(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY(PCT)
`International Bureau
`(19) World Intellectual Property Organization 4 poe
`
`(43) International Publication Date
`)
`i
`ublicati
`gars
`PCT
`15 March 2012 (15.03.2012)
`
`(10) International Publication Number
`WO 2012/034091 Al
`
`
`
`(51) International Patent Classification:
`C07D 471/04 (2006.01)
`A61K 31/4985 (2006.01)
`C07D 487/04 (2006.01)
`A61P 37/00 (2006.01)
`A61K 31/4353 (2006.01)
`
`(21)
`
`(22)
`
`(25)
`
`(26)
`
`(30)
`
`(71)
`
`(72)
`(75)
`
`International Application Number:
`PCT/US2011/051108
`
`International Filing Date:
`9 September 2011 (09.09.2011)
`
`Filing Language:
`
`Publication Language:
`
`English
`
`English
`
`Priority Data:
`61/381,373
`
`9 September 2010 (09.09.2010)
`
`US
`
`Applicant (for ail designated States except US): IRM
`LLC [US/US]; 131 Front Street, P.O. Box HM 2899,
`Hamilton, HM LX (BM).
`
`Inventors; and
`Inventors/Applicants (jor US only): FAN, Yi [CN/US];
`10675 John Jay Hopkins Drive, San Diego, California
`92121 (US). LOREN, Jon [US/US]; 10675 John Jay
`Hopkins Drive, San Diego, California 92121
`(US).
`MOLTENI, Valentina [US/US]; 10675 John Jay Hop-
`kins Drive, San Diego, California 92121 (US). AL-
`BAUGH,Pamela A. [US/US]; 10675 John Jay [lopkins
`Drive, San Diego, California 92121 (US). CHOPIUK,
`Gregory [CA/US]; 10675 John Jay Hopkins Drive, San
`Diego, California 92121 (US). SMITH, Jeffrey M. [US/
`US]; 10675 John Jay Hopkins Drive, San Diego, Califor-
`nia 92121 (US). FLATT, Brenton T. [US/US]; 10675
`John Jay Hopkins Drive, San Diego, California 92121
`(US).
`
`(74) Agents: RAYMOND, Daniel E. et al.; Genomics Insti-
`tute of the Novartis Research Foundation, 10675 John Jay
`Hopkins Drive, San Diego, California 92121 (US).
`
`(81)
`
`Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ,
`CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO,
`DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT,
`HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP,
`KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD,
`ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NL
`NO, NZ, OM, PE, PG, PH, PL, PT, QA, RO, RS, RU,
`RW, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ,
`T, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA,
`ZM, ZW.
`
`(84)
`
`Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM,KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG,
`ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD,RU,TJ,
`TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK,
`EE, ES, FL FR, GB, GR, HR, HU,IE, IS, IT, LT, LU,
`LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SL SK,
`SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ,
`GW, ML, MR, NE, SN, TD, TG).
`Declarations under Rule 4.17:
`
`ofinventorship (Rule 4.17(iv))
`Published:
`
`with international search report (Art. 21(3))
`
`before the expiration of the time limit for amending the
`claims and to be republished in the event of receipt of
`amendments (Rule 48.2(h))
`
`(54) Title: IMIDAZO [1, 2] PYRIDAZIN COMPOUNDS AND COMPOSITIONSAS TRK INHIBITORS
`
`RX
`
`'N
`
`RB
`
`mW WW,
`a, A,0, R")
`Ris
`(57) Abstract: The invention provides compounds of formula (1), pharmaceutical compositions comprising such compounds and
`methods of using such compoundsto treat or prevent diseases or disorders associated with abnormal or deregulated TRK kinase
`activity.
`
`a
`
`R?
`
`oy whe mys
`
`R™ or
`
`RR,
`
`
`
`
`
`wo2012/034091Ax|INTTMMNIININTTATINIAAMONAATAATA
`
`

`

`WO 2012/034091
`
`PCT/US2011/051108
`
`IMIDAZO [1, 2] PYRIDAZIN COMPOUNDS AND COMPOSITIONS AS TRK
`INHIBITORS
`
`FIELD OF THE INVENTION
`
`[0001]
`
`The inventionrelates to protein kinase inhibitors, and methods of using such compounds.
`
`BACKGROUND OFTHE INVENTION
`
`
`
`[0002] Protein kinases (PK) arealarge set of structurally related phosphoryl! transferases having
`
`highly conserved structures and catalytic functions. Protein kinases are enzymatic components of the signal
`
`transduction pathways which catalyze the transfer of the terminal phosphate from ATP to the hydroxy
`
`group of tyrosine, serine and/or threonine residues of proteins, and are therefore categorized into families
`
`by the substrates they phosphorylate: Protemn Tyrosine Kinases (PTK), and Protem Serme/Threonine
`Kinases.
`
`
`
`[0003] Protein kinasesplayacritical role in the control of cell growth and differentiation and are
`
`responsible for the control of a wide variety of cellular signal transduction processes, wherein protein
`
`kinases are key mediators of cellular signals leading to the production of growth factors and cytokines. The
`
`overexpression Or inappropriate expression of normal or mutant protein kinases plays a significant role in
`
`the development of many diseases and disorders including, central nervous system disorders such as
`
`Alzheimer's, inflammatory disorders suchas arthritis, bone diseases such as osteoporosis, metabolic
`
`disorders such as diabetes, blood vessel proliferative disorders such as angiogenesis, autoimmunediseases
`
`such as rheumatoid arthritis, ocular diseases, cardiovascular disease, atherosclerosis, cancer, thrombosis,
`
`psoriasis, restenosis, schizophrenia, pain sensation, transplant rejection and infectious diseases such as
`
`viral, and fungal infections.
`
`[0004]
`
`Examples of protein-tyrosine kinases include, but are not limited to, Irk, IGFR-1, Syk, Zap-70,
`
`Bmx, Btk, CHK (Csk homologous kinase), CSK (C-terminal Src Kinase), Itk-1, Sre (c-Sre, Lyn, Fyn, Lek,
`
`Hck, Yes, Blk, Fer and Frk), Tec, Txk/RIk, Abl, EGFR (EGFR-1/ErbB-1, ErbB-2/NEU/HER-2, ErbB-3
`
`and ErbB-4), FAK, FGFIR (also FGFR1 or FGR-1), FGF2R (also FGR-2), MET (also Met-I or c-MET),
`
`PDGFR(a and B), Tic-1, Tic-2 (also Tck-1 or Teck), VEGFR1 (also FLT-1), VEGFR2 (also KDR), FLT-3,
`
`FLT-4, c-KIT, JAK1, JAK2, JAK3, TYK2, LOK, RET, TRKA, TRKB, TRKC, PYK2, ALK (Anaplastic
`
`LymphomaKinase), EPHA (1-8), EPHB (1-6), RON, Ros, Fes, Fer or EPHB4 (also EPHB4-1).
`
`[0005]
`
`Examples of protein-scrine/threonine kinases include,but are notlimited to, Ark, ATM (1-3),
`
`CamK (1-TV), CamKK, Chk1 and 2 (Checkpoint kinases), CKT, CK2, Erk, IKK-T (also TKK-ATLPHAor
`
`CHUK), IKK-2 (also IKK-BETA), Ik, Jnk (1-3), LimK (1 and 2), MLK3Raf (A, B and C), CDK (1-10),
`
`PKC (including all PKC subtypes), Plk (1-3), NIK, Pak (1-3), PDK1, PKR, RhoK, RIP, RIP-2, GSK3 (a
`
`and B), PKA, P38, Erk (1-3), PKB (including all PKB subtypes) (also AKT-1,AKT-2, AKT-3 or AKT3-1),
`
`TRAK1, FRK, SGK, TAK] or Tp1-2 (also COT).
`
`

`

`WO 2012/034091
`
`PCT/US2011/0351108
`
`SUMMARYOF THE INVENTION
`
`[0006]
`
`Provide herein are compounds and pharmaceutical compositions thereof, which are useful as
`
`inhibitors of Tropomyosin-Related Kinases (TRKA, TRKB and/or TRKC).
`
`[0007]
`
`In oneaspect, the present invention provides compounds having Formula(I), and the
`
`pharmaceutically acceptable salts, pharmaceutically acceptable solvates (e.g. hydrates), the N-oxide
`
`derivatives, prodrug derivatives, protected derivatives, individual stereoisomers and mixture of
`stereoisomersthereof:
`
`OO
`
`ee
`
`whe
`
`RB
`
`Formula (D
`
`wherein:
`
`(Rt)
`
`Sone’
`
`fe RY)X a
`
`ae
`
`aul
`
`fe
`
`by ( IN 2,
`< no
`CFXR ARS
`
`Ru
`
`L
`
`( NS ti,
`SR
`
`;
`R2 .
`
`Ris
`R*
`X is C(R*), O or NR’;
`R?is halo, -CN, -C(O)NHb, -L'R’, -L’?R’, -C(O)NHOR’, -C(O)NR°OR®, -C(O)NHNHb, -C(O)NR?C(O)OR?,
`orR4
`
`n
`
`R20 ;
`
`R22 or
`
`NFP or -SO,NR?R?:
`7%
`-C(O)NR°C(O)N(R3), -NR°C(O)NR?RS,
`L’ is -C(O)NR®-, -C(O)NR*(CR*R"),-, -C(O)-, -C(O)NR*O(CR*R4),-, -C(O)O-, -C(O)-C)-Cgalkylene or
`
`-C(O)-C;-Cgalkenylene;
`L’ is -NR*°C(CO)(CR‘R4),-;
`each L?is independently selected from a C,-Cgalkylene and a C,-Cgalkylene substituted with | to 3
`
`substituents independently selected from C,-Cgalkyl,
`R’is selected from R’, -N(R*);, C\-Cealkyl, phenyl, Cyoaryl, C,garyl, C3-Cgcycloalkyl, 4-6 membered
`
`heterocycloalkyl containing 1 to 2 heteroatoms selected from N, O and S, 5, 6, 9 or 10 membered
`
`heteroaryl containing | to 3 N heteroatoms and C,-Cgalkyl substituted with 1 to 6 groups independently
`selected from halo, C,-Cyalkyl, and -R°,
`or R’is selected from the phenyl, Cy,aryl, C\garyl, C3-Cgcycloalkyl, a 4-6 membered heterocycloalkyl
`
`containing | to 2 heteroatoms selected from N, O andS, and a 5, 6, 9 or 10 membered heteroaryl
`
`containing | to 3 N heteroatoms, each of which is substituted with | to 3 substituents independently
`
`selected from halo, C,-Cgalkyl, C\-Cgalkyl substituted with 1 to 4 hydroxyl groups, 4-6 membered
`heterocycloalkyl containing 1 to 2 heteroatoms selected from N, O and S, -CN, -R®, -OR*, -C(O)R*, -
`C(OJOR*, -C(O)L®R®, —S(O)2R*, and -S(O),NR“R*;
`
`2
`
`

`

`WO 2012/034091
`
`PCT/US2011/051108
`
`each R?is independently selected from H, C,-Cealkyl;
`each R’is independently selected from H, C,-Cgalkyl, and C,-Cgalkyl substituted with 1 to 4 hydroxyl groups;
`R°is C,-C,haloalkyl or —OR’;
`R° is selected from -OC(O)R*, -NHC(O)OR*, -NR*R%, -C(O)N(R’R?), -S(O)2R*, -S(O),NR'R*, -C(O)OR* and
`-OR';
`
`R’is halo, -OC(O)R”, -OR”, -CN, -NHC(O)OR”, -NHC(O)R”or -NR°R°;
`R* is a 4-6 membered heterocycloalkyl containing 1 to 2 heteroatomsselected from N, O and S or 4-6
`
`membered heterocycloalkyl containing | to 2 heteroatoms selected from N, O and S substituted with | to
`4 substituents independently selected from halo, -OR*, C\-Cealkyl and C,-Cehaloalkyl;
`IT
`
`:
`:
`9.
`is cyclohexyl having a C,-Cealkyl bridge,
`
`R’
`
`P
`
`(
`oa
`
`“
`
`(
`
`7
`
`Oo,
`
`p o (
`S,
`
`“
`
`;
`
`P
`
`*
`
`oO
`
`or
`
`:
`, wherein
`
`cach is optionally substituted with 1-3 substituents independently selected from halo, -CN, C,-Cealkyl,-
`R®, and -OR’;
`each R”’is independently selected from halo, C,-Cgalkyl, C,-Cshaloalkyl, -C=NOR’, -CN, -(CR*R"),CN, -
`NR®R’, -C(O)OR*, -C(O)NR®R®,-(CR*R*),R®,- NR°C(O)NR®R’*,- NR*S(O):R*, -NR*8(O),NR'R*,-
`§(O),NR‘R*, -S(O),R*, -OR*, 4-6 membered heterocycloalkyl containing | to 2 heteroatomsselected from
`
`N, O and § and a5 membered heteroaryl containing 1 to 4 N heteroatoms;
`each R!! is independently selected fromhalo, -OR’, deuterium, C\-Cealkyl, hydroxyl substitutedC,-Cealkyl,
`
`C-Cehalolkyl,
`RY isH,C i-Cealkyl, phenyl or phenyl substituted with 1 to 3 groups independently sclected from halo, C)-
`Cyalkyl, and -R°:
`
`SENN AH
`AL a
`RisselectedfromLO Ye KL? LD| Las Lor¢
`
`substituents independently selected from R”,
`
`and /
`
`, each of which is substituted with 1 to 3
`
`[ S
`) SS
`K
`y iL Y whe O ad
`
`N:
`
`and
`7
`,
`or Ris selected from =”
`with | to 3 substituents independently selected from R”’;
`
`, cach of which is optionally substituted
`
`nis 0, 1, 2,3,4,5, 6 or 7; pis 1 or 2 andq is 1, 2,3, 4,5 or 6.
`
`[0008]
`
`Tn certain embodiments, of such compounds of Formula (1):
`
`3
`
`

`

`WO 2012/034091
`
`PCT/US2011/051108
`
`oe (ON 3
`Rul
`( Cy
`rN
`RY,
`x
`R2 (R!')Z
`Riis
`X is C(R*),, O or NR?*;
`R? is halo, -CN, -C(O)NHb, -L'R’, -L°R’, -C(O)NHOR®, -C(O)NR?OR®, -C(O)NHNH>, -NR?C(OYNR?R°.
`orR4
`
`4
`og Ri
`N
`( Nan
`R2,
`‘R20 or
`
`4g
`1
`(R oY
`R2:
`
`cm NF or -SO:NR'R?;
`L’ is -C(O)NR*-, -C(OYNR*(CR‘R*),-, -C(O)-, -C(O)NR*O(CR’R’),-, -C(O)O-, -C(O)-C;-Cgalkylene or
`-C(O)-C,-Csalkenylene;
`L’ isNR°C(O)(CR‘R’),-;
`each L?is independently selected from a C,-Cgalkylene and a C,-Cgalkylene substituted with 1 to 3
`
`substituents independently selected from C\-Cealkyl;
`R’ is selected from R’, -N(R*)s, C i-Cealkyl, phenyl, Ciaryl, C garyl, C3-Cgcycloalkyl, 4-6 membered
`
`heterocycloalkyl containing | to 2 heteroatoms selected from N, O andS, 5, 6, 9 or 10 membered
`
`heteroaryl containing 1 to 3 N heteroatoms and C,-Cgalkyl substituted with 1 to 6 groups independently
`selected from halo, C,-Cyalkyl, and -R°,
`or R’is selected from the phenyl, C,aryl, Caryl, C,-Cgcycloalkyl, a 4-6 membered heterocycloalkyl
`
`containing | to 2 heteroatoms selected from N, O and S, and a5, 6, 9 or 10 membered heteroaryl
`
`containing 1 to 3 N heteroatoms, each of whichis substituted with 1 to 3 substituents independently
`
`selected from halo, C,-Cgalkyl, C\-C,alkyl substituted with 1 to 4 hydroxyl groups, 4-6 membered
`heterocycloalkyl containing | to 2 heteroatoms selected from N, O andS, -CN, -R®, -OR’, -C(O)R*, -
`C(OYOR*, -C(O)L°R®, -S(O)2R*, and -S(O);NR‘R’;
`each R*is independently selected from H, C,-Cealkyl;
`each R*is independently selected from H, C,-Calkyl, and C,-C,alkyl substituted with | to 4 hydroxyl groups;
`Ris C,-Cyhaloalkyl or —OR’;
`R° is selected from -OC(O)R", -NHC(O)OR‘, -NR*R*, -C(O)N(R’R?), -S(O)2R", -S(O),NR'R", -C(O)OR* and
`-OR’;
`
`R’is halo, -OC(O)R”, -OR”, -CN, -NHC(O)OR”, -NHC(Q)R”or -NR?R?:
`R* is a 4-6 memberedheterocycloalkyl containing | to 2 heteroatomsselected from N, O andS or 4-6
`
`membered heterocycloalkyl containing 1 to 2 heteroatoms selected from N, O and S substituted with 1 to
`4 substituents independently selected from halo, -OR*, C,-Cealkyl and C,-C,haloalkyl;
`
`

`

`WO 2012/034091
`
`PCT/US2011/051108
`
`, wherein
`each- is independently selected fromhalo, C,-Cgalkyl, C,-C-haloalkyl, -C=NOR’, -CN, -(CR*R*),CN, -
`
`oO,
`R’is cyclohexyl having a C\-Cgalkylbridge, “
`each is optionally substituted with 1-3 substituents independently selected from halo, -CN, C,-Cealkyl,-
`8 and -OR’;
`
`NR’R’, -C(O)OR*, -C(O)NR’R’, -(CR‘R"),R®, - NR*C(O)NR’R’, - NR*S(O)2R*, -NR*8(O),NR‘R’,-
`S(O),NR'R*, -S(O):R*, -OR*, 4-6 membered heterocycloalkyl containing | to 2 heteroatoms selected from
`
`N, O and § and a5 membered heteroaryl containing 1 to 4 N heteroatoms;
`each R’ is independently selected from halo, -OR’, deuterium, C1-Cealkyl, hydroxyl substitutedC,-Cgalkyl,
`
`C\-Cehalolky1,
`R” isH,C i-Cealkyl, phenyl or phenyl]substituted with 1 to 3 groups independently selected from halo, C,-
`Cyalkyl, and -R°;
`
`H
`
`Ris selected from
`
`:
`
`7%
`
`,
`N
`
`LOW ke 0 LO LO N
`“~S
`| ‘ N-
`.
`~
`IS hk and /
`RAN AS
`substituents independently selected from R”°,
`
`,
`
`4
`
`,
`
`7
`
`,
`
`¢
`
`;
`
`, each of which is substituted with 1 to 3
`
`HSoC
`
`Nw
`
`C
`
`and
`7
`,
`or R’is selected from 7”
`with 1 to 3 substitucnts independently sclected from R”:
`
`nis 0,1, 2,3, 4,5, 6 or 7; pis | or 2 and qis 1, 2,3, 4,5 or 6.
`
`, each of whichis optionally substituted
`
`[0009]
`
`In certain embodiments, such compounds of Formula (1) are compounds havingthe structure of
`
`Formula (1-a):
`
`1
`
`YO
`
`Oe
`(R IS Sy 4
`ct
`R®
`
`R20
`
`[00010]=Incertain embodiments, such compounds of Formula (I) are compoundshaving thestructure of
`
`Formula(II-a):
`
`Formula (1-a).
`
`

`

`WO 2012/034091
`
`PCT/US2011/051108
`
`oN.
`
`RN LR\
`NCY
`
`CN
`
`[00011]=Incertain embodiments, such compounds of Formula (1) are compounds having the structure of
`
`Formula(III-a):
`
`Formula (II-a).
`
`Le
`( oy Sx mfRB
`
`L
`
`p
`
`RU
`
`R20
`
`[00012]=Incertain embodiments, such compounds of Formula(I-a) are compounds having the structure
`
`of Formula(I-b):
`
`Formula (III-a).
`
`Rm
`
`Formula (I-b)
`
`wherein mis 1, 2 or 3.
`
`[00013]
`
`Incertain embodiments, such compounds of Formula (II-a) are compoundshavingthe structure
`
`of Formula (LI-b):
`
`Ao
`aN
`Rs
`SL Zp
`ron N
`x
`R®
`
`\= R
`
`!,,
`
`Formula(II-b)
`
`wherein mis 1, 2 or 3.
`
`[00014]
`
`Incertain embodiments, such compounds of Formula (III-a) are compoundshaving the
`
`structure of Formula (II-b):
`
`

`

`WO 2012/034091
`
`PCT/US2011/051108
`
`
`
`(R 10)
`
`Pormula (II-b)
`
`wherein mis 1, 2 or 3.
`
`[00015]=Incertain embodiments of compounds of Formula (1), Formula (I-a), Formula (II-a), Formula
`(I-a), Formula (I-b), Formula (II-b) and Formula (III-b), R® is -C(O)NH>,
`
`[00016]—In other embodiments of compounds of Formula (1), Formula (I-a), Formula (II-a), Formula
`(III-a), Formula (I-b), Formula (II-b) and Formula(II-b), R" is -L'R’. In certain embodiments of such
`
`compounds of Formula (I), Formula (I-a), Formula (I-a), Formula (III-a), Formula (I-b), Formula(II-b)
`and Formula(III-b), L’ is -C(O)NR*-, -C(O)NR*°(CR“R*),- or -C(O)NR*°O(CR*R’),-. In other embodiments
`
`of such compoundsof Formula (1), Formula (I-a), Formula (I]-a), Formula (II-a), Formula (I-b), Formula
`(II-b) and Formula(III-b), L’ is -C(O)- or -C(O)O-. In still other embodiments of such compoundsof
`
`Formula (I), Formula (I-a), Formula (I]-a), Formula (I]-a), Formula (I-b), Formula CI-b) and Formula (II-
`b), Lis -C(O)-C-Cgalkylene or -C(O)-C,-Cgalkenylene.
`
`In certain embodiments of the aforementioned compounds of Formula (1), Formula (1-a),
`[00017]
`Formula(II-a), Formula (III-a), Formula (I-b), Formula (II-b) and Formula(III-b), R’ is phenyl,
`
`cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In other embodiments of the aforementioned
`
`compounds of Formula (I), Formula (I-a), Formula (I-a), Formula (III-a), Formula (I-b), Formula (II-b)
`and Formula (II-b), R* is phenyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl each of whichis
`
`substituted with 1 to 3 substituents independently selected from halo, C,-Cealkyl, C)-Cealkyl substituted
`
`with | to 4 hydroxyl groups, 4-6 membered heterocycloalkyl containing 1 to 2 heteroatomsselected from
`N, O and §, -CN, -R*, -OR*, -C(O)R*, -C(O)OR*, -C(O)L*R®, —S(O)2B", and -S(O),NR*R*.
`
`In certain embodiments of the aforementioned compounds of Formula (1), Formula (1-a),
`[00018]
`Formula (II-a), Formula (III-a), Formula (I-b), Formula (II-b) and Formula(III-b), R? is tetrahydro-2H-
`
`pyranyl, tetrahydrofuranyl, piperidinyl, pyrrolidinyl, oxetanyl, morpholinyl, tetrahydro-2H-thiopyranyl,
`
`azetidinyl, piperazinyl, pyridyl, pyrazolyl, benzthiazolyl or pyrrolyl. In other embodiments of the
`
`aforementioned compounds of Formula (J), Formula (J-a), Formula (II-a), Formula (I]-a), Formula(I-b),
`Formula (1I-b) and Formula (IIT-b), R? is tetrahydro-2H-pyranyl, tetrahydrofuranyl, piperidinyl,
`
`pytrolidinyl, oxetanyl, morpholinyl, tetrahydro-2H-thiopyranyl, azetidinyl, piperazinyl, pyridyl, pyrazolyl,
`
`benzthiazolyl or pyrrolyl, cach of which is substituted with 1 to 3 substitucnts independentlyselected from
`
`halo, C\-Cgalkyl, Cy-Cealkyl substituted with 1 to 4 hydroxy! groups, 4-6 membered heterocycloalkyl
`containing | to 2 heteroatomsselected from N, O and §, -CN, -R®, -OR*, -C(O)R*, -C(O)OR*, -C(OYLR®, -
`
`

`

`WO 2012/034091
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`PCT/US2011/051108
`
`§(0)2R*, and -S(O),NR‘R*.
`
`[00019]=Incertain embodiments of compounds of Formula (I), Formula (I-a), Formula (II-a), Formula
`(II-a), Formula (I-b), Formula (I-b) and Formula(III-b), R® is -C(OYNHOR’, -C(O)NR*OR®,
`4
`
`‘\ML
`-C(O)NHNEb, -NR°C(O)NR°R° or PONE
`[00020]=Incertain embodiments ofthe aforementioned compounds of Formula (1), Formula (1-a),
`Formula(II-a), Formula (III-a), Formula (I-b), Formula (II-b) and Formula (III-b), R° is pyrrolidinyl,
`
`7k
`
`tetrahydro-2I]-pyranyl, morpholiny] or piperidinyl. In certain embodiments of the aforementioned
`
`compounds of Formula (I), Formula (I-a), Formula (II-a), Formula (I-a), Formula (I-b), Formula (II-b)
`and Formula(III-b), R® is pyrrolidinyl, tetrahydro-2H-pyranyl, morpholiny! or piperidinyl, each of which is
`substituted with 1 to 2 -OR* groups.
`
` Incertain embodiments of the aforementioned compounds of Formula(I), Formula(I-a),
`[00021]
`Formula(II-a), formula (III-a), Formula (I-b), Formula (II-b) and Vormula(II-b), R? is R’, -N(R*)2,
`
`methyl, ethyl, propyl, isopropyl, isobutene, t-butyl, or C)-Cgalkyl substituted with 1 to 6 groups
`independently selected from halo, C)-C.alkyl, and -R°.
`
`Incertain embodiments of the aforementioned compounds of Formula (1, Formula(I-a),
`[00022]
`Formula (II-a), Formula (III-a), Formula (I-b), Formula (II-b) and Formula (II-b), R’ is cyclohexyl having
`H
`
`CO sO‘ EY Oy
`
`a C,alkyl bridge,
`
`7
`
`eN
`
`O,7
`
`\
`
`Oo 7
`;
`
`O or
`
`, wherein cach is optionally
`
`substituted with 1-3 substituents independently selected from C,-Cealkyl.
`
`[00023]=Incertain embodiments of compounds of Formula (1), Formula (I-a), Formula (I-a), Formula
`(Il-a), Formula (I-b), Formula (II-b) and Formula (III-b), R? is —L’R’.
`
`[00024]=Incertain embodiments of compounds of Formula (1), Formula (I-a), Formula (I-a), Formula
`(Il-a), Formula (I-b), Formula (II-b) and Formula (III-b), R® is -Br, -CN and -SO,NR?R’.
`
`[00025]=Incertain embodiments of the aforementioned compounds of Formula (I), Formula(I-a),
`Formula (II-a), Formula (III-a), Formula (I-b), Formula (II-b) and Formula(ITI-b), each R’° is
`independently selected from F, Cl, methyl, -CF;), -C=NOR®, -CN, -(CR‘R"),CN, -NR?R*, -C(O)OR*, -
`C(O)NR®R®, -(CR*R*),R°, - NR°C(OYNR®R’, - NR°S8(O):R", -NR*S(O)2NR‘R*, -S(O):NR*R*, -S(O)R",-
`OR*, morpholinyl andtetrazolyl.
`
`In certain embodimentsofthe aforementioned compounds of Formula (1), Formula (1-a),
`[00026]
`Formula (II-a), Formula (II-a), Formula (I-b), Formula (I[-b) and Formula (I-b), each R”’ is
`independently selected from F, -OR*, deuterium, methyl, hydroxyl substituted C,-C,alkyl or C,-Cehalolkyl.
`
`

`

`WO 2012/034091
`
`PCT/US2011/051108
`
`[00027]=Incertain embodiments of the aforementioned compounds of Formula (1), Formula (I-a),
`Formula (I]-a), Formula (III-a), Formula (I-b), Formula (II-b) and Formula CIII-b), R°is selected from
`-OC(O)R*, -NHC(O)OR*, -NR°R®, -C(O)N(R*R?),-S(O)2R*, -S(O)2NR*R*, -C(O)OR"and -OR’*, and
`wherein each R* is independently selected from H, methyl, ethyl, propyl, isopropyl, t-butyl or a C,-C,alkyl
`
`substituted with 1 to 4 hydroxyl groups.
`
`In certain embodiments of the aforementioned compounds of Formula (1, Formula(I-a),
`[00028]
`Formula (I-a), Formula (III-a), Formula (I-b), Formula (II-b) and Formula (IlI-b), R* is H, methyl or ethyl.
`
`[00029]=In certain embodiments of the aforementioned compounds of Formula (D, Formula(-a),
`
`Formula (II-a), Formula (III-a), Formula (J-b), Formula (II-b) and Formula(III-b), q is 1, 2 or 3.
`
`[00030]=In certain embodiments compounds of Formula(I) are selected from: (2R)-1-{3-
`
`bromoimidazo[] ,2-b]pyridazin-6-yl}-2-(3-fluorophenyl)pyrrolidine; 6-[(2R)-2-(3-fluorophenylpyrrolidin-
`
`1-yl]imidazo[1,2-b]pyridazine-3-carbonitrile; 6-[3-(-fluorophenyl)morpholin-4-yl]imidazo[1,2-
`
`b]pyridazine-3-carbonitrile; 6-[((2R,4S)-3,3-difluoro-2 -(3-fluorophenyl)-4-methylpyrrolidin-1 -
`
`yllimidazo[1,2-b]pyridazine-3-carbonitrile; 6-[2-(3-fluoropheny])pyrrolidin-1-yl]imidazo[1,2-b|pyridazine-
`
`3-carboxamide; 6-[(2R)-2-(3-fluorophenyl)pyrrolidin-1-ylimidazo[1,2-b]pyridazine-3-carboxamide; 6-
`
`[2R,48)-4-fluoro-2-(3-fluorophenyl)pyrrolidin-1 -yl]imidazo[1,2-b]pyridazine-3-carboxamide; 6-[2-(3-
`
`fluorophenyl)-2-hydrogeniopyrrolidin-1-yl]imidazo[1,2-b]pyridazinc-3-carboxamide; 6-[(2S)-2-(3-
`
`fluorophenyl)-2-hydrogeniopyrrolidin-1-yl]imidazo[1 ,2-b]pyridazine-3-carboxamide; 6-[(5S)-5-(3-
`
`fluorophenyl)-2,2-dihydrogeniopyrrolidin- |-yl]imidazo[1,2-b]pyridazine-3-carboxamide; 6-[(SR)-5-(3-
`
`fluorophenyl)-2,2-dihydrogeniopyrrolidin-1-yl]imidazo[1,2-b]pyridazine-3-carboxamide; 6-[5-(3-
`
`fluorophenyl)-2,2,3,3,4,4-hexahydrogeniopyrrolidin- 1 -yl]imidazo[1,2-b]pyridazine-3-carboxamide; 6-[2-
`
`(3-fluorophenyl)-2,3,3,4,4,5,5-heptahydrogeniopyrrolidin-1-yl]imidazo[1,2-b]pyridazine-3-carboxamide; 6-
`
`[2R,48)-4-fluoro-2-(3-fluorophenyl)pyrrolidin-1-yl]-N-(oxan-4-yl)imidazo[1,2-b]pyridazine-3-
`
`carboxamide; 6-[(2R)-2-(3-fluorophenyl)-2,5 -dihydro-1H-pyrrol-1-yl]imidazo[1,2-b]pyridazine-3-
`
`carboxamide; 6-|3-(3-fluorophenyl)morpholin-4-y]Jimidazo|1,2-b|pyridazine-3-carboxamide; 6-|(3R)-3-(-
`
`fluorophenyl)morpholin-4-yl]imidazo[1,2-b]pyridazine-3-carboxamide; 6-[2-(3-fluorophenyl)piperidin-1-
`
`yl}imidazo[1,2-b]pyridazine-3-carboxamide; 6-[(2R)-2-(3 -fluoropheny])piperidin-1-yl]imidazo[1,2-
`
`b]pyridazine-3-carboxamide; 6-[(2R)-2-(-fluorophenyl)pyrrolidin-1-yl]-N-(4-hydroxybutylimidazo[1,2-
`
`b]pyridazine-3-carboxamide; N-ethyl-6-[2-(3-fluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazine-3-
`
`carboxamide; N-(cyclobutylmethy])-6-[(2R)-2-(3-fluorophenyl)pyrrolidin-1 -yl]Jimidazo[1,2-b]pyridazine-3-
`
`carboxamide; 6-[(2R)-2-(3-fluorophenyl)pyrrolidin-1 -yl]-N-[2-(oxolan-2-yDethyl]imidazo[1 ,2-
`
`b]pyridazine-3-carboxamide; N-[(4-fluorophenyl)methy]]-6-[2-(3-fluorophenylpyrrolidin-1-
`
`yljimidazo|1,2-b|pyridazine-3-carboxamide; 6-|(2R)-2-(3-fluoropheny])pyrrolidin-1 -yl]-N-{ |6-(morpholin-
`
`4-yl)pyridin-2-yl]methyl} imidazo[1 ,2-b]pyridazine-3-carboxamide; 2-(4-fluorophenoxy)-N- {6-[(2R)-2-G-
`
`fluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-yl}acetamide; N-[1-(ethanesulfonyl)piperidin-4-
`
`

`

`WO 2012/034091
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`PCT/US2011/051108
`
`yl]-6-[(2R)-2-(3-fluorophenyl)pyrrolidin-1 -yl]imidazo[1 ,2-b]pyridazine-3-carboxamide; 6-[@2R)-2-(3-
`
`fluorophenyl)pyrrolidin- 1 -yl]-N-[(1R,2S)-2-(hydroxymethyl)cyclohexyl]imidazo[1,2-b]pyridazine-3-
`
`carboxamide; 6-|(2R)-2-(3-fluorophenyl)pyrrolidin- 1-yl|-N-(1-sulfamoylpiperidin-4-yl)imidazo|1,2-
`
`b]pyridazine-3-carboxamide; 6-[(2R)-2-(3-fluorophenylpyrrolidin-1-yl]-N-[(3S)-1-
`
`methanesulfonylpyrrolidin-3-yl]imidazo[1,2-b]pyridazine-3-carboxamide; 6-[(2R)-2-@-
`
`fluorophenyl)pyrrolidin- 1 -yl]-N-[(3S)-1-(propane-2-sulfonyl)pyrrolidin-3-yl]imidazo[1,2-b]pyridazine-3-
`
`carboxamide; 6-[(2R)-2-(3-fluorophenyl)pyrrolidin- 1 -yl]-N-[1-(propane-2-sulfonylpiperidin-4-
`
`yljimidazo[1,2-b]pyridazine-3-carboxamide; (2S)-1-(4-{6-[(2R)-2-(3-fluorophenyl)pyrrolidin- | -
`
`yl}imidazo[1 ,2-b]pyridazine-3-amido} piperidin-1-yl)- 1-oxopropan-2-yl acetate; 6-[(2R)-2-3-
`
`fluorophenyl)pyrrolidin- 1-yl]-N-{1-[@S)-2-hydroxypropanoyl]piperidin-4 -yl} imidazo[1,2-b]pyridazine-3-
`
`carboxamide; 6-|(2R)-2-(3-fluorophenyl)pyrrolidin- | -yl|-N-| 1-(propane-1-sulfonyl)piperidin-4-
`
`yl]imidazo[]1 ,2-b]pyridazine-3-carboxamide; N-[(5,5-dimethyloxolan-2-yl)methyl]-6-[(2R)-2-G-
`
`fluorophenyl)pyrrolidin- 1 -yl]imidazo[1,2-b]pyridazine-3-carboxamide; N-[2-(4-fluoropheny])ethy1]-6-
`
`[(2R)-2-(3-fluorophenyl)pyrrolidin-1-ylimidazo[1,2-b]pyridazinc-3-carboxamide; N-(1,3-benzothiazol-2-
`
`ylmethyl)-6-[(2R)-2-(3-fluorophenyl)pyrrolidin-1-yl]imidazo[1 ,2-b]pyridazine-3-carboxamide; 6-[(2R)-2-
`
`(3-fluorophenyl)pyrrolidin-| -yl]-N-(propan-2-ylimidazo[1 ,2-b]pyridazine-3-carboxamide; N-[3-
`
`(diethylamino)propyl]-6-[(2R)-2-(3-fluorophenylpyrrolidin-1-yl]imidazo[1 ,2-b] pyridazine-3-carboxamide;
`
`N-[1-(4-fluorophenyl)-2-methylpropan-2-yl]-6-[(2R)-2-(3-fluorophenyl)pyrrolidin-1-yl]imidazo[1 ,2-
`
`b|pyridazine-3-carboxamide; N-|1-(4-fluoropheny])ethyl]-6-|(2R)-2-(3-fluorophenyl)pyrrolidin-1 -
`
`yl]imidazo[]1 ,2-b]pyridazine-3-carboxamide; 6-[(2R)-2-(3-fluorophenylpyrrolidin-1 -yl]-N-
`
`methylimidazo[1,2-b]pyridazine-3 -carboxamide; N-cyclopropyl-6-[(2R)-2-(3-fluoropheny)pyrrolidin-1-
`
`yl}imidazo[1 ,2-b]pyridazine-3-carboxamide; N-tert-butyl-6-[(2R)-2-(3-fluorophenyl)pyrrolidin-1 -
`
`yl}imidazo[1 ,2-b]pyridazine-3-carboxamide; N-cyclobutyl-6-[(2R)-2-(3-fMluoropheny1)pyrrolidin- 1 -
`
`yljimidazo[1,2-b]pyridazine-3-carboxamide; N-[(4-fluorophenyl)methyl] -6-[(2R)-2-(3-
`
`fluorophenyl)pyrrolidin- | -yl]imidazo[1,2-b]pyridazine-3-carboxamide; N-cyclopentyl-6-[(2R)-2-@-
`[1,2-b]
`
`fluorophenyl)pyrrolidin- | -yl]imidazo[1,2-b]pyridazine-3-carboxamide; N-cyclohexyl-6-[(2R)-2-@3-
`
`] ] |
`
`fluorophenyl)pyrrolidin-| -yl]imidazo[1,2-b]pyridazine-3-carboxamide; ethyl 4-{6-[(2R)-2-@G-
`
`fluorophenyl)pyrrolidin-1-yl]imidazo[1 ,2-b] pyridazine-3-amido} piperidine-1-carboxylate; 6-[(2R)-2-G-
`[1,2-b]
`
`fluorophenyl)pyrrolidin- | -yl]-N-(2-methoxyethylimidazo[1,2-b]pyridazine-3-carboxamide; 6-[2R)-2-(3-
`
`fluorophenyl)pyrrolidin- | -yl]-N-[2-(morpholin-4-ylcthyl]imidazo[1,2-b]pyridazinc-3-carboxamide; 6-
`
`[Q2R)-2-G-fluoropheny])pyrrolidin-1-yl]-N-@2,2,2-tnfluoroethy)inuidazo[1 ,2-b]pyridazine-3-carboxanude;
`
`6-[(QR)-2-(3-fluorophenyl)pyrrolidin-1-yl]-N-[@S)-1-methoxypropan-2-yl]imidazo[1,2-b]pyridazine-3-
`
`carboxamide; N-ethyl-6-[(2R)-2-(3-fluorophenyl)pyrrolidin-1-ylimidazo[1 ,2-b]pyridazine-3-carboxamide;
`
`N-[2-(dimethylamino)ethyl]-6-[(2R)-2-(3-fluorophenyl)pyrrolidin- 1 -yl]imidazo[1,2-b]pyridazine-3-
`
`carboxamide; N-[(6-chloropyridin-3-yl)methyl]-6-[(2R)-2-(3-fluorophenyl)pyrrolidin- 1-yl]imidazo[1,2-
`
`10
`
`

`

`WO 2012/034091
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`PCT/US2011/051108
`
`b]pyridazine-3-carboxamide; 6-[(2R)-2-(3-fluorophenyl)pyrrolidin- 1 -yl]-N-[3-Gnorpholin-4-
`
`yl)propyl]imidazo[1,2-b]pyridazine-3-carboxamide; 6-[(2R)-2-(3-fluorophenyl)pyrrolidin-1 -yl]-N-(thian-4-
`
`yl)imidazo|1,2-b|pyridazine-3-carboxamide; 6-|(2R)-2-(3-fluorophenyl)pyrrolidin-1 -yl]-N-(2,2,3,3,3-
`
`pentafluoropropyDimidazo[1,2-b]pyridazine-3-carboxamide; tert-butyl 3-{6-[(2R)-2-G3-
`
`fluorophenyl)pyrrolidin- 1-yl]imidazo[1,2-b]pyridazine-3-amido} azetidine-1-carboxylate,; tert-butyl (3R)-3-
`
`{6-[(2R)-2-(3-fluoropheny])pyrrolidin- 1-ylimidazo[1 ,2-b]pyridazine-3-amido} pyrrolidine-1-carboxylate;
`
`tert-butyl 4-{6-[(2R)-2-(3-fluorophenyl)pyrrolidin- 1 -y]imidazo[1 ,2-b]pyridazine-3-amido} piperidine-1-
`
`carboxylate; N-(1-acetylazetidin-3-yl)-6-[(2R)-2-(3-fluorophenyl)pyrrolidin- | -yl]imidazo[1 ,2-b]pyridazine-
`
`3-carboxamide; N-(3-cyanophenyl)-6-[(2R)-2-(3-fluorophenyl)pyrrolidin- 1 -ylJimidazo[1 ,2-b]pyridazine-3-
`
`carboxamide; N-[(3R)-1-acetylpyrrolidin-3-yl]-6-[(2R)-2-(3-fluorophenyl)pyrrolidin-1-ylimidazo[1,2-
`
`b|pyridazine-3-carboxamide; N-(1-acetylpiperidin-4-yl)-6-|(2R)-2-(3-fluorophenyl)pyrrolidin-1-
`
`yl]imidazo[1 ,2-b]pyridazine-3-carboxamide; 6-[(2R)-2-G-fluorophenylpyrrolidin-1 -yl]-N-(1 -
`
`methanesulfonylazetidin-3-yl)imidazo[1,2-b]pyridazine-3-carboxamide; N-[(2-fluorophenylmethyl]-6-
`
`[(2R)-2-(3-fluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazinc-3-carboxamide; 6-[(2R)-2-GB-
`
`fluorophenyl)pyrrolidin- 1-yl]-N-[(3R)-1-methanesulfonylpyrrolidin-3-yl]imidazo[1 ,2-b]pyridazine-3-
`
`carboxamide; 6-[(2R)-2-(3-fluorophenyl)pyrrolidin- | -yl]-N-(1-methanesulfonylpiperidin-4-yl)imidazo[1 ,2-
`
`b]pyridazine-3-carboxamide; 2-(4-{6-[(2R)-2-(3-fluorophenyl)pyrrolidin- 1 -yl]imidazo[1 ,2-b]pyridazine-3-
`
`amido} piperidin-1-yl)-2-oxoethy] acetate; N-[(3-fluorophenyl)methyl]-6-[(2R)-2-(3-
`
`fluorophenyl)pyrrolidin- 1 -yl]imidazo|1,2-b|pyridazine-3-carboxamide; 6-|(2R)-2-(3-
`
`fluorophenyl)pyrrolidin-1-yl]-N-[1-(2-hydroxyacety])piperidin-4-yl]imidazo[1,2-b]pyridazine-3-
`
`carboxamide; 6-[(2R)-2-(3-fluorophenyl)pyrrolidin-1 -yl]-N-(3,3,3-trifluoropropylimidazo[1,2-
`
`b]pyridazinc-3-carboxamide; N-(1-cthyl-1H-pyrazol-5-yl)-6-[(2R)-2-(3-fluorophenyl)pyrrolidin-1-
`
`yl}imidazo[1 ,2-b]pyridazine-3-carboxamide; 6-[(2R)-2-@G-fluoropheny)pyrrolidin-1-yl]-N-(-
`
`hydroxyethyl)imidazo[1,2-b]pyridazine-3-carboxamide; 6-[(2R)-2-(3-fluorophenyl)pyrrolidin- | -yl]-N-(4-
`
`hydroxycyclohexyl)imidazo[1 ,2-b]pyridazine-3-carboxamide; 6-[(2R)-2-(-fluorophenyl)pyrrolidin-1-yl]-
`
`N-[(R,2R)-2-hydroxycyclopentyl]imidazo[1,2-b]pyridazine-3-carboxamide; 6-[(2R)-2-G-
`
`fluoropheny])pyrrolidin-1-yl]-N-[(1S,2S)-2-hydroxycyclohexyl]imidazo[1,2-b|pyridazine-3-carboxamide;
`
`6-[QR)-2-3-fluorophenylpyrrolidin-1-y1]-N-(1 -hydroxy-2-methylpropan-2-yl)imidazo[1 ,2-b]pyridazine-
`
`3-carboxamide; 6-[(2R)-2-(3-fluorophenyl)pyrrolidin-1-yl]-N-[(2R)-oxolan-2-ylmethyl]imidazo[1,2-
`
`b]pyrnidazinc-3-carboxamide; 6-[(2R)-2-(3-fluorophenyl)pyrrolidin- 1-yl]-N-[(28)-oxolan-2-
`
`ylmethy!]imidazo[1,2-b]pyridazine-3-carboxamide; 6-[(2R)-2-@-fuorophenyl)pyrrolidin-1-yl]-N-[2-2-
`
`oxopyrrolidin-1-ylethyl]imidazo[1 ,2-b]pyridazine-3-carboxamide; methyl N-[(2S)-1-({6-[(2R)-2-G-
`
`fluorophenyl)pyrrolidin-1 -yl}imidazo[1 ,2-b]pyridazin-3-yl} formamido)propan-2-yl]carbamate; 6-((2R,45)-
`
`4-fluoro-2-(3-fluorophenyl)pyrrolidin-| -yl)-N-(1, 1-dioxo-tetrahydrothiophen-3-yl)imidazo[1,2-
`
`b]pyridazine-3-carboxamide; N-[(4-cyanophenyl)methyl]-6-[(2R)-2-(3-fluorophenyl)pyrrolidin-| -
`
`IL
`
`

`

`WO 2012/034091
`
`PCT/US2011/051108
`
`yl}imidazo[1 ,2-b]pyridazine-3-carboxamide; N-(cyclopropylmethyl)-6-[(2R)-2-(3-fluorophenyl)pyrrolidin-
`
`1-yl]imidazo[1,2-b]pyridazine-3-carboxamide; N-(2-cyclohexylethyl)-6-[(2R)-2-G-
`
`fluorophenyl])pyrrolidin- 1 -yl]imidazo|1,2-b|pyridazine-3-carboxamide; N-(2,2-difluoroethy])-6-|(2R)-2-G-
`
`fluorophenyl)pyrrolidin-1-yl}imidazo[1,2-b]pyridazine-3-carboxamide; 6-[(2R)-2-(-
`
`fluorophenyl)pyrrolidin- 1 -yl]-N-(oxan-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide; 6-[(2R)-2-@G-
`
`fluorophenyl)pyrrolidin-1 -yl]-N-(2-methylpropylimidazo[1,2-b]pyridazine-3-carboxamide; N-
`
`(cyclohexylmethy])-6-[QR)-2-(3-fluorophenyl)pyrrolidin- 1 -yl]imidazo[1,2-b]pyridazine-3-carboxamide;
`
`N-(2-fluoroethy])-6-[(2R)-2-(3-fluorophenyl)pyrrolidin- | -yl]imidazo[1,2-b]pyridazine-3-carboxamide; 6-
`
`[(2R)-2-(3-fluorophenylpyrrolidin-1-yl]-N-(oxan-3-yl)imidazo[1,2-b]pyridazine-3-carboxamide; methyl
`
`(2R)-2-({ 6-[2R)-2-G-fluorophenyl)pyrrolidin-1-yl]imidazo[1,2-b]pyridazin-3-y1}formamido)-3-
`
`hydroxypropanoate; 6-|(2R)-2-(3-fluoropheny])pyrrolidin-1-yl]-N-({ 6-|(3R)-3-hydroxypyrrolidin-1-
`
`yl]pyridin-3-yl} methyl imidazo[1 ,2-b] pyridazine-3-carboxamide; 6-[(2R)-2-(3-fluorophenyl)pyrrolidin-1 -
`
`yl]-N-[(3R)-2-oxooxolan-3-yl]imidazo[1,2-b]pyridazine-3-carboxamide; N-[1,3-dihydroxy-2-
`
`(hydroxymethyl)propan-2-yl]-6-[(2R)-2-(3-fluorophenyl])pyrrolidin-1-yl]imidazo[1,2-b]pyridazinc-3-
`
`carboxamide; 6-[(2R)-2-(3-fluorophenyl)pyrrolidin- 1 -yl]-N-[(2R)-1-hydroxy-3-methylbutan-2-
`
`yljimidazo[1,2-b]pyridazine-3-carboxamide; 6-[(2R)-2-(3-fluorophenyl)pyrrolidin-1 -yl]-N-[(2S)-1-
`
`hydroxy-3,3-dimethylbutan-2-yl]imidazo[1 ,2-b]pyridazine-3-carboxamide; 6-[(2R)-2-(3-
`
`fluorophenyl)pyrrolidin- 1 -yl]-N-[(2S)-1-hydroxy-4-methylpentan-2-yl]imidazo[1 ,2-b]pyridazine-3-
`
`carboxamide; N-|(28)-2,3-dihydroxypropyl]-6-|(2R)-2-(3-fluorophenyl)pyrrolidin-1 -yl]imidazo|1,2-
`
`b]pyridazine-3-carboxamide; 6-[(2R)-2-(-fluorophenyl)pyrrolidi