 438.1.Intermediate 42d:4-(8-(4-(Benzylthio)phenyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(2-(methoxymethoxy)phenyl)pyridazin-3-amine

[0724] A vial containing K2CO3 (0.694 g, 5.02 mmol), Pd XPhos G3 (0.213 g, 0.25 mmol), (2-(methoxymethoxy)-phenyl)-boronic acid (0.548 g, 3.01 mmol) and Intermediate 42c (1.10 g, 2.51 mmol), 1,4-dioxane (20.9 mL) and water (4.2 mL) was purged with N2 for 5 min then heated to 100°C for Ih. After cooling to r.t. the mixture was diluted with EtOAc (50 mL) and washed with water (25 mL). The organic layer was separated, dried (Na2SO4) and concentrated under reduced pressure to give the title compound (1.35 g, 100 %) as a red solid. ’HNMR: (CDCI3) 52.03-2.13 (2H, m), 2.16-2.23 (2H, m), 3.09-3.24 (4H, m), 3.34 (3H, s), 3.98 (2H, s), 4.34 (2H, br s), 5.13 (2H, s), 6.72 (3H, d), 7.11-7.24 (10H, m), 7.33-7.41 (2H, m), 7.69 (1H, dd); m / z (ES+) [M+H]+= 540.2.Intermediate 42e:tert-Butyl (4-(8-(4-(benzylthio)phenyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6-(2-(methoxymethoxy)phenyl)pyridazin-3-yl)(tert-butoxycarbonyl)carbamate

[0725] A flask containing Intermediate 42d (1.35 g, 2.50 mmol) was charged with di-tert-butyl dicarbonate (1.146 g, 5.25 mmol) and DMAP (61 mg, 0.50 mmol). DCM (20 mL) was then added, followed by triethylamine (1.046 mL, 7.50 mmol). The mixture was stirred at r.t. for 19h and then concentrated under reduced pressure. Purification by FSC (gradient: 0-60% EtOAc in hexanes) gave the title compound (1.166 g, 63 %) as a light orange foam.1H NMR: (CDCl3) δ 1.45 (18H, s), 1.95-2.03 (2H, m), 2.07-2.15 (2H, m), 3.30-3.41 (7H, m), 3.98 (2H, s), 4.29 (2H, br s), 5.17 (2H, s), 6.72 (2H, d), 7.13-7.25 (9H, m), 7.37-7.46 (2H, m), 7.92 (1H, dd); m / z (ES+) [M+H]+= 740.3.Intermediate 42f:tert-Butyl (tert-butoxycarbonyl)(4-(8-(4-(chlorosulfonyl)phenyl)-3,8-diaza-bicyclo[3.2.1]octan-3-yl)-6-(2-(methoxymethoxy)phenyl)pyridazin-3-yl)carbamate

[0726] A mixture Intermediate 42e (0.102 g, 0.14 mmol), DCM (3 mL), water (0.050 mL) and AcOH (0.100 mL) was cooled to 0°C, then l,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (62.5 mg, 0.32 mmol) was added as a solid in one portion. After stirring at this temperature for 20 min further 1,3-dichloro-5, 5 -dimethyl -imidazolidine-2, 4-dione (18 mg, 0.09 mmol) was added and the mixture was stirred for an additional 20 min. The mixture was then diluted with brine (5 mL). The organic layer was separated, dried (Na2SO4) and concentrated under reduced pressure. Purification by FSC (gradient: 0-60% EtOAc in DCM) gave the title compound (23 mg, 23 %) as a yellow oil. m / z (ES+) [M+H]+= 716.2.Intermediate 42g:tert-Butyl N-tert-butoxycarbonyl-N-[4-[8-[4-[[4-[[4-[4-(2,4-dioxohexahydropyrimidin-1-yl)indol-1-yl]-1-piperidyl]methyl]-1-piperidyl]sulfonyl]phenyl]-3,8-diazabicyclo[3.2.1]octan-3-yl]-6-[2-(methoxymethoxy)phenyl]pyridazin-3-yl]carbamate

[0727] A 20 mL vial was charged with Intermediate 42f (0.013 g, 0.02 mmol) and DMA (0.6 mL), then Intermediate 7b (0.011 g, 0.02 mmol) and triethylamine (0.008 mL, 0.05 mmol) were sequentially added. After stirring for Ih at r.t. the mixture was concentrated under reduced pressure to give the title compound (0.020 g, 100%) as a white solid, m / z (ES+) [M+H]+= 1089.5.Example 421-[1-[1-[[1-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]phenyl]sulfonyl-4-piperidyl]methyl]-4-piperidyl]indol-5-yl]hexahydropyrimidine-2,4-dione

[0728] Intermediate 42g (20 mg, 0.02 mmol) was stirred in 4M HC1 in 1,4-dioxane (0.80 mL, 3.20 mmol). The mixture was stirred at r.t. for 0.5h then concentrated under reduced pressure. Purification by RPC (gradient: 40-70% methanol in water with 0.1% FA) gave the title compound in the form of a formate salt (2 mg, 12 %) as a white solid.1H NMR (DMSO-d6): δ 1.73-1.80 (2H, m), 1.84-1.90 (3H,m), 1.90-1.95 (2H, m), 1.98-2.04 (3H, m), 2.04-2.09 (2H, m), 2.11-2.15 (2H, m), 2.18-2.26 (5H, m), 2.75-2.78 (2H, m), 2.84-2.91 (3H, m), 3.03-3.08 (3H, m), 3.58-3.63 (2H, m), 3.75-3.80 (2H, m), 4.26-4.35 (1H, m), 4.56-4.62 (2H, m), 5.94-6.04 (2H, m), 6.35-6.43 (1H, m), 6.82-6.88 (2H, m), 6.94-6.99 (1H, m), 7.03-7.08 (2H, m), 7.11-7.18 (1H, m), 7.18-7.24 (1H, m), 7.46-7.53 (5H, m), 7.84-7.93 (1H, m), 10.24-10.36 (1H, m), 14.01-14.17 (1H, m); m / z (ES+) [M+H]+= 845.4.EXAMPLE 43Intermediate 43a:tert-Butyl 4-[[4-[3-cyano-5-(2,4-dioxohexahydropyrimidin-1-yl)indol-1-yl]-1-piperidyl]methyl]piperidine-1-carboxylate

[0729] Intermediate 33c (0.045 g, 0.1 mmol) and tert-butyl 4-formylpiperidine-1-carboxylate (0.023 g, 0.11 mmol) in DCM (2 mL) and DMF (0.1 mL) were stirred at r.t for 2h then NaBH(OAc)3(0.064 g, 0.30 mmol) was added. The mixture was stirred at r.t. for 2h then concentrated under reduced pressure. Purification by FSC (gradient: 0-8% MeOH in DCM) gave the title compound (0.051 g, 95 %) as a white solid.1H NMR (CDCl3): δ 1.06 (2H, qd), 1.42-1.49 (9H, m), 1.60-1.70 (1H, m), 1.74 (2H, br d), 1.95-2.07 (2H, m), 2.07-2.13 (2H, m), 2.14-2.22 (2H, m), 2.21-2.28 (2H, m), 2.69 (2H, br s), 2.84 (2H, t), 3.04 (2H, br d), 3.90 (2H, t), 4.01-4.15 (2H, m), 4.19-4.32 (1H, m), 7.31 (1H, dd), 7.52 (2H, br d), 7.60-7.67 (1H, m), 7.81 (1H, s); m / z (ES+) [M+H]+= 535.4.Intermediate 43b:5-(2,4-Dioxohexahydropyrimidin-1-yl)-1-[1-(4-piperidylmethyl)-4-piperidyl]indole-3-carbonitrile27FA

[0730] Prepared in an analogous method to Intermediate 4e starting from Intermediate 43a (51 mg, 0.10 mmol). Concentration under reduced pressure to give the title compound in the form of a bis-trifluoroacetate salt (45 mg, 71 %) as a yellow solid, m / z (ES+) [M+H]+= 435.3.Example 431-[1-[[1-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]octan-8-yl]benzoyl]-4-piperidyl]methyl]-4-piperidyl]-5-(2,4-dioxohexahydropyrimidin-1-yl)indole-3-carbonitrile

[0731] Prepared in an analogous method to EXAMPLE 1 starting from Intermediate Ij (13 mg, 0.03 mmol) and Intermediate 43b (20 mg, 0.03 mmol). Purification by RPC (gradient: 5-30% MeCN in water with 0.1% FA) gave the title compound in the form of a formate salt (11 mg, 44 %) as a white solid. ’H NMR (DMSO-d6): 5 1.02-1.16 (2H, m), 1.70-1.85 (3H, m), 1.92-2.01 (6H, m), 2.12-2.27 (6H, m), 2.68-2.75 (2H, m), 2.83-2.95 (2H, m), 2.98 (2H, br d), 3.08 (2H, br d), 3.19-3.29 (4H, m), 3.77-3.84 (2H, m), 4.43-4.54 (3H, m), 5.95 (2H, s), 6.81-6.88 (2H, m), 6.92 (2H, d), 7.19-7.30 (4H, m), 7.47 (1H, s), 7.59 (1H, d), 7.76-7.81 (1H, m), 7.89 (1H, d), 8.48 (1H, s), 10.32 (1H, s), 14.00-14.32 (1H, m); m / z (ES+) [M+H]+= 834.5.EXAMPLE 44Intermediate 44a:tert-Butyl 4-(5-bromo-7-fluoro-indol-1-yl)piperidine-1-carboxylate

[0732] Prepared in an analogous method to Intermediate la starting from 5 -bromo-7 -fluoro- IH-indole (1.07 g, 5.0 mmol). Purification by FSC (gradient: 0-20% EtOAc in heptane) gave the title compound (0.885 g, 45 %) as a white solid.1H NMR (DMSO-d6): δ 1.42 (9H, s), 1.83 (2H, qd), 2.00 (2H, d), 2.91 (2H, s),4.12 (2H, d), 4.65 (1H, tt), 6.53 (1H, dd), 7.17 (1H, dd), 7.59 (1H, d), 7.65 (1H, d); m / z (ES+) [M-tBu+2H]+= 341.0.Intermediate 44b:tert-Butyl 4-[5-(2,4-dioxohexahydropyrimidin-1-yl)-7-fluoro-indol-1-yl]piperidine-1-carboxylate

[0733] Prepared in an analogous method to Intermediate 4b starting from Intermediate 44a (0.846 g, 2.13 mmol). Purification by FSC (gradient: 0-100% EtOAc in heptane) gave the title compound (0.180 g, 20 %) as an off-white solid.1H NMR (DMSO-d6): δ 1.43 (9H, d), 1.86 (2H, qd), 1.96-2.09 (2H, m), 2.72 (2H, t), 2.92 (2H, s), 3.78 (2H, t), 4.13 (2H, s), 4.68 (1H, tt), 6.51-6.6 (1H, m), 7.00 (1H, dd), 7.32 (1H, d), 7.63 (1H, d), 10.32 (1H, s); m / z (ES+) [M-tBu+2H]+= 375.1.Intermediate 44c:l-[7-Fluoro-l-(4-piperidyl)indol-5-yl]hexahydropyrimidine-2, 4-dione

[0734] Prepared in an analogous method to Intermediate 23c starting from Intermediate 44b (30 mg, 0.07 mmol) to give the title compound (23 mg, 100%) as a golden brown solid. [M+H]+= 331.5.Intermediate 44d:tert-Butyl 4-[[4-[5-(2,4-dioxohexahydropyrimidin-1-yl)-7-fluoro-indol-1-yl]-1-piperidyl]methyl]-4-fluoro-piperidine-1-carboxylate

[0735] Prepared in an analogous method to Intermediate 22g starting from Intermediate 44c (23 mg, 0.07 mmol) and Intermediate 21d (28 mg, 0.08 mmol). Purification by FSC (gradient: 0-20% MeOH in DCM) gave the title compound (17 mg, 45 %) as an orange solid. ’H NMR (DMSO-c / 6): 5 1.41 (9H, s), 1.52-1.68 (2H, m), 1.79-1.89 (2H, m), 1.92-2.06 (4H, m), 2.28-2.37 (2H, m), 2.57-2.62 (2H, m), 2.72 (2H, t), 3.06 (4H, br d), 3.66-3.82 (4H, m), 4.41-4.55 (1H, m), 6.51-6.59 (1H, m), 6.99 (1H, dd), 7.32 (1H, d), 7.63 (1H, d), 10.32 (1H, s); m / z (ES+) [M+H]+= 546.3.Intermediate 44e:l-[7-Fluoro-l-[l-[(4-fluoro-4-piperidyl)methyl]-4-piperidyl]indol-5-yl]hexa-hydropyrimidine-2, 4-dione2TFA

[0736] Prepared in an analogous method to Intermediate 22h starting from Intermediate 44d (17 mg, 0.04 mmol) to give the title compound in the form of a bis-trifluoroacetate salt (16 mg, 76 %) as a light brown solid after trituration with diethyl ether, m / z (ES+) [M+H]+= 446.3.Example 44l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8-yl]benzoyl]-4-fluoro-4-piperidyl]methyl]-4-piperidyl]-7-fluoro-indol-5-yl]hexahydropyrimidine-2, 4-dione

[0737] Prepared in an analogous method to Example 1 starting from Intermediate Ij (9.9 mg, 0.02 mmol) and Intermediate 44e (16 mg, 0.02 mmol). Purification by RPC (gradient: 5-30% MeCN in water with 0.1% FA) gave the title compound in the form of a formate salt (7.3 mg, 37 %) as a white solid. ’H NMR (DMSO-d6): 5 1.60-1.80 (2H, m), 1.83-2.06 (8H, m), 2.15-2.25 (2H, m), 2.30-2.40 (2H, m), 2.59-2.67 (2H, m), 2.72 (2H, t), 3.08 (4H, br dd), 3.22 (4H, br d), 3.78 (2H, t), 3.85-4.03 (2H, m), 4.42-4.59 (3H, m), 5.96 (2H, s), 6.81-6.91 (2H, m), 6.92-7.02 (3H, m), 7.19-7.26 (1H, m), 7.28-7.35 (3H, m), 7.48 (1H, s), 7.62 (1H, d), 7.91 (1H, dd), 8.37 (1H, s), 10.32 (1H, s), 14.13 (1H, br s); m / z (ES+) [M+H]+= 845.5EXAMPLE 45Intermediate 45a:( 1 -Acetyl -6-bromo-indol-3 -yl) acetateAc

[0738] DMAP (0.385 g, 3.15 mmol) was added to a mixture of (6-bromo-lH-indol-3-yl) acetate (4.0 g, 15.74 mmol), acetic anhydride (14.85 mL, 157.43 mmol), and triethylamine (4.39 mL, 31.49 mmol) in THF (60 mL) at r.t. The mixture was stirred at 80°C for 2h then cooled to r.t. and concentrated under reduced pressure. Purification by FSC (gradient: 0-20% EtOAc in petroleum ether) gave the title compound (2.34 g, 50 %) as a purple solid. 'H NMR (DMSO-d6): 5 2.36 (3H, s), 2.60 (3H, s), 7.48 (2H, t), 7.92 (1H, s), 8.48-8.55 (1H, m); m / z (ES+) [M+H]+= 296.0.Intermediate 45b: / / 7- Butyl 4-( 1 -acetyl-6-bromo-indol-3 -yl)piperazine- 1 -carboxylateAc

[0739] 4-Methylbenzene-1-sulfonic acid (0.256 g, 1.49 mmol) was added to a mixture of Intermediate 45a (2.2 g, 7.43 mmol) and tert-butyl piperazine-1-carboxylate (6.92 g, 37.15 mmol) in toluene (50 mL) at r.t. The resulting mixture was stirred at 120°C for 24h then cooled to r.t. and concentrated under reduced pressure. Purification by FSC (gradient: 0-30% EtOAc in petroleum ether) gave a 2:3 mixture of the title compound and side product tert-butyl 4-(6-bromo-1H-indol-3-yl)piperazine-1-carboxylate (1.090 g) as a purple solid, which was used in the next step without further purification, m / z (ES+) [M+H]+= 422.1.Intermediate 45c:tert- Butyl 4-(6-bromo- I H-indol -3 -yl)piperazine- 1 -carboxylateHBrBoc /

[0740] Triethylamine (1.80 mL, 12.90 mmol) was added to a 2:3 mixture of Intermediate 45b and tert-butyl 4-(6-bromo-1H-indol-3-yl)piperazine-1-carboxylate (1.090 g) in MeOH (40 mL) at r.t. The resulting mixture was stirred at 60°C for 2h then cooled to r.t. and concentrated under reduced pressure to give the title compound (1.0 g, 36 % over two steps) as a purple solid. ’H NMR (DMSO-r / 6): 5 1.43 (9H, s), 2.89 (4H, t), 3.51 (4H, t), 6.92 (1H, d), 7.07 (1H, dd), 7.48 (2H, dd), 10.74 (1H, s); m / z (ES+) [M+H]+= 380.1.Intermediate 45d: / ert-Buty I 6-bromo-3 -(4-tert-butoxy carbonylpiperazin- 1 -yl)indole- 1 -carboxylateBocBrBoc /

[0741] Di-tert-butyl dicarbonate (1.22 mL, 5.26 mmol) was added to a mixture of Intermediate 45c (1.0 g, 2.63 mmol), triethylamine (1.10 mL, 7.89 mmol), and DMAP (0.032 g, 0.26 mmol) in DCM (30 mL) at r.t. The resulting mixture was stirred at r.t. for Ih then concentrated under reduced pressure. Purification by FSC (gradient: 0-15% EtOAc in petroleum ether) gave the title compound (1.20 g, 95 %) as a pale yellow solid. ’HNMR (DMSO-d6): 5 1.42 (9H, s), 1.61 (9H, s), 2.95 (4H, t), 3.51 (4H, t), 7.07 (IH, s), 7.40 (IH, dd), 7.62 (IH, d), 8.24 (IH, s); m / z (ES+) [M+H]+= 480.2.Intermediate 45e: / ert-Buty I 3 -(4-tert-butoxy carbonylpiperazin- 1 -yl)-6-(2,4-dioxohexahydropyrimidin- 1 -yl)indole- 1 - carboxylateBocr) OBoc'

[0742] Prepared in an analogous method to Intermediate 3g starting from Intermediate 45d (1.20 g, 2.50 mmol). Purification by FSC (gradient: 0-70% EtOAc in petroleum ether) gave the title compound (1.00 g, 78 %) as an off-white solid. ’H NMR (DMSO-d6): 5 1.43 (9H, s), 1.61 (9H, s), 2.73 (2H, t), 2.94-3.01 (4H, m), 3.49-3.55 (4H, m), 3.83 (2H, t), 7.07 (1H, s), 7.21 (1H, dd), 7.64 (1H, d), 8.05 (1H, s), 10.37 (1H, s); m / z (ES+) [M+H]+= 514.3.Intermediate 45f:1 -(3 -Piperazin- 1 -yl- I H-indol -6-y I )hcxahydrop rim idinc-2.4-dioneH N O

[0743] Tert-butyldimethylsilyl trifluoromethanesulfonate (1.467 g, 5.55 mmol) was added to a stirred solution of Intermediate 45e (0.95 g, 1.85 mmol) in DCM (30 mL) at r.t. The resulting mixture was stirred at r.t for 16h then concentrated under reduced pressure. Purification by RPC (gradient: 0-20% MeCN in water with NH4HCO3) gave the title compound (0.490 g, 85 %) as a pale yellow solid. ’H NMR: 52.72 (2H, t), 2.90-3.01 (8H, m), 3.78 (2H, t), 6.85-6.92 (2H, m), 7.22 (1H, d), 7.49 (1H, d), 10.28 (1H, s), 10.60 (1H, d); m / z (ES+) [M+H]+= 314.1.Intermediate 45g:tert-butyl 4-||4-|6-(2.4-dioxohcxahydropyrimidin-l-yl)-IH-indol-3-yl |pipcrazin-l-yl |mcthyl |pipcridinc- 1 -carboxylate

[0744] A mixture of tert-butyl 4-formylpiperidine-1-carboxylate (0.020 g, 0.10 mmol) and Intermediate 45f (0.030 g, 0.10 mmol) in DCM (0.2 mL) and MeOH (0.2 mL) was stirred at r.t. for 5 min then NaBH(OAc)3(0.061 g, 0.29 mmol) was added. The mixture was stirred at r.t. for 45 min then concentrated under reduced pressure. Purification by RPC (gradient: 10-100% MeCN in water with 0.1% FA) gave the title compound in the form of a formate salt (0.042 g, 86 %) as a yellow gum. m / z (ES+) [M+H]+= 511.3.Intermediate 45h:1 -[3-[4-(4-Piperidylmethyl)piperazin- 1 -yl] - 1 H-indol-6-yl |hcxahydropyrimidinc-2.4-dione

[0745] 4M HC1 in 1,4-dioxane (0.21 mL, 0.82 mmol) was added to a stirred solution of Intermediate 45g (0.042 g, 0.08 mmol) in 1,4-dioxane (0.2 mL). The mixture was stirred at r.t for 0.5h then concentrated under reduced pressure to give the title compound in the form of a bis-hydrochloride salt (0.026 g, 64 %) as a tan solid, m / z (ES+) [M+H]+= 411.2.Example 45l-[3-[4-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8- yl]benzoyl]-4-piperidyl]methyl]piperazin- 1 -yl] - lH-indol-6-yl]hexahydropyrimidine-2, 4-dione

[0746] Prepared in an analogous method to EXAMPLE 1 starting from Intermediate Ij (15 mg, 0.03 mmol) and Intermediate 45h (12 mg, 0.03 mmol). Purification by RPC (gradient: 5-15% MeCN in water with 0.1% FA) gave the title compound in the form of a formate salt (10 mg, 40 %) as a white solid. ’H NMR (DMSO-d6): 5 1.03-1.15 (2H, m), 1.71-1.80 (2H, m), 1.80-1.89 (1H, m), 1.96-2.03 (2H, m), 2.16-2.22 (2H, m), 2.22-2.27 (2H, m), 2.55-2.59 (3H, m), 2.69-2.77 (2H, m), 2.84-2.93 (2H, m), 2.98 (4H, br s), 3.06-3.14 (2H, m), 3.21-3.29 (4H, m), 3.75-3.80 (2H, m), 4.01-4.21 (1H, m), 4.45-4.54 (2H, m), 5.91-5.98 (2H, m), 6.83-6.90 (4H, m), 6.91-6.97 (2H, m), 7.19-7.26 (2H, m), 7.26-7.31 (2H, m), 7.44-7.50 (2H, m), 7.87-7.95 (1H, m), 10.20-10.32 (1H, m), 10.49-10.65 (1H, m), 13.58-14.63 (1H, m); m / z (ES+) [M+H]+= 810.4.EXAMPLE 46Intermediate 46a:tert-Butyl 4-[[4-[5-(2,4-dioxohexahydropyrimidin- 1 -yl)indol- 1 -yl] - 1 -piperidyl] -methyl] -4-methoxy- piperidine- 1 -carboxylate

[0747] Tetraisopropoxytitanium (0.089 mL, 0.30 mmol) was added to a stirred solution of tert-butyl 4-formyl-4-methoxy-piperidine-l -carboxylate (0.062 g, 0.2 mmol) and Intermediate 3h (0.097 g, 0.40 mmol) in THF. The mixture was stirred at 50°C for Ih then NaBH(OAc)3(0.106 g, 0.50 mmol) was added. The resulting suspension was stirred at 50°C for 16h then cooled to r.t. and concentrated under reducedpressure. Purification by FSC (gradient: 0-100% EtOAc in hexanes) gave the title compound (0.059 g, 54 %) as a white solid, m / z (ES+) [M+H]+= 540.3.Intermediate 46b:l-[l-[l-[(4-Methoxy-4-piperidyl)methyl]-4-piperidyl]indol-5-yl]hexahydro-pyrimidine-2, 4-dione

[0748] Prepared in an analogous method to Intermediate 4e starting from Intermediate 46a (59 mg, 0.11 mmol) to give the title compound in the form of a bis-trifluoroacetate salt (50 mg, 83 %) as a pink solid after trituration with diethyl ether, m / z (ES+) [M+H]+= 440.3.Example 46l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8- yl]benzoyl]-4-methoxy-4-piperidyl]methyl]-4-piperidyl]indol-5-yl]hexahydropyrimidine-2, 4-dione

[0749] Prepared in an analogous method to EXAMPLE 1 starting from Intermediate Ij (21 mg, 0.05 mmol) and Intermediate 46b (22 mg, 0.05 mmol). Purification by RPC (gradient: 0-40% MeCN in water with 0.1% FA) gave the title compound in the form of a formate salt (12 mg, 29 %) as a yellow solid. ’H NMR (DMSO-d6): 5 1.53 (2H, br s), 1.90 (4H, br s), 1.93-2.06 (4H, m), 2.20 (2H, br d), 2.46 (5H, s), 2.73 (2H, t), 3.17 (9H, s), 3.25-3.29 (2H, m), 3.77 (3H, t), 4.21-4.42 (1H, m), 4.51 (2H, br s), 5.96 (2H, s), 6.45 (1H, d), 6.82-6.90 (2H, m), 6.94 (2H, d), 7.07 (1H, dd), 7.19-7.26 (1H, m), 7.30 (2H, d), 7.43-7.50 (2H, m), 7.50-7.57 (2H, m), 7.91 (1H, dd), 10.25 (1H, s), 14.14 (1H, br s); m / z (ES+) [M+H]+= 839.4.EXAMPLE 47Intermediate 47a: / / 7- Butyl ( I / ?.5. S'.6,s)-6-| 14-| 4-(2.4-dioxohcxahydropyrim idin- 1 -yl)indol- 1 -yl] - 1 -piperidyl]methyl] -3 - azabicyclo[3.1,0]hexane-3-carboxylate

[0750] NaBH(OAc)3(848 mg, 4.00 mmol) was added to tert-butyl (lJ?,5S,6r)-6-formyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (338 mg, 1.60 mmol) and Intermediate 5c (250 mg, 0.80 mmol) in THF (16 mb). The resulting mixture was stirred at r.t for 2h then concentrated under reduced pressure. Purification by RPC (gradient: 0-100% MeCN in water, contains 0.1% NH4HCO3) gave the title compound (0.310g, 76 %) as awhite solid. 'HNMR (DMSO- 6: 50.61 (1H, s), 1.25 (1H, d), 1.38 (9H, s), 1.90-2.07 (6H, m), 2.25-2.42 (4H, m), 2.72-2.81 (3H, m), 3.17 (3H, d), 3.77 (2H, t), 4.10 (1H, s), 4.38 (1H, s), 6.42 (1H, d), 6.91-6.99 (1H, m), 7.10-7.18 (1H, m), 7.47-7.56 (2H, m), 10.33 (1H, s); m / z (ES+) [M+H]+= 508.4.Intermediate 47b:l-[l-[l-[[(lJ?,5S,6r)-3-Azabicyclo[3.1.0]hexan-6-yl]methyl]-4-piperidyl]indol-4-yl]hexahydropyrimidine- 2,4-dione

[0751] Prepared in an analogous method to Intermediate 3j starting from Intermediate 47a (300 mg, 0.59 mmol). Purification by RPC (gradient: 5-100% MeCN in water with 0.1% FA) gave the title compound in the form of a formate salt (100 mg, 29 %) as a white solid, m / z (ES+) [M+H]+= 408.3.Example 47l-[l-[l-[[(lJ?,5S,65)-3-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo- [3.2. l]octan-8-yl]benzoyl]-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-4-piperidyl]indol-4-yl]hexahydro- pyrimidine-2, 4-dione

[0752] Prepared in an analogous method to Example 3 starting from Intermediate Ij (102 mg, 0.25 mmol) and Intermediate 47b (100 mg, 0.25 mmol). Purification by RP-HPLC (gradient: 12-22% MeCN in water with 0.1% FA) gave the title compound in the form of a formate salt (20 mg, 9.6 %) as a white solid.1HNMR(DMSO-d6): 50.56-0.69 (1H, m), 1.34-1.52 (2H, m), 1.90-2.11 (6H, m), 2.13-2.26 (2H, m), 2.26-2.39 (2H, m), 2.39-2.42 (2H, m), 2.73-2.82 (2H, m), 3.05-3.18 (6H, m), 3.26-3.31(2H, m), 3.73-3.84 (2H, m), 4.01-4.10 (2H, m), 4.35-4.44 (1H, m), 4.45-4.52 (2H, m), 5.96 (2H, s), 6.41 (1H, d), 6.77-7.01 (5H, m), 7.12-7.23 (2H, m), 7.38-7.43 (2H, m), 7.45-7.54 (3H, m), 7.81-7.96 (1H, m), 10.33 (1H, s), (-OH not observed); m / z (ES+) [M+H]+= 807.4.EXAMPLE 48Intermediate 48a:tert-Butyl 4-[3-[4-[5-(2,4-dioxohexahydropyrimidin- 1 -yl)indol- 1 -yl]- 1 -piperidyl] -propyl] piperidine- 1 - carboxylate

[0753] NaBH(OAc)3(1.357 g, 6.40 mmol) was added to tert-butyl 4-(3-oxopropyl)piperidine-l-carboxylate (1.159 g, 4.80 mmol), sodium acetate (0.788 g, 9.60 mmol), Intermediate 3h (1 g, 3.20 mmol) and AcOH (0.367 mL, 6.40 mmol) in DCM (100 mL) at r.t. The resulting mixture was stirred at r.t. for 18h. The mixture was quenched with sat. aq. NaHCO₃ (100 mL) and extracted with DCM (3 x 100 mL). The combined organic solutions were dried (Na2SO4) and concentrated. Purification by FSC (gradient: 0-8% MeOHin DCM) gave the title compound (1.300 g, 76 %) as a pink solid.1H NMR (DMSO-6): 5 1.39 (9H, d), 1.57-1.71 (3H, m), 1.91-2.04 (4H, m), 2.16 (2H, s), 2.34 (2H, s), 2.73 (5H, t), 3.02 (2H, d), 3.37 (3H, q), 3.77 (2H, t), 3.93 (3H, d), 4.10 (1H, q), 4.36 (1H, t), 6.46 (1H, d), 7.08 (1H, d), 7.31-7.63 (3H, m), 10.27 (1H, s); m / z (ES+) [M+H]+= 538.3.Intermediate 48b:1 -[ 1 -[ 1 -[3-(4-Piperidyl)propyl] -4-piperidyl]indol-5-yl]hexahydropyrimidine-2, 4-dione

[0754] Intermediate 48a (1.2g, 2.23 mmol) was stirred in FA (25 mL) at 40°C for Ih then cooled to r.t. The resulting solid was collected by filtration, washed with water (20 mL) and dried under reduced pressureto give the title compound in the form of a formate salt (0.860 g, 88 %) as a white solid, m / z (ES+) [M+H]+= 438.4.Example 48l-[l-[l-[3-[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8- yl]benzoyl]-4-piperidyl]propyl]-4-piperidyl]indol-5-yl]hexahydropyrimidine-2, 4-dione N^NH2N— 1 / A

[0755] Prepared in an analogous method to EXAMPLE 1 starting from Intermediate Ij (16 mg, 0.04 mmol) and Intermediate 48b (20 mg, 0.04 mmol). Purification by RPC (gradient: 2.5-25% MeCN in water with 0.1% FA) gave the title compound in the form of a formate salt (0.011 g, 33 %) as a white solid. ’H NMR (DMSO-d6): 5 1.04-1.12 (2H, m), 1.22-1.32 (2H, m), 1.46-1.55 (3H, m), 1.67-1.74 (2H, m), 1.87-2.06 (7H, m), 2.11-2.25 (5H, m), 2.31-2.38 (3H, m), 2.70-2.77 (2H, m), 2.79-2.97 (2H, m), 2.97-3.05 (2H, m), 3.06-3.14 (2H, m), 3.74-3.80 (2H, m), 3.98-4.22 (1H, m), 4.29-4.40 (1H, m), 4.47-4.54 (2H, m), 5.92-5.99 (2H, m), 6.44-6.47 (1H, m), 6.82-6.91 (2H, m), 6.91-6.95 (2H, m), 7.04-7.10 (1H, m), 7.19-7.25 (1H, m), 7.25-7.31 (2H, m), 7.44-7.51 (2H, m), 7.51-7.57 (2H, m), 7.84-7.96 (1H, m), 10.25 (1H, s), 14.14 (1H, s); m / z (ES+) [M+H]+= 837.2.EXAMPLE 49Intermediate 49a:tert- Butyl 4-(6-bromo- 1 -methyl -indol-3 -yl)piperazine- 1 -carboxylate

[0756] Sodium hydride (60% dispersion in mineral oil) (0.205 g, 5.13 mmol) was added to a stirred solution of Intermediate 45c (1.3 g, 3.42 mmol) in DMF (20 mL) at 0°C under N2. The resulting mixture was stirred at 0°C for 0.5h. Iodomethane (0.485 g, 3.42 mmol) was added and the resulting mixture was stirred for 1h at r.t. The mixture was diluted with saturated aq. NH4Cl (50 mL) and the aqueous layer was extracted with EtOAc (3 x 100 mL). The combined organic solutions were dried (Na2SO4) and concentrated under reduced pressure. Purification by FSC (gradient: 0-30% EtOAc in petroleum ether) gave the title compound (1.02 g, 76 %) as a purple gum. ’HNMR (DMSO-t / 6): 5 1.41 (9H, s), 2.86 (4H, t), 3.49 (4H, t), 3.66 (3H, s), 6.88 (IH, s), 7.07 (IH, dd), 7.47 (IH, d), 7.61 (IH, d); m / z (ES+) [M+H]+= 394.1.Intermediate 49b:tert- Butyl 4-[6-(2,4-dioxohexahydropyrimidin- 1 -yl)- 1 -methyl -indol-3-yl]piperazine- 1 -carboxylate Me0 oBocz

[0757] Prepared in an analogous method to Intermediate 3g starting from Intermediate 49a (1.00 g, 2.54 mmol). Purification by FSC (gradient: 0-4% MeOH in DCM) gave the title compound (1.00 g, 92 %) as a brown solid.1H NMR (DMSO-6): 5 1.41 (9H, s), 2.71 (2H,t), 2.83-2.93 (4H, m), 3.46-3.55 (4H, m), 3.66 (3H, s), 3.78 (2H, t), 6.81-6.98 (2H, m), 7.31 (1H, d), 7.50 (1H, d), 10.27 (1H, s); m / z (ES+) [M+H]+= 428.2.Intermediate 49c:1 -( 1 -Methyl-3 -piperazin- 1 -yl-indol-6-yl)hexahydropyrimidine-2, 4-dioneMeo

[0758] tert-Butyldimethylsilyl trifluoromethanesulfonate (0.835 g, 3.16 mmol) was added to a stirred solution of Intermediate 49b (0.90 g, 2.11 mmol) in MeCN (20 mL) at 0°C. The resulting mixture was stirred at r.t. for Ih then concentrated under reduced pressure. Purification by RPC (C18, gradient: 0-25% MeCN in water with 0.1% NH4HCO3) gave the title compound (0.570 g, 83 %) as a light brown solid. 'H NMR (DMSO-d6): 52.74 (2H, t), 2.84-2.96 (8H, m), 3.68 (3H, s), 3.80 (2H, t), 6.85 (IH, s), 6.92 (IH, dd), 7.32 (IH, d), 7.50 (IH, d), 10.29 (IH, s); m / z (ES+) [M+H]+= 328.2.Intermediate 49d:tert-Butyl 4-[ [4-[6-(2,4-dioxohexahydropyrimidin- 1 -yl)- 1 -methyl -indol-3 -yl]piperazin- 1 - yl]methyl]piperidine- 1 -carboxylate

[0759] A mixture of tert-butyl 4-formylpiperidine-1-carboxylate (0.023 g, 0.11 mmol) and Intermediate 49c (0.030 g, 0.09 mmol) in DCM (1 mL) and MeOH (1 mL) was stirred at r.t. for 5 min and then NaBH(OAc)3(0.058 g, 0.27 mmol) was added. The mixture was stirred at r.t. for 45 min then concentrated under reduced pressure. Purification by RPC (C18, gradient: 15-95% MeCN in water with 0.1% FA) gave the title compound in the form of a formate salt (0.038 g, 78 %) as a colorless waxy solid.1H NMR (DMSO-6): 50.92-1.01 (2H,m), 1.38-1.42 (9H, m), 1.67-1.74 (3H, m), 2.18-2.23 (2H, m), 2.54-2.58 (4H, m), 2.65-2.77 (4H, m), 2.91-3.00 (4H, m), 3.65-3.69 (3H, m), 3.77-3.82 (2H, m), 3.88-3.97 (2H,m), 6.83-6.87 (1H, m), 6.89-6.95 (1H, m), 7.29-7.34 (1H, m), 7.45-7.51 (1H, m), 10.24-10.31 (1H, m); m / z (ES+) [M+H]+= 525.3.Intermediate 49e:1 -[ 1 -Methyl-3-[4-(4-piperidylmethyl)piperazin- 1 -yl]indol-6-yl]hexahydropyrimidine-2, 4-dione2HCO2H

[0760] tert-Butyldimethylsilyl trifluoromethanesulfonate (0.027 g, 0.10 mmol) was added to a stirred solution of Intermediate 49d (0.035 g, 0.07 mmol) in MeCN (0.7 mL) at 0°C. The resulting mixture was stirred at r.t for Ih then concentrated under reduced pressure. Purification by RPC (C18, gradient: 10-95% MeCN in water with 0.1% FA) gave the title compound in the form of a bis-formate salt (0.046 g, 95 %) as a yellow waxy solid. 'H NMR (DMSO-d6): 5 1.33-1.41 (2H, m), 1.90-1.96 (2H, m), 2.10-2.19 (IH, m), 2.71-2.75 (2H, m), 2.85-3.00 (5H, m), 3.25-3.37 (5H, m), 3.53-3.57 (2H, m), 3.60-3.65 (2H, m), 3.68-3.72 (3H, m), 3.78-3.83 (2H, m), 6.96-7.00 (IH, m), 7.02-7.05 (IH, m), 7.36-7.39 (IH, m), 7.56-7.59 (IH, m), 9.08-9.26 (IH, m), 10.28-10.34 (IH, m); m / z (ES+) [M+H]+= 425.3.Example 49l-[3-[4-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8- yl]benzoyl] -4-piperidyl]methyl]piperazin- 1 -yl] -1 -methyl -indol-6-yl]hexahydropyrimidine-2, 4-dione Mefl

[0761] Prepared in an analogous method to EXAMPLE 1 starting from Intermediate Ij (13 mg, 0.03 mmol) and Intermediate 49e (26 mg, 0.04 mmol). Purification by RP-HPLC (gradient: 15-50% MeCN in water with 0.1%NH4OAc) gave the title compound (10 mg, 41 %) as an off-white solid. ’HNMR(DMSO-d6): 51.02-1.12 (2H,m), 1.72-1.78 (2H, m), 1.96-2.01 (2H, m), 2.16-2.20 (2H, m), 2.21-2.26 (2H,m),2.53-2.59 (4H, m), 2.71-2.76 (2H, m), 2.93-3.00 (4H, m), 3.06-3.12 (3H, m), 3.27-3.30 (4H, m), 3.65-3.69 (3H, m), 3.77-3.82 (2H, m), 3.96-4.25 (2H, m), 4.47-4.53 (2H, m), 5.92-6.00 (2H, m), 6.83-6.88 (3H, m), 6.90-6.95 (3H, m), 7.19-7.24 (IH, m), 7.25-7.29 (2H, m), 7.30-7.33 (IH, m), 7.45-7.50 (2H, m), 7.88-7.92 (IH, m), 10.12-10.46 (lH,m), 13.28-14.83 (IH, m); m / z (ES+) [M+H]+= 824.4.EXAMPLE 50Intermediate 50a:tert- Butyl 4-(difluoromethyl)-4-[[4-[5-(2,4-dioxohexahydropyrimidin- 1 -yl)indol- 1-yl] - 1 - piperidyl]methyl]piperidine- 1 -carboxylateo.

[0762] Tetraisopropoxytitanium (0.089 mL, 0.30 mmol) was added to a stirred solution of Intermediate 3h (0.062 g, 0.2 mmol) and tert-butyl 4-(difluoromethyl)-4-formylpiperidine-l -carboxylate (0.105 g, 0.40 mmol) in THF. The mixture was stirred at r.t for 20 min then NaBH(OAc)3 (0.106 g, 0.50 mmol) was added. The resulting mixture was stirred at r.t for 3h then concentrated under reduced pressure. Purification by FSC (gradient: 0-100% EtOAc in hexanes) gave the title compound (0.049 g, 44 %) as a white solid, m / z (ES+) [M+H]+= 560.3.Intermediate 50b:I-[I-[I-[[4-(Difluoromethyl)-4-piperidyl]methyl]-4-piperidyl]indol-5-yl]hexa-hydropyrimidine-2, 4-dione2TFA

[0763] Prepared in an analogous method to Intermediate 4e starting from Intermediate 50a (59 mg, 0.10 mmol) to give the title compound in the form of a bis-trifluoroacetate salt (50 mg, 83 %) as a pink solid after trituration with diethyl ether, m / z (ES+) [M+H]+= 460.3.Example 50l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8- yl]benzoyl]-4-(difluoromethyl)-4-piperidyl]methyl]-4-piperidyl]indol-5-yl]hexahydro-pyrimidine-2,4- dione

[0764] Prepared in an analogous method to EXAMPLE 1 starting from Intermediate Ij (29 mg, 0.07 mmol) and Intermediate 50b (32 mg, 0.07 mmol). Purification by RPC (gradient: 0-40% MeCN in water with 0.1% FA) gave the title compound in the form of a formate salt (0.022 g, 36 %) as a yellow solid. ’HNMR (DMSO-6): 51.60 (5H, br s), 1.88 (2H, br s), 1.93-2.08 (5H, m), 2.19 (2H, br d), 2.59-2.65 (3H, m), 2.73 (2H, t), 2.81-2.99 (3H, m), 3.09 (2H, br d), 3.34-3.44 (2H, m), 3.77 (4H, br t), 4.35 (1H, br s), 4.51 (2H, br s), 5.96 (2H, s), 6.06 (1H, s), 6.46 (1H, d), 6.80-6.90 (2H, m), 6.95 (2H, d), 7.08 (1H, dd), 7.22 (1H, s), 7.31 (2H, d), 7.42-7.50 (2H, m), 7.50-7.60 (2H, m), 7.91 (1H, dd), 10.25 (1H, s), 14.00-14.26 (1H, m); m / z (ES+) [M+H]+= 859.3.EXAMPLE 51Intermediate 5 la: / c / 7- Butyl 4-(5-bromo-3 -methyl -pyrrolo[ 2,3-b ]pyridin- 1 -yl)piperidine- 1 -carboxylate

[0765] Prepared in an analogous method to Intermediate la starting from 5 -bromo-3 -methyl- 1H-pyrrolo[2,3-6]pyridine (1.60 g, 7.58 mmol). Purification by FSC (gradient: 0-50% EtOAc in petroleum ether) gave the title compound (1.30 g, 43 %) as a white solid. ’H NMR (DMSO-t / 6): 5 1.44 (9H, s), 1.82- 1.90 (3H, m), 2.00-2.10 (1H, m), 2.21 - 2.26 (3H, m), 3.75-3.82 (1H, m), 4.12 (2H, d), 4.65-4.87 (1H, m), 5.62-5.84 (1H, m), 7.53 (1H, d), 8.16 (1H, d), 8.27 (1H, d); m / z (ES+) [M+H]+= 394.1Intermediate 51b: / - Butyl 4-[5-(2,4-dioxohexahydropyrimidin-l-yl)-3-methyl-pyrrolo[2,3-6]pyridin-l-yl ]piperidine-l- carboxylateBoo— N / O^N^OH

[0766] Prepared in an analogous method to Intermediate 3g starting from Intermediate 51a (1.30 g, 3.30 mmol). Purification by RPC (gradient: 5-100% MeCN in water with 0.1% NH4HCO3) gave the title compound (0.600 g, 43 %) as a white solid. ’HNMR (DMSO-d6): 5 1.43 (9H, s), 1.84-1.96 (4H, m), 2.24 (3H, d), 2.73-2.81 (2H, m), 2.89 (2H, s), 3.76-3.84 (2H, m), 4.12 (2H, d), 4.74-4.87 (1H, m), 7.50 (1H, d), 7.89 (1H, d), 8.18 (1H, d), 10.38 (1H, s); m / z (ES+) [M+Na]+= 450.2.Intermediate 51c:l-|3-Mcthyl-l-(4-pipcridyl)pyrrolo|2.3- / ?|pyridin-5-yl |hcxahydropyrimidinc-2.4-dione

[0767] 4M HCl in 1,4-dioxane (8 mL, 32 mmol) was added to Intermediate 5 lb (600 mg, 1.40 mmol). The resulting mixture was stirred at r.t for Ih then concentrated under reduced pressure. The crude product was triturated with DCM, solid was filtered and dried to give the title compound in the form of ahydrochloride salt (0.350 g, 68 %) as a white solid. 'H NMR (DMSO-d6): 52.09 (1H, d), 2.25-2.41 (5H, m), 2.73-2.82 (2H, m), 3.07-3.21 (2H, m), 3.41 (2H, d), 3.78-3.85 (2H, m), 4.91-5.05 (1H, m), 7.37 (1H, s), 7.95-7.99 (1H, m), 8.23 (1H, d), 9.30 (2H, s), 10.41 (1H, s); m / z (ES+) [M+H]+= 328.2.Intermediate 5 Id: / c / - But l 4-[ [4 - [ 5 -(2,4-dioxohexahydropyrimidin- 1 -yl)-3 -methyl -pyrrolo [2,3 -b\ -pyridin- 1 -yl] - 1 - piperidyl]methyl]-4-fluoro-piperidine-l-carboxylate

[0768] NaBH(OAc)3(680 mg, 3.21 mmol) was added to a solution of tert-butyl 4-fluoro-4-formylpiperidine- 1 -carboxylate (494 mg, 2.14 mmol) and Intermediate 51c (350 mg, 1.07 mmol) in NMP (2 mL) and DCE (2 mL) at r.t. The resulting mixture was stirred at r.t for Ih then concentrated under reduced pressure. Purification by RPC (gradient: 5-100% MeCN in water with 0.1% NH4HCO3) gave the title compound (0.300 g, 58 %) as a white solid. ’HNMR: 5 1.39 (9H, s), 1.49-1.70 (2H, m), 1.83 (4H, s), 1.95-2.11 (2H, m), 2.23 (3H, d), 2.27-2.39 (2H, m), 2.53 (IH, s), 2.61 (IH, s), 2.71-2.80 (2H, m), 3.02 (4H, d), 3.67-3.84 (4H, m), 4.51-4.72 (IH, m), 7.48 (IH, d), 7.86 (IH, d), 8.15 (IH, d), 10.36 (IH, s); m / z (ES+) [M+H]+= 543.4.Intermediate 51e:1 -[ 1 -[ 1 -[(4-Fluoro-4-piperidyl)methyl] -4-piperidyl] -3 -methyl -pyrrolo 12.3 - / ? | py ridin-5 - yl]hexahydropyrimidine-2, 4-dione

[0769] Prepared in an analogous method to Intermediate 3j starting from Intermediate 5 Id (150 mg, 0.28 mmol). Purification by RPC (gradient: 5-100% MeCN in water with 0.1% NH4HCO3) gave the title compound (0.050 g, 41 %) as a white solid. ’HNMR (DMSO-t / 6): 5 1.50-1.79 (4H, m), 1.79-1.88 (2H, m), 1.99-2.13 (2H, m), 2.25 (3H, s), 2.29-2.38 (2H, m), 2.51 (1H, m), 2.57 (1H, s), 2.65-2.79 (6H, m), 3.03 (2H, d), 3.76-3.84 (2H, m), 4.55-4.64 (1H, m), 7.50 (1H, s), 7.87 (1H, d), 8.17 (1H, d), 10.38 (1H, s) (NH proton not observed); m / z (ES+) [M+H]+= 443.4.Example 51l-[l-[l-[[l-[4-[3-[3-Amino-6-(2-hydroxyphenyl)pyridazin-4-yl]-3,8-diazabicyclo[3.2.1]-octan-8- yl]benzoyl] -4-fluor...

Claims

1. WHAT IS CLAIMED IS:2.A compound of Formula (I), or pharmaceutically acceptable salt thereof:

4. 6.wherein:7.E is:

9. 11.X1is -CR3= or -N=;12.R3is H, halogen, or (Ci-Ce)alkyl;13.X2is -CR4= or -N=;14.R4is H, halogen, or (Ci-Ce)alkyl;15.X3is -CH2CH2- or -CH2-O-CH2-;16.R5ais H, halogen, (Ci-Ce)alkyl, (C3-C6)cycloalkyl, 4- to 6-membered heterocycloalkyl, - CN, aryl, or 5- or 6-membered heteroaryl, wherein (Ci-Ce)alkyl is optionally substituted with 1 to 3 substituents independently selected from halogen or -CN; and 4- to 6-membered heterocycloalkyl, aryl, or 5- or 6-membered heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halogen, -CN, or (Ci-Ce)alkyl;17.R5bis H, (Ci-C6)alkyl, or (C3-C6)cycloalkyl;18.R1is H, halogen, (Ci-Ce)alkyl, (Ci-Ce)alkoxy, or20. 22.R2is H, halogen, (Ci-Ce)alkyl, (Ci-Ce)alkoxy, or23. 25.with the provisos:26.(i) when R1is H, halogen, (Ci-Ce)alkyl, or (Ci-Ce)alkoxy, then R2is:

28. 30.(ii) when R2is H, halogen, (Ci-Ce)alkyl, or (Ci-Ce)alkoxy, then R1is:31.. N NR1133. 35.R6is H, (Ci-C6)alkyl, or -CN;36.R7is H, halogen, (Ci-Ce)alkyl, -CN, or (C3-C6)cycloalkyl, wherein (Ci-Ce)alkyl is optionally substituted with 1 to 3 halogen;37.R8is H, halogen, (Ci-Ce)alkyl, -CN, or (C3-C6)cycloalkyl, wherein (Ci-Ce)alkyl is optionally substituted with 1 to 3 halogen;38.R9is H, halogen, (Ci-Ce)alkyl, -CN, or (C3-C6)cycloalkyl, wherein (Ci-Ce)alkyl is optionally substituted with 1 to 3 halogen;39.R10is H, halogen, (Ci-Ce)alkyl, -CN, or (C3-C6)cycloalkyl, wherein (Ci-Ce)alkyl is optionally substituted with 1 to 3 halogen;40.R11is H or -(Ci-C6)alkyl-O-P(=O)-(OH)2;41.W is -C(=O)-, -S(=O)2-, -CH2-, -C≡C-, or direct bond;42.L is -G’-G2-G3-, wherein G3is attached to E;43.G1is (Ci-Ce)alkylenyl; 4- to 6-membered heterocycloalkylenyl optionally substituted with 1 to 3 substituents independently selected from halogen, (Ci-Ce)alkyl, halo(Ci-C3)alkyl, (Ci- Ce)alkoxy, or -CN; or 7- to 11 -membered heterocycloalkylenyl optionally substituted with 1 to 3 substituents independently selected from halogen, (Ci-Ce)alkyl, halo(Ci-C3)alkyl, (Ci-Ce)alkoxy, or -CN;44.G2is (Ci-Ce)alkylenyl or a direct bond; and45.G3is 4- to 6-membered heterocycloalkylenyl optionally substituted with 1 to 3 substituents independently selected from halogen, (Ci-Ce)alkyl, halo(Ci-C3)alkyl, (Ci-Ce)alkoxy, or-CN, or 7- to 11 -membered heterocycloalkylenyl optionally substituted with 1 to 3 substituents independently selected from halogen, (Ci-Ce)alkyl, halo(Ci-C3)alkyl, (Ci-Ce)alkoxy, or -CN;46.Rais hydrogen or halogen; Rbis hydrogen or halogen; and47.Rcis hydrogen or -CH2OP(=O)(OH)2.

2. The compound of claim 1, or pharmaceutically acceptable salt thereof, having Formula (II):

50.

3. The compound, or pharmaceutically acceptable salt thereof, according to claims 1 or 2, wherein W is -C(=O)-.

4. The compound, or pharmaceutically acceptable salt thereof, according to claims 1 or 2, wherein W is -CH2-.

5. The compound, or pharmaceutically acceptable salt thereof, according to claims 1 or 2, wherein W is a direct bond.

6. The compound or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein W is a -S(=O)2-.

7. The compound, or pharmaceutically acceptable salt thereof, according to any one of claims 1-6, wherein X1is -CR3= and R3is H.

8. The compound, or pharmaceutically acceptable salt thereof, according to any one of claims 1-6, wherein X1is -CR3= and R3is halogen.

9. The compound, or pharmaceutically acceptable salt thereof, according to any one of claims 1-6, wherein X1is -CR3= and R3is (Ci-Ce)alkyl.

10. The compound, or pharmaceutically acceptable salt thereof, according to any one of claims 1-6, wherein X1is -N=.

11. The compound, or pharmaceutically acceptable salt thereof, according to any one of claims 1-10, wherein X2is -CR4= and R4is H.

12. The compound, or pharmaceutically acceptable salt thereof, according to any one of claims 1-10, wherein X2is -CR4= and R4is halogen.

13. The compound, or pharmaceutically acceptable salt thereof, according to any one of claims 1-10, wherein X2is -CR4= and R4is (Ci-Ce)alkyl.

14. The compound, or pharmaceutically acceptable salt thereof, according to any one of claims 1-13, wherein R6is H.

15. The compound, or pharmaceutically acceptable salt thereof, according to any one of claims 1-13, wherein R6is (Ci-Ce)alkyl.

16. The compound, or pharmaceutically acceptable salt thereof, according to any one of claims 1-13, wherein R6is -CN.

17. The compound, or pharmaceutically acceptable salt thereof, according to any one of claims 1-16, wherein:66.R1is:

68. 70.R2is H, halogen, (Ci-Ce)alkyl, or (Ci-Ce)alkoxy.

18. The compound, or pharmaceutically acceptable salt thereof, according to any one of claims 1-16, wherein:72.R2is:

74. 76.R1is H, halogen, (Ci-Ce)alkyl, or (Ci-Ce)alkoxy.

19. The compound, or pharmaceutically acceptable salt thereof, according to any one of claims 1-18, wherein E is E- 1.

20. The compound, or pharmaceutically acceptable salt thereof, according to claim 19, wherein R5ais hydrogen.

21. The compound, or pharmaceutically acceptable salt thereof, according to claim 19, wherein R5ais (Ci-Ce)alkyl optionally substituted with 1 to 3 substituents independently selected from halogen or -CN.

22. The compound, or pharmaceutically acceptable salt thereof, according to claim 19, wherein R5ais (C3-Ce)cycloalkyl.

23. The compound, or pharmaceutically acceptable salt thereof, according to claim 19, wherein R5ais 4- to 6-membered heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from halogen, -CN, or (Ci-Ce)alkyl.

24. The compound, or pharmaceutically acceptable salt thereof, according to claim 19, wherein R5ais -CN.

25. The compound, or pharmaceutically acceptable salt thereof, according to claim 19, wherein R5ais aryl optionally substituted with 1 to 3 substituents independently selected from halogen, -CN, or (Ci-C6)alkyl.

26. The compound, or pharmaceutically acceptable salt thereof, according to claim 19, wherein R5ais 5- or 6-membered heteroaryl optionally substituted with 1 to 3 substituents independently selected from halogen, -CN, or (Ci-Ce)alkyl.

27. The compound of claim 19, wherein E-l is:

85.

86. N87.III88.

90.

28. The compound, or pharmaceutically acceptable salt thereof, according to any one of claims 1-18, wherein E is E-2.

29. The compound, or pharmaceutically acceptable salt thereof, according to claim 28, wherein R5bis hydrogen.

30. The compound, or pharmaceutically acceptable salt thereof, according to claim 28, wherein R5bis (Ci-C6)alkyl.

31. The compound, or pharmaceutically acceptable salt thereof, according to claim 28, wherein R5bis (C3-Ce)cycloalkyl.

32. The compound of claim 28, wherein E-2 is:

97.

33. The compound, or pharmaceutically acceptable salt thereof, according to any one of claims 1-32, wherein:100.R7is halogen, (C1-C6)alkyl, -CN, or (C3-C6)cycloalkyl, wherein (C1-C6)alkyl is optionally substituted with 1 to 3 halogen; and101.R8, R9, and R10are H.

34. The compound, or pharmaceutically acceptable salt thereof, according to any one of claims 1-32, wherein:103.R8is halogen, (C1-C6)alkyl, -CN, or (C3-C6)cycloalkyl, wherein (C1-C6)alkyl is optionally substituted with 1 to 3 halogen; and104.R7, R9, and R10are H.

35. The compound, or pharmaceutically acceptable salt thereof, according to any one of claims 1-32, wherein:106.R9is halogen, (C1-C6)alkyl, -CN, or (C3-C6)cycloalkyl, wherein (C1-C6)alkyl is optionally substituted with 1 to 3 halogen; and107.R7, R8, and R10are H.

36. The compound, or pharmaceutically acceptable salt thereof, according to any one of claims 1-32, wherein:R10is halogen, (C1-C6)alkyl, -CN, or (C3-C6)cycloalkyl, wherein (C1-C6)alkyl is optionally substituted with 1 to 3 halogen; and109.R7, R8, and R9are H.

37. The compound, or pharmaceutically acceptable salt thereof, according to any one of claims 1-32, wherein R7, R8, R9, and R10are H.

38. The compound, or pharmaceutically acceptable salt thereof, according to any one of claims 1-37, wherein G1is 4- to 6-membered heterocycloalkylenyl optionally substituted with 1 to 3 substituents independently selected from halogen, (C1-C6)alkyl, halo(C1-C3)alkyl, (C1-C6)alkoxy, or -CN.

39. The compound, or pharmaceutically acceptable salt thereof, according claim 38, wherein G1is:

114.

117. 119.wherein the bond marked with an "*" is attached to G2.

40. The compound, or pharmaceutically acceptable salt thereof, according to any one of claims 1-37, wherein G1is 7- to 11 -membered heterocycloalkylenyl optionally substituted with 1 to 3 substituents independently selected from halogen, (C1-C6)alkyl, halo(C1-C3)alkyl, (C1-C6)alkoxy, or -CN41. The compound, or pharmaceutically acceptable salt thereof, according claim 40, wherein G1is:

123. 125.wherein the bond marked with an "*" is attached to G2.

42. The compound, or pharmaceutically acceptable salt thereof, according to any one of claims 1-41, wherein G2is a direct bond.

43. The compound, or pharmaceutically acceptable salt thereof, according to any one of claims 1-41, wherein G2is (C1-C6)alkylenyl.

44. The compound, or pharmaceutically acceptable salt thereof, according to claim 43, wherein G2is -CH2- or -CH(CH3)-.

45. The compound, or pharmaceutically acceptable salt thereof, according to any one of claims 1-44, wherein G3is 4- to 6-membered heterocycloalkylenyl optionally substituted with 1 to 3 substituents independently selected from halogen, (C1-C6)alkyl, halo(C1-C3)alkyl, (C1-C6)alkoxy, or -CN.

46. The compound, or pharmaceutically acceptable salt thereof, according claim 45, wherein G3is:

131.

132. wherein the bond marked with an "*" is attached to E.

47. The compound, or pharmaceutically acceptable salt thereof, according to any one of claims 1-44, wherein G3is 7- to 11 -membered heterocycloalkylenyl optionally substituted with 1 to 3 substituents independently selected from halogen, (C1-C6)alkyl, halo(C1-C3)alkyl, (C1-C6)alkoxy, or -CN.

48. The compound, or pharmaceutically acceptable salt thereof, according to claim 47, wherein G3is:135.H136.

137. wherein the bond marked with an "*" is attached to E.

49. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 1-37, wherein L140.

142.

143. wherein the bond marked with an "*" is attached to E.

50. The compound, or pharmaceutically acceptable salt thereof, according to claim 1 selected from Compound List 1.

51. A pharmaceutical composition comprising the compound, or pharmaceutically acceptable salt thereof, according to any one of claims 1-50 and a pharmaceutically acceptable excipient.

52. A method of degrading SMARCA2 protein in a human, comprising administering to a human in need thereof an effective amount of the compound, or pharmaceutically acceptable salt thereof, according to any one of claims 1-50, or the composition of claim 51.

53. A method of reducing the level of SMARCA2 activity in a human, comprising administering to a human in need thereof an effective amount of the compound, or pharmaceutically acceptable salt thereof, according to any one of claims 1-50, or the composition of claim 51.

54. A method of treating cancer in a human, comprising administering to a human in need thereof an effective amount of the compound, or pharmaceutically acceptable salt thereof, according to any one of claims 1-50, or the composition of claim 51.

55. The method of claim 54, wherein the cancer is a SMARCA2-sensitive cancer.

56. The method of claim 54, wherein the cancer is a SMARCA2 -mutated cancer.

57. The method of any one of claims 54-56, wherein the cancer is a solid tumor.

58. The method of any one of claims 54-56, wherein the cancer is lung, liver, colon, skin, bladder, cervical or ovarian cancer.

59. A compound, or pharmaceutically acceptable salt thereof, according to any one of claims 1-50, or the composition of claim 51 for use in degrading SMARCA2 protein in a human.

60. A compound, or pharmaceutically acceptable salt thereof, according to any one of claims 1-50, or the composition of claim 51 for use in reducing the level of SMARCA2 activity in a human.

61. A compound, or pharmaceutically acceptable salt thereof, according to any one of claims 1-50, or the composition of claim 51 for use in treating cancer in a human.

62. The compound for use of claim 61, wherein the cancer is a SMARCA2-sensitive cancer.

63. The compound for use of claim 61, wherein the cancer is a SMARCA2 -mutated cancer.

64. The compound for use of any one of claims 61-63, wherein the cancer is a solid tumor.

65. The compound for use of any one of claims 61-63, wherein the cancer is lung, liver, colon, skin, bladder, cervical or ovarian cancer.

66. Use of a compound, or pharmaceutically acceptable salt thereof, according to any one of claims 1-50, or the composition of claim 51 in the manufacture of a medicament for degrading SMARCA2 protein in a human.

67. Use of a compound, or pharmaceutically acceptable salt thereof, according to any one of claims 1-50, or the composition of claim 51 in the manufacture of a medicament for reducing the level of SMARCA2 activity in a human.

68. Use of a compound, or pharmaceutically acceptable salt thereof, according to any one of claims 1-50, or the composition of claim 51 in the manufacture of a medicament for treating cancer in a human.

69. The compound for use of claim 68, wherein the cancer is a SMARCA2-sensitive cancer.

70. The compound for use of claim 68, wherein the cancer is a SMARCA2 -mutated cancer.

71. The compound for use of any one of claims 68-70, wherein the cancer is a solid tumor.

72. The compound for use of any one of claims 68-70, wherein the cancer is lung, liver, colon, skin, bladder, cervical or ovarian cancer.

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