PDElOa INHIBITORS FOR THE TREATMENT OF TYPE II DIABETES

CROSS-REFERENCE TO RELATED APPLICATIONS This Application claims priority to United States Provisional Patent Application No. 61/833491, filed June 1 1, 2013 which is hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to novel substituted imidazo[l,2-a]pyridazine derivatives which are inhibitors of the phosphodiesterase 10 enzyme (PDE1Q) and are useful for the treatment of disorders that are affected by the PDEl Oa enzyme. The invention also relates to pharmaceutical compositions comprising such compounds, to processes to prepare such compounds and compositions, and to the use of such compounds or pharmaceutical compositions for the treatment of various diseases, syndromes and disorders, mcluding Type II diabetes.

BACKGROUND OF THE INVENTION

Phosphodiesterases (PDEs) are a family of enzymes encoded by 21 genes and subdivided into 1 1 distinct families according to structural and functional properties. These enzymes are hydrolases that metabolically inactivate widely occurring intracellular second messengers, 3',5' ^" -eyciie adenosine monophosphate (cAMP) and 3 ',5 '-cyclic guanosine monophosphate (cGMP) by catalytic hydrolysis of the 3 '-ester bond, forming the inactive 5 '-monophosphate. These two messengers regulate a wide variety of biologicai processes, -including pro-inflammat ory mediator production and action, ion channel function, muscle contraction, learning, differentiation, apoptosis, lipogenesis, glycogeno lysis, and gluconeogenesis. They do this by activation of protein kinase A (PKA) and protein kinase G (PKG), which in turn phosphorylate a wide variety of substrates including transcription factors and ion channels that regulate innumerable physiological responses. In neurons, this includes the activation of cAMP and cGMP-dependent kinases and subsequent phosphorylation of proteins involved in acute regulation of synaptic transmission as well as in neuronal differentiation and survival.

On the basis of substrate specificity, the PDE families can be divided into three groups: i) the cAMP-specific PDEs, which include PDE4, 7 and 8; ii) the cGMP- selective enzymes PDE5 and 9; and iii) the dual-substrate PDEs, PDE1 , 2 and 3, as well as PDE 10 and 11.

Furthermore, PDEs are expressed differentially throughout the organism, including the central nervous system. Different PDE isozymes therefore may play different physiological funciions. Compounds that selectively inhibit PDE families or isozymes may display particular therapeutic activity, fewer side effects, or both.

PDE 10a is highly expressed in the brain with the highest expression residing in the iiAcc olfactory tubercle, striatum and spiny neurons. There is a high co-incidence of PDE 10a, D2 and Dl expression in these areas. Antipsy chotics normalize a

dopamine-evoked cAMP decrease, i.e. agonists at Gs-cou led Dl receptors result in increased intracellular cAMP and antagonists of the Gi -coupled D2. receptor also elevate the intracellular cAMP.

Since PDE 10a hydro lyzes cAMP and cGMP, it is to be expected that PDE 10a inhibitors will increase intracellular levels of c AMP and cGMP, thereby mimicking dopamine transmission at Dl mediated synapses (Dl agonism) and decreasing dopamine transmission at D2 mediated synapses (D2 antagonism). Therefore, PDElOa inhibitors are expected to have antipsychotic and cognitive-improving properties and may provide benefits for the treatment of schizophren a.

Besides being a potential treatment for psychiatric disorders, PDEl Oa inhibitors may also be beneficial for the treatment of metabolic diseases. Although PDElOa is predominantly expressed in the brain, it is also expressed in neuroendocrine tissues such as pancreatic islets, adrenal gland, pituitary gland, and in the neuronal ganglion throughout the intestine. Because cAMP is a major regulator of glucose-stimulated insulin secretion from pancreatic islet β cells, PDElOa inhibitors may enhance insulin secretion and reduce blood glucose levels. They may also potentiate the actions of GLP- 1, GPR 1 19 agonists and other Gs-coupled GPCR agonists which signal via increased cAMP and the protein kinase A pathway. In addition, PDElOa inhibitors may potentiate incretin effects such as β ceil proliferation and survival. A peripherally restricted PDEl Oa inhibitor has been shown to enhance insulin secretion and reduce the glucose excursion in lean Wistar rats (Bioorg. Med. Chem. Lett. 17 (2007) 2869-2873).

Further validation that PDElOa inhibition may have beneficial effects on metabolis includes the phenotype of the PDElOa knockout mice (US Patent Appl. US2009/0162286 Al), These mice are resistant to weight gain on a high fat diet, without an appreciable change in food consumption, and the differences in weight between the PDE1 Oa knockout and wild type mice are predominantly due to differences in adiposity and not lean mass. When compared to wild type mice, the PDElOa knockout mice have lower plasma insulin, triglycerides, non-esterified free fatty acids and leptin. Although there does not appear to be a difference in the glucose excursion between knockout and wild type mice on a chow diet, there is a reduction in the glucose excursion during an oral glucose tolerance test. Additionally, there was a slight increase in oxygen consumption. Furthermore, PDElOa inhibitor treatment in mice fed a high fat diet showed similar changes to those observed between wild type and PDE10a knockout mice. PDElOa inhibitor treated mice exhibited 6% weight loss during the 14 day study with little changes in food intake and slight increases in oxygen consumption, In addition, they exhibited improvements in the glucose excursion during an oral glucose tolerance test.

Taken together, these data suggest that PDElOa inhibitors may be beneficial for the treatment of type 11 diabetes and obesity with potentiation of glucose-stimulated insulin secretion and the potential for weight loss. Additivity and/or synergy may be expected between PDElOa inhibitors and DPPIV inhibitors, GLP-1 mimetics and GPR1 19 agonists. They may work well as monotherapy or in conjunction with common treatments of type Π diabetes, such as metformin, SGLT2 inhibitors, PP AR gamma agonists and DPPIV inhibitors.

Therefore, there is a need in the art for PDEl Oa inhibitors that are useful for the treatment of a disease, syndrome, or condition in a mammal in which the disease, syndrome, or condition is affected by the inhibition of the PDElOa receptor, such as Type II diabetes. It has been suggested in the scientific literature that compounds that do not accumulate in the brain tissue may possess fewer potential CNS side effects. Therefore, it is an objective of the present invention to identify compounds of Formula (1) that do not accumulate in the brain tissue where they may exert CNS effects.

SUMMARY OF THE INVENTION

The present invention is directed to compounds of Formula (I)

Formula (I)

wherein

R ¹ is hydrogen or chloro;

R ² is

(i) hydrogen;

(si) a heteroaryl selected from the group consisting of pyridinyi, thienyl, furanyl, 5- pyrimidinyl, 2-pyrazenyl, 2 -hydroxy- lH-imidazo[4,5-b]pyridin-6-y], 1 H- imidazo[4,5-b]pyridin-6-yl, lH-benzo[d]imidazol-6-yl, benzo[d]oxazol-2(3H)- one-6-yl, 3,3-difluoroindolin-2-one-5-yl, benzo[d]isothiazol-3(2H)-one 1 , 1 - dioxide-5-yl, 1 -methyl- 1 ,3-dihydrobenzo[c] [l ,2,5]thiadiazole 2,2-dioxide-6-yl, 4-methyl-2H-benzo[e] [1 ,2,4]miadiazin-3(4H)-one 1 , 1 -dioxide- 7-yl, 2,4- dimethyl-2H-benzo[e] [l ,2,4]thiadiazin-3(4H)-one l, l -dioxide-7-yl, 2-methyl- 2H-benzo[e] [ 1 ,2,4]thiadiazin-3(4H)-one 1 , 1 -dioxide-7-yl, and lH-pyrazol-4-yl; wherein the pyridinyi, thienyl and furanyl of group (ii) are optionally substituted with one substituent selected from the group consisting of C _h lky 1, hydroxy, earboxy(C}.4)aikyL Ci .4alkylsulfonylaminocarbonyl(Cj 4)aikyl, 1 - methyl- 1,2,3 ,6-tetrahydropyridin-4-yl, Q^alkoxy, carboxy, NR ^a R ^b , carboxymethylamino, Ci^alkylsulfonylaminocarbonyl, tetrazolyl, oxadiazolyl, triazolyl, and triazolylthio; wherein said oxadiazolyl and triazolyl groups are optionally substituted with one hydroxy or C^alkoxy substituent;

and wherein said py ridinyi, thienyl, and furanyl rings of group (ii) are optionally further substituted with one or two additional substituents selected from the group consisting of fluoro, chloro, and hydroxy; R ^a and R° are independently hydrogen or Ci^alkyl; or R ^a and R ^b are taken together with the nitrogen atom to which they are both attached to form a monocyclic heterocyciyi optionally containing one additional O, S, or N atom; wherein said heterocyciyi is optionally substituted at a carbon atom with C;_ 4alkyl, C- alkylsulfonylarninocarbonyl, or carboxy;

and wherein said heterocyciyi is optionally substituted at a nitrogen atom with aminosuifonyi or C _h alky!; phenyl optionally substituted with one substituent that is ^alkoxy, cyano, C|_ 4a.lkoxycarbonyl,

aminosuifonyi, hydroxy, Ci ^alkylsulfonyiaminocarbonyl, carboxy, carboxy(Ci_ ₆ )alkyl, Ci _-4 a3kylsulfonylaminocarbonyl(C]- ₄ )alkyl,

earboxy(Ci_4)aikylaminocarbonyl, 2-carboxypyrrolidin~ 1 -ylcarbonyl,

1 -carboxy-2-methyl-propylammo, carboxy(Ci-4)a]Jkylcarbonylamino,

CMalkylsulfonylaminocarbonylam no, Ci. ₄ alkylsulfonylamino,

carboxy (Cj _-4 )alkylamino, 1 , 1 , 1 ,3,3,3-hexafluoro-2-hydroxy-propan-2-yl, 4-carboxypiperidin- 1 -yl, carboxycyclopropyl,

(3-carboxy(Ci - ₄ )alkyl)-oxetan-3-y], piperazin-l-yl, tetrazoiyl, triazoiyl, thienyl, furanyl, or oxazolyl; wherein said tetrazoiyl, triazoiyl, thienyl, furanyl, or oxazoiyi substituents are optionally independently substituted with one or two substituents selected from the group consisting of C;- ₄ alkyl and hydroxy; and wherein said phenyl of group (iii) is optionally independently turiher substituted with one or two additional substituents selected from the group consisting of C _h alky!, fiuoro, and hydroxy; phenyl substituted with one substituent that is r- 1 , r-2, r-3, or r-4;

r ^{"2 r"4} : wherein phenyl of group (iv) is optionally further substituted with one additional fSuoro substituent;

(v) phenyl substituted with one substituent that is a- 1, a-2, a-3, a-4, or a-5;

(vi) piperidin-4-yl optionally substituted at the 1 -position with carboxy, carboxy(C 4)alkyl, or (C )aJ]iylsidfonyiammocarbonyl;

(vis) piperidin- 1 -yl optionally substituted at the 4-position with carboxy, carboxy(C;.

4)a]kyl, or (Ci^alkylsulfonyiaminocarbonyl;

(viii) piperazin- 1-yl optionally substituted at the 4-position with (Ci..

4)alk}'1suifonyiaminocarbonyl, carboxy(Ci-4)alkylcarbonyl, ammocarbonyl, aminosulfonyl, or (C-i-4)alkylcarbony3aminosulfony3;

(iv) phenylamino w3ierein the phenyl is optionally substituted with carboxy or carboxy(C]..4)afkyl; and % ^r 3ierein the pl enyi is optionally further substituted with one additional substituent selected from the group consisting of Ci^alkoxy, Ci . :;i ii-. i. hydroxy, and one or two fluoro subsii!uen!s;

or

(x) cyclohexylarnino wherein cyciohexyl is optionally substituted with carboxy or earboxy(C}..4)aikyl; L is a bivalent linker that is ethyl, ethenyf, ethynyl, trans- 1 ,2-cyclopropyl, trans- 1 ,3 -cyclobutyl, cw-lJ-cyclobutyl, azetidin-3-yl, -XCH ₂ -, -0(CH ₂ ) ₂ -, -CH ₂ NH-, •Ni !(·(())· . or ·(·( () )% ! !·:

wherein X is O, S, S0 ₂ , or CR' ^* ); and wherein R ⁴ is hydrogen, methyl, or ethyl;

Q is quinolin-2-yl, quinolin-3-yl, 5,6,7,8-tetrahydroquinolin-2-yi, pyridinyl, benzothiazol-2-yl, benzimidazol-2-yl, pyrimidin-2-yl, or quinazolin-2-yl;

wherein said Q is optionally independently substituted with one or two substituents selected from the group consisting of fluoro, chloro, hydroxy, cyano, trifluoromethyi, carboxy, hydroxy aminocarbonyl, or Ci.

4alkylsulfonylaminocarbonyl; or an enantiomer, diastereomer, or pharmaceutically acceptable salt form thereof.

The present invention also provides a pharmaceutical composition comprising, consisting of and/or consisting essentially of a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, and/or a pharmaceutically acceptable diluent and a compound of Formula (I) or a pharmaceutically acceptable salt form thereof.

Also provided are processes for making a pharmaceutical composition comprising, consisting of, and/or consisting essentially of admixing a compound of Formula (I) and a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, and/or a pharmaceutically acceptable diluent.

The present invention further provides methods for treating or ameliorating a disease, syndrome, or condition in a subject, including a mammal and/or human in which the disease, syndrome, or condition is affected by the inhibition of PDEl Oa, such as Type II diabetes, using a compound of Formula (I).

The present invention also is also directed to the use of any of the compounds described herein in the preparation of a medicament wherein the medicament is prepared for treating a disease or condition that is affected by the inhibition of PDEl Oa enzyme, such as Type II diabetes, in a subject in need thereof.

The present invention is also directed to the preparation of substituted imidazo[l ,2-a]pyridazine derivatives that act as selective inhibitors of the PDE10a enzyme and are peripherally restricted, thereby reducing centrally-mediated side effects.

Exemplifying the invention are methods of treating a disorder modulated by PDEl Oa, wherein the disorder is Type ΐί diabetes, comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above.

In another embodiment, the present invention is directed to a compound of Formula (I) for use in the treatment of a disorder affected by the inhibition of PDE10a wherein the disorder is Type II diabetes.

In another embodiment, the present invention is directed to a composition comprising a compound of Formula (I) for the treatment of a disorder affected by the inhibition of PDEi Oa, wherein the disorder is Type II diabetes.

DETAILED DESCRIPTION OF THE INVENTION

With reference to substituents, the term "independently" refers to the situation where when more than one substituent is possible, the substituents may be the same or different from each other.

The term "alkyl" whether used alone or as part of a substituent group, refers to straight and branched carbon chains having 1 to 8 carbon atoms. Therefore, designated numbers of carbon atoms (e.g., Ci .g) refer independently to the number of carbon atoms in an alkyl moiety or to the alkyl portion of a larger alkyl-containing substituent. In substituent groups with multiple alkyl groups such as, (Ci_ ₆ aiky1)?ammo-, the C _h lky! groups of the dialkylamino may be the same or different.

The term "alkoxy" refers to an -O-aUkyl group, wherein the term "alkyi" is as defined above.

The terms "alkenyl" and "alkynyl" refer to straight and branched carbon chains having 2 to 8 carbon atoms, wherein an alkenyl chain contains at least one double bond and an alkynyl chain contains at least one triple bond.

The term "cycloalky " refers to saturated or partially saturated, monocyclic or poly cyclic hydrocarbon rings of 3 to 14 carbon atoms. Examples of such rings include cyclopropyl, cyciobutyl, cyciopentyl, cyclohexyl, cyclolieptyl, and adamantyl.

The term "heterocyclyl" refers to a nonaromatic monocyclic or bicyclic ring s tem having 3 to 10 ring members that include at least 1 carbon atom and from 1 to 4 heteroatoms independently selected from N, O, and S. Included within the term heterocyclyl is a nonaromatic cyclic ring of 5 to 7 members in which 1 to 2 members are N, or a nonaromatic cyclic ring of 5 to 7 members in which 0, 1 or 2 members are N and up to 2 members are O or S and at least one member must be either , O, or S; wherein, optionally, the ring contains 0 to 1 unsaturated bonds, and, optionally, when the ring is of 6 or 7 members, it contains up to 2 unsaturated bonds. The carbon atom ring members that form a heterocycle ring may be folly saturated or partially saturated. The term "heterocyclyl" also includes two 5 membered monocyclic beterocycloalkyl groups bridged to form a bicyclic ring. Such groups are not considered to be fully aromatic and are not referred to as heteroaryl groups. When a heterocycle is bicyclic, both rings of the heterocycle are non- aromatic and at least one of the rings contains a heieroatom ring member. Examples of heterocycle groups include, and are not limited to, pyrroiinyl (including 2H-pyrroie, 2-pyrrolinyl or 3 -pyrroiinyl), pyrroiidinyi, irmdazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, and piperazinyl. Unless otherwise noted, the heterocycle is attached to its pendant group at any heteroatom or carbon atom that results in a stable structure.

The term "aryf ' refers to an unsaturated, aromatic monocyclic or bicyclic ring of 6 to 10 carbon members. Examples of and rings include phenyl and naphma!enyl.

The term "heteroaryl" refers to an aromatic monocyclic or bicyclic aromatic ring system having 5 to 10 ring members and which contains carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O, and S. Included within the term heteroaryl are aromatic rings of 5 or 6 members wherein the ring consists of carbon atoms and has at least one heteroatom member. Suitable heteroatoms include nitrogen, oxygen, and sulfur. In the case of 5 membered rings, the heteroaryl ring preferably contains one member of nitrogen, oxygen or sulfur and, in addition, up to 3 additional nitrogens. In the case of 6 membered rings, the heteroaryl ring preferably contains from I to 3 nitrogen atoms. For the case wherein the 6 membered ring has 3 nitrogens, at most 2 nitrogen atoms are adjacent. Examples of heteroaryl groups include fury], thienyl, pyrrolyi, oxazolyl, thiazolyl, imidazofyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, ihiadiazoiyi, pyridinyl, pyridazinyl, pyrimidinyi, pyrazinyl, indolyl, isoindolyl, benzofuryi, benzothienyl, indazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzisoxazolyl,

benzothiadiazolyl, benzo triazolyl, quinolinyl, isoquinolinyl and quiiiazolinyl. Unless otherwise noted, the heteroarvi is attached to its pendant group at any heteroatom or carbon atom that results in a stable structure.

The term "halogen" or "halo" refers to fluorine, chlorine, bromine and iodine atoms.

The term "carboxy" refers to the group -C(=0)OH.

The term "formyl" refers to the group -C(=0)H.

The term "oxo" refers to the group (=0).

Whenever the term "alkyl" or "aryl" or either of their prefix roots appear in a name of a substituent (e.g., arylalkyl, alkyiamino) the name is to be interpreted as including those limitations given abo ve for "alkyl" and "aryl." Designated numbers of carbon atoms (e.g., Ci-Ce) refer independently to the number of carbon atoms in an alkyl moiety, an aryl moiety, or in the alkyl portion of a larger substituent in which alkyl appears as its prefix root. For alkyl and aikoxy substituents, the designated number of carbon atoms includes all of the independent members included within a given range specified. For example Ci-e alkyl would include methyl, ethyl, propyl, butyl, penryl and hexyl individually as well as sub-combinations thereof (e.g., Ci _-2 , Cj. 3, C , Cus, C _2- 6, Cj- , C4-6, C5-6, C _2- s, etc.).

in general, under standard nomenclature rules used throughout this disclosure, the terminal portion of the designated side chain is described first followed by the adjacent functionality toward the point of attachment. Thus, for example, a "Q -Ce alkylcarbonyl" substituent refers to a group of the formula:

For compounds of Formula (I) that possess a cyclopropyi group as their L- substituent, the following numbering convention at the stereocenters shall be adopted:

For compounds of Formula (I) that possess an azetidm-3-yi group as their L- substituent, the following nu dopted:

The term "R" at a stereocenter designates that the stereocenter is purely of the ^-configuration as defined in the art; likewise, the term "S" means that the stereocenter is purely of the ^-configuration. As used herein, the terms "*R" or "*S" at a stereocenter are used to designate that the stereocenter is of pure but unknown configuration. As used herein, the term "RS" refers to a stereocenter that exists as a mixture of the R- and ^-configurations. Simi larly, the terms "*RS" or "*SR" refer to a stereocenter that exists as a mixture of the R- and ^-configurations and is of unknown configuration relative to another stereocenter within the moiecule.

Compounds containing one stereocenter drawn without a stereo bond designation are a mixture of two enantiomers. Compounds containing two stereocenters both drawn without stereo bond designations are a mixture of four diastereomers. Compounds with two stereocenters both labeled "RS" and drawn with stereo bond designations are a two-component mixture with relative stereochemistry as drawn. Compounds with two stereocenters both labeled "*RS" and drawn with stereo bond designations are a two-component mixture with relative stereochemistry unknown. Unlabeled stereocenters drawn without stereo bond designations are a mixture of the R- and ^'-configurations. For unlabeled stereocenters drawn with stereo bond designations, the absolute stereochemistry is as depicted.

Unless otherwise noted, it is intended that the definition of any substituent or variable at a particular location in a molecule be independent of its definitions elsewhere in that molecule. Tt is understood that substituents and substitution patterns on the compounds of Fonnuia (T) can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by- techniques known in the art as well as those methods set forth herein.

The term "subject" refers to an animal, preferably a mammal, most preferably a hitman, who has been the object of treatment, observation or experiment. The term "therapeutically effective amount" refers to an amount of an ac tive compound or pharmaceutical agent, including a compound of the present invention, which elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation or partial alleviation of the symptoms of the disease, syndrome, condition, or disorder being treated.

The term "composition" refers to a product that includes the specified ingredients in therapeutically effective amounts, as well as any product that results, directly, or indirectly, from combinations of the specified ingredients in the specified amounts.

The term "PDElOa inhibitor" is intended to encompass a compound that interacts with PDElOa to substantially reduce or eliminate its catalytic activity, thereby increasing the concentrations of its substrate(s).

The term "PDE1 Oa-modulated" is used to refer to the condition of being affected by the modulation of the PDElOa enzyme, including but not limited to, the state of being mediated by the PDElOa enzyme, for the treatment of a disease or condition such as type II diabetes.

As used herein, unless otherwise noted, the term "affect" or "affected" (when referring to a disease, syndrome, condition or disorder that is affected by inhibition of PDElOa) includes a reduction in the frequency and / or severity of one or more symptoms or manifestations of said disease, syndrome, condition or disorder; and / or include the prevention of the development of one or more symptoms or manifestations of said disease, syndrome, condition or disorder or the development of the disease, condition, syndrome or disorder.

The compounds of Formula (I) are useful in methods for treating or ameliorating a disease, a syndrome, a condition or a disorder that is affected by the inhibition of PDElOa. Such methods comprise, consist of and/or consist essentially of administering to a subject, including an animal, a mammal, and a human in need of such treatment, amelioration and / ^' or prevention, a therapeutically effective amount of a compound of Fonnula (I), or an enaniiomer, diasiereomer, solvate or pharmaceutically acceptable salt thereof.

In particular, the compounds of Formula (I), or an enaniiomer, diasiereomer, solvate or pharmaceutically acceptable salt thereof are useful for treating or ameliorating diseases, syndromes, conditions, or disorders such as type II diabetes. More particularly, the compounds of Formula (T), or an enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof are useful for treating or ameliorating type II diabetes, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I), or an enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof as herein defined.

Embodiments of the present invention include a compound of Formula (!)

Formula (I)

wherein

R" is

(i) hydrogen;

(ii) a heteroaryi selected from the group consisting of pyridiny i, ihienyi, and fur anyl;

wherein the heteroaryi of group (ii) is optionally substituted with one subsii!ueni selected from the group consisting of hydroxy, carboxy(Ci..4)alkyl, Cj alkylsulfonylammocarbonyl(C;.4)alkyl, 1 -methyl- l,2,3,6-tetrahydropyridm-4-yl, d^alkoxy, carboxy, R ^" R ³ ,

carhoxy methylamino, C i _-4 alky lsulfonylaminocarbony 1, tetrazolyl, oxadiazolyi, triazoiyi, and triazolylthio; wherein said oxadiazolyl and triazolyl substituents are optionally substituted with one hydroxy or d- 4alkoxy substituent;

R ^d and R° are taken together with the nitrogen atom to which they are both attached to form piperazinyl ring; wherein said piperazinyl ringis optionally substituted at a nitrogen atom with methyl or aminosulfonyl; phenyl optionally substituted with one substituent that is Ci^alkoxy, cyano, aminos ulfonyi, hydroxy, Ci^alkylsulfonylaminocarbonyi, carboxy, carboxy(C;.4)alkyl, Ci../ialkylsulfonyfarainocarbonyl(C]..4)afkyl,

carboxy(Ci_4)alkyiamiriocarbony 1, 2-carboxypyrrolidin- 1 -y learbony 1, l-carboxy-2-methyl-propylamino, carboxy(C]^)alkylearbonylarnino, Cj alky]sulfonylammocarbony]amino, Ci^alkyisulfonylaniino, carboxy(C ₁ -4)alkylamino, 1,1 ,1 ,3,3,3-hexafluoro-2-hydroxy-propan-2-yl, 4-carbo piperidin- 1 -yl, tetrazolyi, triazolyl, thienyl, furanyl, or oxazolvl; wherein said tetrazolyi, triazolyl, thienyl, furanyl, and oxazolvl substituents are optionally independently substituted with one or two substituents selected from the group consisting of C _h alky! and hydroxy; and wherein said phenyl of group (Hi) is optionally independently further substituted with one or two additional substituents selected from the group consisting of C|../iafkoxy, fluoro, and hydroxy; phenyl substituted with one substituent that is r- 1, r-2, r-3, or r-4;

O O O O HN O HN NH N NH

¾ V V or

^ ^{! "2 r"4} ; wherein phenyl of group ( v) is optionally iurther substituted with one additional fluoro substituent; phenyl substituted with one substituent that is a-1, a-2, a-3, a-4, or a-5;

H ^H NH-.

(vi) piperidin-4-yl optionally substituted at the 1 -position with carboxy,

carboxy(Ci.4)alkyl, or (Cj 4)aikylsuifonylaminoearbonyl;

( vii) piperidin- 1 -yl optionally substituted at the 4-position with carboxy,

carboxy(Ci-4)alkyL or (Ci^jalkylsulfonylaminocarbonyl;

(viii) piperazin- l -yl optionally substituted at the 4-position with (C|_

4)alkylsulfonylaminocarbonyl, carboxy(C] -4)alkyl, carboxy(Ci_

4)aikylcarbonyl, a iinocarbonyl, aminosulfonyl, or (Ci ..

4)alkylcarbonylaminosulfonyl;

(iv) p enylamino wherein the phenyl is optionally substituted with carboxy or carboxy(Ci-4)alky{; and wherein the phenyl is optionally further substituted with one additional substituent selected from the group consisting of Ci . 4aIkoxy, C _h al y!, hydroxy, and one or two fluoro substituents; or

(x) cyclohexylamino wherein cyclohexyl is optionally substituted with carboxy or carboxy(Ci-4)alkyl;

R ² is

(ϊ) hydrogen;

(ii) a heteroaryl selected from the group consisting of pyridinyl, thienyl, and furanyl;

wherein the heteroaryl of group (ii) is optionally substituted with one substituent selected from the group consisting of carboxy ( Chalk ! Ci -4alkylsulfonyiaminoearbonyl(C;-4)aikyl, 1 -metihyl- 1 ,2,3,6-tetra hydiopyridin-4-yl, Ci-4alkoxy, carboxy, NR ^a R°, carboxymethylamino, C i ^alkylsulfonylaminoearbonyl, tetrazoiyi, oxadiazolyl, triazolyl, and triazolylthio;

wherein said oxadiazolyl is optionally substituted with one hydroxy or C] -/jalkoxy substituent;

R ^a and ^B are independently hydrogen; or R ^a and R ^b are taken together with the nitrogen atom to which they are both attached to form a piperazinyl ring; wherein said piperaziny l ring is optionally substituted at a nitrogen atom with methyl or aminosulfonyl;

) phenyl optionally substituted with one substituent that is Ci^alkoxy, cyano, C] ^alkoxycarbonyl, Ci^alkylcarbonylaminosuifonyl, aminosulfonyl, Cj alky1sulfonylaminocarbony1, carboxy, carboxy(C].4)alkyl,

Ci- ₄ alky3sulfonylaminocarbony3(Ci- )alkyl,

carboxy(Ci-4)alkylaminocarbonyl, 2-carboxypyrrolidin- 1 -ylcarbonyl, l-carboxy-2-metliyl~propylamino, carboxy(Ci^)alkylcaAonylaniino, C .a3k ^" .ylsulfonylaminocarbonylamino, Ci^alkyisulfonylarnino, carboxy(Ci_4)alkyiamino, 1, 1,1 ,3,3,3-hexafluoro-2-hydroxy-propan-2-yl, 4-carboxypiperidin- 1 -yl, tetrazoiyi, triazolyl, thienyl, furanyl, or oxazolyl; wherein said tetrazoiyi, triazolyl, thienyl, furanyl, and oxazolyl substituents are optionally independently substituted with one or two subsiituenis selected from the group consisting of Q^alkyl and hydroxy; and wherein sa id phenyl of group (iii) is optionally independently further substituted with one or two additiona3 substituents selected from the group consisting of Ci^alkoxy, fluoro, and hydroxy;

(iv) phenyl substituted with one substituent that is r- 1 , r-2, r-3, or r-

r-1 r-2 r-3 r-4

(v) phenyl substituted with one substituent that is a-1 , a-2, or a-3;

(vi) piperidin-4-yl optionally substituted at the 1 -position with carboxy,

carboxyi Ci.-4)alkyi, or (Cj )a.lkylsulfonylaminocarbonyl;

( vii) piperidin- 1 -yl optionally substituted at the 4-position with carboxy,

carboxy(Ci- ₄ )alkyL or (Ci^)alkylsulfonylaminocarbonyl;

(viii) piperazin- 1 -y 1 optionally substituted at the 4-position with (C

4)alkylsulfonylaminocarbonyl, carboxy(Ci_/i)alkyL carboxy(Ci_ 4jalkylcarbonyl, aminocarbonyl, aminosulfonyl, or (Ci .

/i)alkylcarbonyla.niinosulfonyl;

(iv) phenylamino wherein the phenyl is optionally substituted with carboxy or carboxy(Ci- ₄ jalky{; and wherein the phenyl is optionally further substituted with one additional substituent selected from the group consisting of C;. 4alkoxy, Ci^alkyl, hydroxy, and one or two ffuoro substituents; or

(x) cyclohexylamino wherein cyclohexyl is optionally substituted with carboxy or carboxy(C-i- ₄ )alkyl; c) L is a linker that is 1,2-cyclopropyl, trans- 1 ,3-cyclobutyI, or cis- 1,3 -eyclobutyi; d) Q is quiiiolin-2-yl, 5,6,7,8-tetrahydroquinolin-2-yl, pyridinyl, benzothiazol-2-yl, or benzimidazoi-2-yl: wherein said Q is optionally independently substituted with one or two substiiuents selected from the group consisting of eya.no,

trifluoromethyl, carboxy, hydroxyaminocarbonyl, or Cj..

4a]kylsu]fonylaminocarbonyl; and any combination of embodiments a) through d) above, provided that it is understood that combinations in which different embodiments of the same substituent would be combined are excluded;

or an enantiomer, diastereomer, or pharmaceutically acceptable salt form thereof.

An embodiment of the present invention includes a compound of Formula (I)

Formula (i)

wherein

R ¹ is hydrogen or chloro; R ² is

(i) hydrogen;

(ii) a heteroaryl selected from the group consisting of pyridinyl, thsenyl, and furanyl;

wherein the heteroaryi of group (ii) is optionally substituted with one substituent selected from the group consisting of C _h alky!, hydroxy, carboxy(Ci..4)a]jkyf, Ci../ialkylsulfonyfaminocarbonyl(C]..4)afkyl, 1 -methyl- 1 ,2,3,6- tetrahydropyridin-4-yl, d^alkoxy, carboxy, NR ^a R ^b , carboxymethylamino, Ci -4alkylsuifonyiaminoearbonyL tetrazolyl, oxadiazolyl, triazolyl, and triazolylthio; wherein said oxadiazoiyl and triazoiyi subsiituenis are optionaily substituied with one hydroxy or Cj 4alkoxy substituent;

R ^a and R ^'J are taken together with the nitrogen atom to which they are both attached to form a piperazinyi ring: wherein said piperazinyi ring is optionally substituted at a nitrogen atom with methyl or aminosulfonyl; phenyl optionally substituied with one substituent that is

cyano, Ci _-4 aIkoxycarbonyl, C i ^alkylcarbonylaminosulfonyl, aminosulfonyl, hydroxy, Ci _-4 alkylsulfonylaminocarbonyl, carboxy, carboxy(C] _ )alliyL C] ^alkylsulfonylaminocarbonyl(Ci-4)aLkyl, carboxy(C i ^alkylaminocarbonyl, 2~carboxypyrrolidin- 1 -ylcarbonyl, l -earboxy-2-methy]-propylamino, carboxy(Ci.4)aJkylcarbonylamino, C]..4afkylsuffonylaminocarbonylammo, Ci- alky3sulfonylarnino, carboxy(C i^alkylamino, 1 , 1 , 1 ,3,3,3-hexafluoro-2-hydroxy-propan-2-yl, 4-carboxypiperidin- l -yl, tetrazolyl, triazolyl, thienyi, furanyl, or oxazolyl;

wherein said tetrazolyl, triazolyl, thienyi, furanyl, and oxazolyl subsiituenis are optionaily independently substituied with one or two subsiituenis selected from the group consisting of Ci_ ₄ a]kyl and hydroxy; and wherein said phenyl of group (in) is optionally independently further substituted with one or two additional substituents selected from the group consisting of fluoro, and hydroxy;

(iv) phenyl substituted with one substituent that is r- 1 , r-2, r-3, or r-4;

r ^{"2 r"4} ; wherein phenyl of group (iv optionally further substituted with one additional fluoro substituent;

(v) phenyl substituted with one substituent that is a- ! , a-2, a-3, a-4, or a-5;

piperidin-4-yl optionally substituted at the 1 -position with carboxy, carboxyi C i _4)a3kyl, or (Cj ^)alkylsulfonylaminocarbonyl; piperidin- 1 -yl optionally substituted at the 4-position with carboxy, carboxy(Ci_4)alkyl, or (Ci. ₄ )alky3sulfony3ammocarbony3; piperazin- 1 ~yl optionally substituted at the 4-position with (Ci..

4)al3iy3sulfonylammocarbony3., carboxy(C]../i)aikyl, carboxy(0- 4)alky3carbony3, aminocarbonyl, aminosu3fonyl, or

(Ci _-4 )alkylcarbonylaniinosuifonyl; phenylamino wherein the phenyl is optionally substituted with carboxy or carboxy(Ci- ₄ )alkyl; and wherein the phenyl is optionally further substituted with one additional substituent selected from the group consisting of Cj ₄ aikoxy, C;- ₄ alkyi, hydroxy, and one or two fluoro substituents; or

(x) cyclohexylamino wherein cyciohexyi is optionally substituted with carboxy or carboxy(Ci- ₄ )alkyl; L is a linker that is ethyl, ethenyl, ethynyl, 1 ,2-cyclopropyl,

trans- 1 ,3-cyclobutyl, cis- 1 ,3-cyelobutyl, azetidin-3-yl, -XCH ₂ -, or -CH ₂ NH-; wherein X is O, S, or (R ); and wherein Κ* is hydrogen or methyl;

Q is quinolin-2-yl, 5,6,7,8-tetrahydroquinolin-2~yi, pyridinyl, benzothiazol-2-yi, or benzirmdazol-2-yl;

wherein said Q is optionally independently substituted with one or two substituents selected from the group consisting of Ci^aikoxy, cyano, trifluoromethyl, carboxy, hydroxyaminocarbonyl, or Ci^alkylsulfonylaminocarbonyl;

or an enantiomer, diastereomer, or pharmaceutically acceptable salt form thereof.

An embodiment of the present invention includes a compound of Formula (I)

Formula (I)

wherein

R ¹ is hydrogen or chloro;

R ² is

(i) hydrogen;

(ii) a heteroaryl selected from the group consisting of pyridinyl, thienyl, and furanyl; wherein said heteroaryl is optionally substituted with one substituent that is carboxy(Ci-4)alkyl; Ci-4alkylsulfonylaminocarbonyl{Ci . )alky!; 1 -methyl- 1,2,3,6- tetrahydropyridin-4-yl; C^alkoxy; carboxy; R ^a R ^b ; carboxymethylamino; Q.

4alkyisulfonylaminocarbonyl; teirazoiyl; oxadiazolyl optionally substituted with hydroxy or Ci^alkoxy; triazoiyl; or triazolylthio; and wherein said heteroaryl of group (ii) is optionally independently further substituted with one or two additional substituents selected from the group consisting of fluoro, chloro, and hydroxy;

R ^a and R ^b are independently hydrogen; or R ^a and R ³ are taken together with the nitrogen atom to which they are both attached to form a monocyclic heterocyclyl optionally containing one additional O, S, or N atom; wherein said heterocyclyl is optionally substituted at a carbon atom with Chalky], or Q.

aalkylsulfonyiammocarbonyl; and wherein said heterocyclyl is optionally substituted at a nitrogen atom with aminosulfonyl;

(iii) phenyl optionally substituted with one substituent that is C1.4aI.koxy, cyano, Ci-4alkylcarbonyl, Ci^aikylcarbonylaminosulfonyl, aminosulfonyl, hydroxy, C ^' i _ ₄ alkyisulfonylaminocarbonyl, carboxy, carboxy(Cj-4)alkyl: Ci_

4alkylsulfony1aminocarbonyl{Ci.4)alkyi; carboxy(C; .4)alky1aminocarbonyl, 2- carboxypyrrolidin- 1 -ylcarbonyl, 1 -carboxy-2-methy 3-propy laminocarbonyl, 1 -carboxy- 2-methyl-propylamino, carboxy(Ci_4)alkylcarbonylamino, Cj _

4alkyisulfonyla:minocarbonylamino, Ci^alkylsulfonylamino, carboxy(C]^)alkylamino, 1,1 , 1,3,3 ,3-hexaf!uoro-2-hydroxy-propan-2-y1, 4-carboxypiperidin- 1 -yl, tetrazolyl, triazoiyi, thienyi, furanyl, or oxazolyl; wherein tetrazolyl, triazoiyi, thienyi, furanyl, or oxazolyl is optionally substituted with one to two substituents selected from the group consisting of Chalky I and hydroxy;

and wherein said phenyl of group (iii) is optionally independently further substituted with one or two additional substituents selected from the group consisting of fluoro, and hydroxy;

(iv) phenyl substituted with one substituent that is r-l , r-2, r-3, or r-4;

r-1 r-2 r-3 r-4

(v) phenyl substituted with one substituent that is a- 1, or a-3;

(vi) piperidin-4-yl optionally substituted at the 1 -position with carboxy, carboxy(Ci-4)alkyl, or (Ci-4)alkylsulfonylaminocarbonyi;

(vii) piperidin-l-yl optionally substituted at the 4-position with carboxy, ca.rboxy(Ci-4)alkyl, or (Ci^)alkylsulfonyla.minocarbonyl;

(vi i) piperazin- 1 -yi optionally substituted at the 4-position with (Ci_

4)alkylsulfonylaminocarbonyl, carboxy(C|_4)alkyl, carboxy(Ci _4)aikylcarbonyl, aminocarbonyi, aminosulionyl, or (Cj ^alkylcarbonylaminosulfonyl;

(iv) phenylamino wherein the phenyl is optionally substituted with carboxy or carboxy(Ci -4)alkyi; and wherein the phenyl is optionally further substituted with one additional substituent selected from the group consisting of

hydroxy, and one or two fluoro substituents; or

(x) cyciohexylamino wherein cyclohexyl is optionally substituted with carboxy or carboxy(Ci_4)alky];

L is a linker that is 1 ,2-cyclopropyl, trans- 1 ,3-cyclobutyl, or cis- 1 ,3-cyclobutyl;

Q is qumolin-2-yl, 5,6,7, 8-tetrahydroqumolin-2-yi, pyridinyl, benzothiazoJ-2-yl, or benzimidazol-2-yl; wherein said Q is optionally independently substituted with one or two substituents selected from the group consisting of methyl, cyano, trifSuoromethyl, carboxy, hydroxyaminocarbonyl, or Cj^alkyisulfonylarmnocarbonyi; or an enantiomer, diastereomer, or pharmaceutically acceptable salt form thereof.

An embodiment of the present invention includes a compound of Formula (I)

Formula (I)

wherein

R is hydrogen; i is

(i) hydrogen;

(ii) pyridinvl optionally substituted with one substituent that is selected from the group consisting of carboxy, c rboxy ^' : )aik i. carboxymethylainino, and Ci-aalkylsulfonylammocarbonyl;

(iii) phenyl optionally substituted with one substituent that is Ci- 4alkyicarbonylaminosuifonyL Ci^alkylsulfonylaminocarbonyl, carboxy, carboxyfCi- 4)alkyl, carboxy(C;.4)alkyJaminocarbonyl, carboxy(C j 4)alkylcarbonylamino, 4- carboxypiperidin- 1 -yl, triazolyl, or oxazolyf; wherein said triazolyl or oxazolyf substituents are optionally substituted with one or two substituents selected from the group consisting of and hydroxy ;

and wherein said phenyl of group (iii) is optionally independently further substituted with one or two additional substituents selected from the group consisting of C]-4alkoxy and fluoro;

(i v) phenyl substituted with r- 1 ;

r-1

or

(v) piperidin-4-yl optionally substituted at the 1 -position with carboxy(Cj_

₄ )alkyl;

L is a linker that is ethyl, ethenyl, ethynyl, 1,2-cyclopropyl, trans-\,?>- cyclobutyl, or cis- 1,3-cyclobutyl;

Q is quinolin-2-yi or 5,6,7, 8-tetrahydroqumolin-2-yl; wherein said Q is optionally substituted with a substituent selected from the group consisting of methyl, C;- ₄ alkoxy, cyano, trifluoromethyl, carboxy, hydroxyaininocarbonyl, and C]_ ₄ alkylsulfonylaminocarbonyl;

or an enantiomer, diastereomer, or pharmaceutically acceptable salt form thereof.

Additional embodiments of the present invention include compounds of Formula (I) as herein defined, or an enantiomer, diastereomer, solvate, or a pharmaceutically acceptable salt form thereof, wherein the substituents selected from one or more of the variables defined herein (e.g. R ¹ , R ² , R ^J , L, and Q) are independently selected to be any individual substituent or any subset of substituents from those exemplified in the listing in Table 1 , below.

In the tables that follow, the linkers (under column "L") are depicted such that they can be directly inserted into the structure of Formula (T). More specifically, the right terminus of the linker is attached to Q, while the left terminus of the linker is attached to the core ring structure.

Table 1.

Compounds of Formula (I)

8 H pyridin-3-yi NHC(O quinoiin-2-yl

17 H arnino pyridiri-3-y! 5-ethenyi quinoiin-2-yl

27 H pyridin-3-y! £-etheny! quinoiin-2-yi

36 H yi £-etheny! quino!in-2-yi

177 H pyridin-3-yi f-ethenyi quinoiin-2-yl

Additional embodiments of the present invention include compounds of Formula (la), wherein L is ethyny] and Q is quinolm-2-y3, as herein defined, or an enantiomer, diastereomer, solvate, or a pharmaceutically acceptable salt form thereof, wherein ihe substituents selected from one or more of the variables defined herein (e.g. R ¹ , R\ R ^J ) are independently selected to be any individual substituent or any subset of substituents from those exemplified in the listing in Table 2, below.

Formula (la) Table 2. Compounds of Formula ( l a ) wherem L is ethyny] and 0 is quinolin-2-yl

In a further embodiment of the present invent on includes compou Formula (I)

Formula (I)

selected from the group consisting of

Cpd 1, 2- {[3-(6-Me hyl yridin-3-yl)-8-moφho]m-4-ylimidazo[l ,2-b] yridazi1 - yljmethoxy } quinoline;

Cpd 2, 2-[(8-Morpholin-4-y!-3-pyridm-3-ylimidazo[i,2-b]pyridazin-2- y])metlioxy]quinol ne; Cpd 3, 8-Moφhoiin-4- l-3-(6- i eΓazin-l-yl ridin-3-yl)-N-quinolin-2-yiimidazo[l ,2- b]pyxidazine-2-carboxamide;

Cpd 4, N- {[8-Mo^holin-4-yi-3-(6-piperazin-l-ylpyridin-3-yl)imidazo[l ,2- b]pyridazii -2-yl]methyi}quinolin-2-amine;

Cpd 5, N,N-Dimethyl-5- {8-morpholin-4-yl-2-[(quinolin-2-yloxy)methyl]imidazo[l ,2- b jpyridazin- 3 -yl } pyridin- 2 - amine :

Cpd 6, 2-({[8-Morpholin-4-yl-3-(6-piperazin- 1 -ylpyridin-3-yl)imidazo[l ,2- b]pyridazin-2-y3]methyl}sulfanyl)quinoline;

Cpd 7, N,N-Diethyl-5- {8-morpholm-4-yl-2-[(quinolin-2-yloxy)methyl]imidazo[l ,2- b]pyridazin-3-yl}pyridin-2-a.mine;

Cpd 8, N-[8-Morpholin-4-yl-3-(6-piperazin-l -ylpyridin-3-yl)imidazo[l ,2-b]pyridazin-

2- yl]quinoline-2-carboxamide;

Cpd 9, 2-({[8-Morpholin-4-yi-3-(6-piperazin- l-ylpyridin-3-yl)imidazo[l,2- b]pyridazin-2-yl]methyl} sulfonyl)quinoline;

Cpd 18, Γ-Methyl- -{8-moφhoiin-4-yl-2-[(quinolm-2-ylo y)methyl]irnidazo[ϊ,2- b]pyridazin-3-yli;-r,2',3',6 ^, -tetrahydro-2,4 ^, -bipyridine;

Cpd 11, 8-Mo^ olin -yl-3-(6-piperazin-l-ylpyridin-3-yl)- J-(quino -2

ylm etby 1) im idazo [ 1 ,2 -b j pyridazin -2-amine ;

Cpd 12, 2-{[8-ΜοφΗο1πι-4-νί-3-(6-ρίρ6Γ3ζϊη-1- ρ\ ίάϊη-3^1)πηίά ζο[1,2- b]pyridazin~2 -yl] ethynyl} quinoline ;

Cpd 13, 2- {2-[8-M φboli -4-yl-3-(6-pi eΓazin- l-yl yridm-3-yl)imidazo[l ,2- b]pyridazin-2-y3]etbyl}qumoline;

b]pyridazin-2 -yl] ethoxy ) quinoline;

Cpd IS, Ν-Μβ^1-Ν-({3-[6-(4^6^1ρϊρε»ζϊη-1^1)ρ^άΐη-3^1 ]-8-ηιοφίιοΗη-4- ylitnidazo[3 ,2-b]pyridazin-2-yl}methy3)quinolin-2-amine;

Cpd 16, 5- {8-Moφholi ^" n-4-yl-2-[(E)-2-qui olm-2-ylethenyl]imidazo[l ,2-b]pyridazin-

3- yl}pyridin-2-ol:

Cpd 17, -(5- {8-Moφholin-4-yl-2-[(E)-2-quΐnoiin-2-yletheny3]imidazo[l,2 - b]pyridazin-3-yl}pyridin-2-yl)glycine;

3 -y I } pyridin- 2 - amine ;

Cpd 19, 2-[(E)-2-{8-Moφho3m-4-yl- -[6-(lH-tetrazol-5-y3)py^ dm-3-yl]inlίdazo[3 ,2- b]pyridazm-2-yl} ethenyl]qumoline; Cpd 28, 4-(5- {8-MoTpholin-4-yl-2-[(qumo]m-2-ylsuifany3)methyl]irnidazo[ l,2- bjpyridazin- 3 -yl}pyridin-2-yl)piperazine- l -sulfonamide;

Cpd 21, 2-( {8-M^hojin-4-yl-3-[6-(lH-tetrazol-5-y])pyri.dm-3-yl]imidazo[ l ,2- b]pyridazii -2-yl}ethynyl)qumolme;

Cpd 22, 2-[(E)-2- \ 8-Morpholin-4-yl-3-[6-(4H- 1 ,2,4-triazol-3-ylsulfanyl)pyridin-3- yl]iinidazo[l,2-b]pyridazin-2-yl} ethenyi]quinoline;

Cpd 23, 2-[(E)-2-{8-Moφho -4-y{-3-[6-(lH-l,2,3-triazol·5-ylsulf nyl) yridin-3- y]]imidazo[l,2-b]pyridazm-2-yl}ethenyi]quiiiolme;

yl]pyridin-2-yl}glycine;

Cpd 25, {4-[8-MΌ holm-4-yΐ-2-(qlJi oli -2-ylethyΐlyl)imidazo[ 1 ,2-b]pyridazm-3- yl]piperidin- 1 -yl} acetic acid;

Cpd 26, 3- ^■ {5-[8-Moφholin~4-yl-2 ^■■ (quinolm-2-ylethynyl)imidazo[ l,2-b] yridaz ^■ in-3- y]]pyridin-2-yl} - 1 ,2,4-oxadiazol-5-ol;

Cpd 27, N-(Methylsulfonyl)-5- {8^οφ!ιοΗη-4^1-2-[(Ε)-2- ϋίηοΗη-2- ylethenyl]imidazo[l,2-b]pyridazin-3-yl}pyridme-2-carboxamide ;

b]pyridazin-3-yl]pyridine-2-carboxamide;

Cpd 29, (4- { 8-Moφholm-4-yί-2-[{E)-2-qumoίin-2-ylethenyl]imidazo[l,2-b ] yridazin-

3-yl}piperidin-l-yl)acetie acid;

Cpd 38, Ν-(Μ ΐ]^ΐ8υ1Γο^1)-5-[8^οφΗο1ϊη-4^1^^

b]pyri(kzin-3-y]]p ^r ridine-2-carboxamide;

€ρά 31, 2-(2- {8-Μοφ1ιο1ϊη-4-γ1-3-[6-(1Η-ίβΐΓ3ζο1-5-γ1)ρ� �ΓΪάίη-3-γ1]ΐιηΐά3ζο[1,2- b]pyridazin-2-yl ethyl)quinoline;

Cpd 32, H-tetrazol-5-yl)pyridin-3-yl]imidazo[l ,2- b]pyridazii -2-yl}methyl)sulfanyl]quino]me;

Cpd 33, 2-( \ 8-Μοφ1ιο1ί ^η -4-γ1-3-[6-( lH-tetrazol-5- l)pyridin-3-yl]imidazo[ 1 ,2- b]pyridazin-2-yl} methoxy)quinoiine;

Cpd 34, 3-(5- {8-Moφbolin-4-yl-2-[(E)-2-quinolm-2-ylethenyl]ίmίdazo[l ,2- b]pyridazin-3-yl}pyTidin-2-yl)- l,2,4-oxad ^" iazoi-5-ol;

Cpd 35, 3 -(5- { 8-Μοφ1ιο11η- 4 -y 1-2 ^■ [(quinolin-2-yloxy)methy 1 j imidazo [1,2- b]pyridazin-3-yl}pyridin-2-yl)-l ,2,4-oxadiazol-5-ol;

Cpd 36, Ν-[(4-{8-ΜοφΗο1ίη-4^1-2-[(Ε)-2- ώηο1ίη-2^1είη^1]ίιηίάΒζο[1,2- b]pyridazin-3-yl} phenyl)sulfonyl]acetamide; Cpd 37, 3- {5-[8-Moiphoiin-4-yl-2-(2-qumolm-2-ylethyl)irnida2:o[ 1 ,2-b]pyridazm-3- yl]pyridin-2-yl} ^■■ 1 ,2,4-oxadiazoi-5-oi;

Cpd 38, 4-[8-Mo holm-4-yl-2-(2-quinolin-2-ylethyl)imidazo[l,2-b]pyrid zin-3- yljbenzenesulfonamide;

Cpd 39, N-(Methylsulfonyl)-4- {8-moipholin-4-yl-2-[(E)-2-quinoliR-2- ylethenyljiinidazo [ 1 ,2 - b jpyridazin-3 -y i } benzamide;

Cpd 46, 4-{8-Mo^holin-4-yl-2-[(E)-2-quinolm-2-ylethenyl]imidazo[l,2- b]pyridazin

3-yl}benzoic acid;

Cpd 41, 4-[8-Morpholin-4-yl-2-(2-qumolin-2-ylethyl)imidazo[l ,2-b]pyridazin-3- yljbenzoic acid;

Cpd 42, N-({4-[8-Moφholm-4-yl-2-(2-quinolin-2-ylethyl)imidazo[l ,2-b] yridazίn-3 yljpheny 1 } sulfonyl)acetamide;

Cpd 43, N- MetliylsulfoiTyl)-4- [8-^^

b]pyridazin-3-yl] benzamide;

Cpd 44, -[(4~ {8-Μο Ηο1ΐη-4^1-2-[(Ε)-2- υΐηο1ίη-2^ΐ6ΐ1ι^1]ΐη ΐά ζο[1 ,2- b]pyridazin-3-yHphenyl)carbonyl]-beta-alamne;

Cpd 45, ,2 - b jpyridazin- 3 - yljpheny] }meth.anesulfonamide;

Cpd 46, N-( {4-[8-Moφholi -4-yl-2-(2-quinolm-2- lethyl)imidazo[l ,2-b]pyridazm-3- yl jphenyl } carbonyi) - be!a-alanine;

Cpd 47, N-(4- { 8-Μοφ1ιοίίη-4~νΙ -2- [(E)-2-quinQiin-2-ylethenyl j imidazo [ 1 ,2- bjpyridazin-3-y]}phenyl)methanesuifonamide;

Cpd 48, 4-[(4- {8-Mo holi -4- l-2-[(E)-2-qmnoli -2-ylethenyljimidazo[l ,2- b]pyridazin-3-yl phenyl)amino]-4-oxobutanoic acid;

yljpheny 3 } amino)-4-oxobutanoic acid;

Cpd 58, -[(4- {8-Moφholin-4-yl-2-[(E)-2-quinolm-2-ylethen l]imidazo[l,2- bjpyTidazin~3-yl} phenyi)carbamoyi]methanesuifonainide;

Cpd 51, -({4-[8-Mo holΐn-4-y1-2-(2-quinoli -2-ylethy1)imidazo[l,2-b] yridazin-3 y ljpheny 1 } c arbamoy l)methanes ulfonamide;

Cpd 52, 1 , 1, 1 ,3,3,3 -Hexafluoro-2-(4- {8 -n^hoiin-4--yl-2--[(E)--2--quinolin--2- ylet3ienyl]imidazo[l ,2-b]pyridazin-3-yl}phenyl)propan-2-ol;

Cpd 53, 1,1, 1 ,3,3,3-Hexafluoro-2- {4-[8-m(^holin-4-y3-2-(2-quinolin-2- ylethy l)imidazo [ 1 ,2-b]pyridazin-3 -yljphenyl } propan-2 -ol ; Cpd 54, 1 -(4- {8-Morpholin-4-yl-2-[(E)-2-quinolin-2-ylethenyl]imi<tozo[ l ,2- bjpyridazin- 3 -yl}phenyl)- 1H- 1 ,2,4-triazol- 3 -ol;

Cpd SS, l-(4-{8-Mo^holin-4-yl-2-[(E)-2-quinolin-2-yiethenyl]iraidazo [l,2- b]pyridaziii-3-yl}pbenyl)- 1 H-tetrazol-5-ol;

Cpd 56, l-(5- {8-Mo^holm-4-yl-2-[(E)-2-qtunolin-2-ylethenyl]imidazo[l,2- b]pyridazin~3-yl} pyridin-2-yl)-lH- l,2,4-triazol-3-ol:

Cpd 57, 5-{8-Mo^hoUn-4-yl-2-[(E)-2-quinolm-2-ylethenyl]imidazo[l,2-b ]pyridazin-

3-yl} biophene-2-carboxylic acid;

Cpd 58, 5- {8-Mo hoίm-4-yl-2-[(E)-2-quinolin-2- lethenyl]imidazo[l,2-b] τidazi -

3-yi } furan-2~carboxylic acid;

Cpd 59, 1- {4-[8-Morpholin-4-yl-2-(2-quinolin-2-yletbyl)imidazo[l ,2-b]pyridazin-3- yljpheny 1 } - 1 H- 1 ,2,4-triazol-3-ol;

Cpd 68, 5-[8-Mo holill-4-yl-2-(2-quinoiin-2-ylethyl)imidazo[l,2-b] r ^■ idazin-3- y 1 ] fur an - 2 - carb oxy lie ac i d ;

Cpd 61, 5-[8-Moφholin-4-yl-2-(2-quΐnolin-2-ylethyl)imidazo[l ,2-b] τidazi -3- y 1] thiophene-2-carbox lie acid;

Cpd 62, l- {4-[8-Moφholin-4- l-2-(2-quinolin-2-ylethyl)itnidazo[l,2-b]pyridazin-3- yl]pheny] } - 1 H-tetrazol-5-οΐ;

Cpd 63, 2-HydΓoxy-4- { 8-moφholm-4- l-2-[(E)-2-qui ^" nolm-2-yίethenyl]imidazo[l,2- bjpyridazin-3-yl) benzoic acid;

Cpd 64, 2-Hydτoxy-4-[8-moφho{in-4-yl-2-(2-quinolin-2-ylethyl)inlid azo[l ,2- b]pyridazin-3-y3]benzoic acid;

Cpd 65, 5-(4- {8-Moφholin-4- l-2-[(E)-2-qui ^■ nolm-2-ylethenyl]imidazo[l ,2- b]pyridazin-3-yl phenyl)- 1 ,3-oxazole-2,4-diol;

Cpd 66, N-[(4- {8-Moφholin-4-yl-2-[(E)-2-quinolm-2-ylεtheny{]iImdazo[l _! 2- b]pyridaziii-3-yl}pbenyl)earbonyl]glycine;

Cpd 67, 2-Methoxy-4- {8-moφholm-4-yl-2-[(E)-2-qu ^" inolin-2-ylethen l]imidazo[l,2- bjpyridazin-3-yl) benzoic acid;

Cpd 68, Ν-({4-[8-Μοφηο1ΐη-4^!-2-(2^αίηο1ίη^

yljphenyl} carbony l)glycine;

Cpd 69, 2-Meίhoxy-4 8-moφholm-4-yl-2-(2-quinolin-2-ylethyl)imidazo[l,2- blpyri dazin- 3 -yljbenzoic acid;

Cpd 78, 5- {4-[8-Moφholm-4-yl-2-(2-quΐnolin-2- letbyl)imidazo[l ,2-b]pyridazin-3- yljphenyH - 1 ,3-oxazole-2,4-diol; Cpd 71, 1 -[(4- {8-Mo hoim-4-yl-2-[(E)-2-qumo3m-2-ylethenyl]imidazo[l ,2- bjpyridazin- 3 -y 1 } phenyl)carbonylJ -L-proline:

Cpd 72, l-({4-[8-Mo^hoUn-4-yl-2-(2-qumolin-2-ylethyl)iniidazo[l,2-b] pyri^zin-3 yl]pheny 3 } carboi yl)-L-proline;

Cpd 73, -[(4- {8-Moφholm-4-yl-2-[(E)-2-quinolm-2-ylethen l]imidazo[l,2- b]pyridazin-3-yl) phenyi)carbonyl] -L-valine;

Cpd 74, 1 -Methyl-3-(4 - {8-raorpholin-4 -yl-2-[(E)-2-quinolin-2-yiethenyl]imidazo [ 1 , b]pyridazin-3-y]}phenyi)-lH-l,2,4-triazol-5-o];

Cpd 75, Ν-({4-Τ8-Μοφηο1ίη-4^1-2-(2 }υίη^^

yl]phenyl) carbonyi)-L -valine;

Cpd 76, 4- {8-Moφholm-4-yl-2-[(E)-2-(5,6,7,8-tetrahydroqvιinolin-2- yliethenyi] imidazo [ 1 ,2 -b]pyridazin-3 -y 1 benzoic acid;

Cpd 77, 4- [8 -Morpliolin-4-yl--2-(quinolin-2--yiethynyl)imidazo[ 1 ,2-b]pyridazin-3- y]] benzoic acid;

Cpd 78, 1 -Methyl-3- {4-[8-moφholm-4-yl-2-(2-quiΏolί -2-y3e byΓ)imidazo[ 1 ,2- b]pyridazin-3-yl]phenyl} - 1H- i ,2,4-triazol-5-ol;

Cpd 79, 4- {8-Moφhoiin-4-yl-2 2 5,6,7,8-tetΓahyώΌqυnlolin-2-yl)ethylJimidazo[l, blpyridazin- 3 -yl } benzoic aci d ;

Cpd 88, 2,6-Difluoro-4- {8-moφholi -4-yί-2-[{Έ)-2-qui olm ^■ -2 ^■■ ylethenyl]i ^■ midazo[l , bjpyridazin-3-yl) phenol;

Cpd 81, 2,6-Difluoro-4-[8-moφholi -4-yl-2-(2-qui oli -2-yletbyl)imidazo[l ,2- b]pyridazin-3-y3]phenol;

Cpd 82, -({4-[8-Moφholin-4- l-2-(quinoli -2-yίethyllyl)imidazo[l,2 ^■ -b] yrida m-l yl]phenyl}carbonyl)-beta -alanine;

Cpd 83, N-(Methylsulfony{)-4-[8-mo^holin-4-yl-2-(quijiolin-2-ylethyn y{)iim

bjpyri dazin-3 -yljbenzaraide;

Cpd 84, 2-[(8-Mo holi -4-ylimidazo[l,2- ^■ b] yridazi -2- ^■ yl)ethynyl]quinoli ^" e; Cpd 85, 5- [8 -Morpholin-4-yl--2-(quinolin-2--ylethynyl)imidazo[ 1 ,2-b]pyridazin-3- y3]thiophene-2-carboxy3ic acid;

Cpd 86, 4 ^■ -[8-Moφholi ^■ -4-yl-2- ^■ ( yridi -2- ^■ yleth yί)imidazo[l,2-b] yridazi ^■ -3- yljbenzoic acid:

Cpd 87, 4-[2-(l ,3-Benzothi zol-2-ylethy yΐ)-8-moφholm-4-ylimidazo[l ,2- bjpyri dazin-3 -yljbenzoic acid; Cpd 88, 3-[8-Moφholm-4-yl-2-(quinolin-2-ylethynyl)imidazo[ 1 ,2-b]pyridazin-3- yljbenzoic acid;

Cpd 89, 4- {8-Mo^holin-4-yl-2-[(E)-2-pyridm-2-ylethenyl]imidazo[l,2-b]p yridazin-3- yl} benzoic add;

Cpd 98, 4- {2 (E)-2-( l,3-Benzothiazol-2-yl)ethen l]-8-moφholi -4-ylimidazo[l,2- b]pyridazin~3-yl) benzoic acid;

Cpd 91, 2-Methoxy-4-[8-mo holi -4-yj-2-(qui olin-2-yleth y])imida o[l,2- b]pyridazm-3-y]]benzoic acid;

Cpd 92, 5- {8-Moφhoίm-4-yl-2-[(E)-2-quinolin-2- lethe yl]imidazo[l,2-b]pyridazi -

3-yl yridine -2~carboxy lie acid;

Cpd 93, N-(4- {8-Moφholin-4-yl-2-[(E)-2-quinoUn-2-ylethεnyl]iImdazo[l,2- b]pyridazin-3-yl}phenyl)-beta-alanine;

Cpd 94, 2-[(E)-2-(6-Chloro-8-moφholin-4-yiimidazo[l,2-b]p r ^■ idazin-2- y])et enyl]quinoline-7-carboxylic acid;

Cpd 95, 2-[(E)-2-(6-Chloro-8-mo^holm-4-ylimidazo[l ,2-b]p>TndaCTi-2- yl)ethenyl]quinoline-5-carboxylic acid;

Cpd 96, 4~ {2-[(5-Cya opyridin-2- l)eth n l]-8-moφholin~4-ylimidazo[l,2- b]pyridazin- 3 -yl } benzoic aci d ;

Cpd 97, 4-(8-Moφholin-4-yl-2- { [5-(trifluoromethyl)p ridin-2-yl]ethynyl} imidazo[l,2- b]pyridazin-3 -yl)benzoic acid;

Cpd 98, 3-Methoxy-4- {8-moφboli -4-y]-2-[(E)-2-qumo]m-2-ylethe yl]imidazo[l ,2- b]pyridazm-3-y]} benzoic acid;

Cpd 99, N-(4- {8-Mo holin-4-yl-2 (E)-2-quinoli -2-yle1henyί] ^■ imida o[l,2- b]pyridazui-3-yl}phenyl)-L -valine;

Cpd 100, l -(4-{8-Mo^holin-4-yl-2-[(E)-2-quinolm-2-ylethenyl]imidazo[l, 2- b]pyridazin-3-yl}phenyl)piperidine-4-carboxylic acid;

Cpd 181, N-({4 ^■ -[8-Moφhoίm ^■■ 4-yl ^■ -2-(quinolm-2-ylethynyl)imidazo[l,2-b]pyridazm-3- yl]phenyl}carbonyi)-L-valine;

Cpd 182, 3-(4- {8-Moφholi -4-yl-2-[(E)-2-quinolm-2-ylethe yl]imidazo[ 1 ,2- b]pyridazin-3-yl}phenyl)-l,2,4-oxadiazol-5(4H)-one;

Cpd 103, 2-Fiuoro-4- {8-mo hoiin-4-yl-2-[(E) ^■■ 2-qu ^■ inolin-2-ylethenyl]inlidazo[l,2- blpyridazin- 3 -yl } benzoic aci d ;

Cpd 184, 2-[( )-2-(6-Chioro-8-moφholm-4-ylΐmΐdazo[l ₅ 2-b]pyridazi -2-yl)ethe yl]-

N-(methylsulfonyl)quinoline-5-carboxamide; Cpd 185, 2-[(E)-2- {8-Mo holm-4-yl-3-[3-(lH-tetΓazol-5-yl) henyl]imidazo[l,2- b]pyridazui-2-yl}ethenyl]quinoline;

Cpd 106, 2-[(E)-2- {8-Mo^holin-4-yl-3-[5-(lH-tetrazol-5-yl)pyridin-3-yl]imidazo [l,2- b]pyridazii -2-yl}etheny3]quinoline;

Cpd 187, 5- \ 8-Morpholin-4-yl-2-[(E)-2-(5,6,7,8-te4rahy(froquinolin-2- yl)ethenylJimidazo[l,2-b]pyridazin-3-yl}pyridine-2-carboxyl ^" ic acid;

Cpd 108, 4-[2-(lH-Bεnzimidazoί-2-ylεthynyl)-8-mo holΐn-4-yliImdazo[l _! 2- b]pyridazm-3 -y3] benzoic acid;

Cpd 189, 4- {2-[(6-Methoxypyridin-2-yl)ethynyl]-8-mo^holin-4-yJiinidazo[ l,2- bjpyridazin- 3 -yl} benzoic acid:

Cpd 110, 4- {2-[(5-Methoxy yridin-2-yl)ethy]iyl]-8-morp3iolin-4-ylimidazo[l ,2- b]pyridazin-3-yl} benzoic acid;

Cpd 111, 4-(8-Morpholin-4-yl-2- {[6-(irifluoromethyi)pyridin-2- y3]etbyny3j midazo[l,2-b]pyri.dazin-3-yl)benzoic acid;

Cpd 112, N-(Methylsulfonyl)-5- {8-morpho3in-4-yl-2-[(E)-2-(5,6,7,8- tetrahydroqiunolin-2-yl)ethenyl]imidazo

carboxamide;

Cpd 113, 6- i8-Morpiio3in-4-yl-2-[(E)-2-qi]inolin-2~y{etlienyi]iinidazo[ l,2

3-yl} yridine-3-carboxylic acid;

Cpd 114, 2 (lR,2S)-2-(6-Cωoro-8-mo hol ^■ in-4-ylimidazo[l,2-b] yridazin-2- y3)cyclopropyl]quinolme;

Cpd 115, 2-[(E)-2-(8-Mo^holin-4-y3imidazo[l ,2-b]p>Tidazin-2-y3)ethenyl]quinoline-

5-carboxylic acid;

Cpd 116, 4- {8-Mo hol ^■ in-4-yl-2-[(quinoli -2-yisulfanyl)methyl]imidazo[l,2- blpyridazin- 3 -yl } benzoic aci d ;

Cpd 117, 4- { 2-[( 3 -Methyl- 1 H-benzimidazol-2-yl)ethyny3] -8-ηιοφ3ιοΗη-4- ylimidazo[l,2-b]pyridazin-3-yl} benzoic acid

Cpd 118, N-Hydroxy-2-[(E)-2-(8-moφholin-4-yUl]aidazo[l,2-b] yridazin-2- y3)ethenyl]quinoiine-5-carboxamide;

Cpd 119, 4- i2-[(E)-2-(3-Meihoxyquino&^

bjpyridazin- 3 -yl} benzoic acid:

Cpd 120, N-(Methylsulfony3)-4- {8-moφholi -4-y3-2-[(qumo3m-2- ylsulfanyl)methyl]imidazo[l,2-b]pyridazin-3-yl}benzamide; Cpd 121 , 2-[(E)-2-(8-Morpholin-4-y3-3-phenyiimidazo[l ,2~b]pyridazirs~2~

yl)ethenyi]quinoline-5-carboxylic acid;

Cpd 122, N-(Methylsulfony])-2-[(E)-2-(8-morpholin-4-y]-3-phenylimidaz o[ 1 ,2- b]pyridazii -2-yl)ethenyi]quii oline-5-carboxamide;

Cpd 123, 5- { 8-Morpholin-4-yl-2-[(E)-2-qumolin-2-ylethenyl]imidazo[l,2-b] pyridazin-

3-yl}pyridine-3-carboxyiic acid;

3-yl}benzoic acid;

Cpd 125, 3-(5- {8-Morpholin-4-yl-2 (E)-2 iuinolm-2-ylethenyl]imidazo[l,2- b]pyridazin-3 -yl}pyridin-2-yl)propanoic acid;

Cpd 126, 2-[(E)-2-(6-Chloro-8-morpholm-4-ylimidazo[l ,2-b]pyridazin-2- yl)ethenyl]quinoime-4-carboxylic acid:

Cpd 127, 2 (E)-2-(6-Chloro-8-moφholi ~4-ylimidazo[l,2-b]p ridazin~2-yl)eίhenylJ-

N-(met ylsu]fonyl)qumolme-4-carboxamide;

Cpd 128, 3-(4- {8-Morpholin-4-yl-2-[(E)-2-quinolin-2-ylethenyl]imidazo[l ,2- b]pyridazin-3-yl}phenyl)propanoic acid;

Cpd 129, N-(Meίhyisulfonyl)-3-(5- {8-mo hol ^■ in-4-yl-2-[(E)-2-qυinolin-2- ylethenyl]imidazo[l ,2-b]pyridazin-3-yj pyridm-2-yl)propananiide;

Cpd 130, 2-[tra s-3-(6-C·hloro-8-moφhoί ^" in-4-ylimidazo[ 1 ,2-b]pyridazin-2- yl)cyclobutyl]quinoline;

Cpd 131 , 1 - {8-Moφholin-4-yj-2-[(E)-2-qui olm-2-yΐethenyl]imidazo[ 1 ,2-b]pyridazin-

3-yl}piperidine-4-carboxyl c acid;

Cpd 132, N-(Methylsulfonyl)-3-(4- {8-ηιοφίιο1ΐη-4^1-2-[(Ε)-2- ιιΐηο1ϊη-2- ylethenyl]imidazo[l,2-b]pyridazin-3-yl}phenyl)propanamide;

Cpd 133, 4- {2-[(E)-2-(6-Methoxyp ridin-^^

b]pyridazin-3 -yl} benzoic ac d;

Cpd 134, 2-Fluoro-N-(methylsLUfonyl)-4- {8-moφholm-4-yl-2-[(E)-2-qumolin-2- ylethenyljiinidazo [ 1 ,2 - b jpyridazin-3 -yl } benzamide:

Cpd 135, 4- {2-[(E)-2-(4-Methoxyquinolin-2-yl)ethOTyl]-8-mo^holm-4-ylimi dazo[l ,2- bjpyridazin-3-yli; benzoic acid;

Cpd 136, 4-- {2 (E)-2-(4-Hydroxyquinoli ^■ -2-yl)ethenyl]-8-moφholin-4-yiinlidazo[l,2 ^■ - b]pyridazin- 3 -yl } benzoic aci d ;

Cpd 137, 2-[(E)-2-(8-Moφho3in-4-yl-3- yridi -3-y3imidazo[l,2-b^ yrida i -2- yl)ethenyl]quinolme-5-carboxylic acid; Cpd 138, 4-({8-Morpholin-4-yl-2-[(E)-2-quinolin-2-ylethenyl]imidazo[l ,2- bjpyridazin- 3 -yl } amino)benzoic acid;

Cpd 139, 3-Fluoro-4-( {8-morpholin-4-yl-2-[(E)-2-quinolin-2-ylethenyl]imidazo[l,2- b]pyridaziii-3-yl}ammo)benzoic acid;

Cpd 140, 2-[(E)-2-(6-Chloro-8-morpholin-4-yl-3-pyridin-3-ylimidazo[ 1 ,2-b]pyridazin-

2-yl)ethenyl]quinoline-5-carboxylic acid;

Cpd 141 , 2-[(E)-2-(6-Chΐoro-8-mo holiΏ-4-yj-3- yridi - -ylimidazo[l ,2-b] yτidazin-

2- yl)ethenyl]-N-(methylsulfoi yl)qu noiine-5-carboxam de;

Cpd 142, 2-[(E)-2-(6-Chioro-8-morpholin-4- l-3-pyridm-3-ylimidazo[ 1 ,2-b]pyridazin-

2~yi)ethenyl]quinoline-4-carboxylic acid;

Cpd 143, 2-[(E)-2-(6-Chloro-8-morpholin-4-ylimidazo[l ,2-b]pyridazin-2- yl)ethe ^" nyl]qumoline-3-carboxylic acid;

Cpd 144, 2 (E)-2-(8-Moipholin-4-ylimidazo[l,2-b]pyridazin~2-yl)ethenyl] quinoline-

3- carboxylic acid;

Cpd 145, N-(Metliylsulfonyl)-2-[(E)^^

b]pyridazin-2-yl)ethenyl]quinoline-5-carboxamide;

Cpd 146, tert-Butyl 4- {6-chioro-8-moipholin- -yi-2-[( lR,2R)-2-quinolin-2- ylcyc]opropyl]imidazo[l,2-b]pyridazin-3-yl}benzoate;

Cpd 147, 4- {6-Chloro-8-morpholm-4-yl-2-[( lR,2R)-2-quinolm-2- ylcyclopropyi]imidazo[l ,2-b]pyridazin~3-yl}be ^" nzoic acid;

Cpd 148, 2- {(B)-2-[3-(4-Cyan.ophenyl)-8-moipbolin-4-y]imidazo[ 1 ,2-b]pyridazin-2- y]]etbeiiyl}quinolme-5-carboxylic acid;

Cpd 149, 2- i(E)-2-[3-(3-Methox\pl^

yl]ethenyi}quinoline-5-carboxyiic acid;

Cpd ISO, 2- {(E)-2-[3-(3-Metho y henyl)-8-moφholin-4-ylimidazo[l,2-b] yridazin-2- yl]ethenyi}-N-(methylsulfonyl)qumo]me-5-carboxamide;

Cpd 152, 4-({8-ΜοφΗο1ίη-4^1-2-[(Ε)-2^αίηο1ϊη-2^ΐ6 ίΐ6ΐ^1]ίηιίά3ζο[1,2- b]pyridazin~3-yl} amino)cyclohexanecarboxylic acid;

Cpd 153, N-( ethylsulfonyl)- 1 - {8-mt^holm-4-yl-2-[(E)-2-qumolin-2- ylethenyl]imidazo[l,2-b]pyridazin-3-yl}piperidine-4-carboxan iide;

Cpd 154, 2 (Ε)-2-(8-Μοφ ^η ο1ϊη-4^1-3 ϊρεπά^

yl)ethenyi]quinolme;

Cpd 155, 4-(4- {8-Moφholin-4-yi-2-[(E)-2-quinolΐn-2- 3etbe1 yl]imidazo[ϊ,2- b]pyridazin-3-yl}piperazin- l-yl)-4-oxobutanoic acid; Cpd 156, (l- {8-Mo^holin-4-y3-2-[(E)-2-quinolin-2-ylethenyl]imidazo[l .2- b]pyridazin-3-yl piperidin-4-yl)acetic acid;

Cpd 157, 4-[8-M φhoj½-4-yΐ-2-(l-qumolm-2-yla etidm-3-yl)imidazo[l ,2- b]pyridazin-3-ylJbenzoic acid;

Cpd 158, 1 -(2-Fluoro-4- ί 8-morpholin-4-yl-2- [(E)-2-q uinolin-2-yletheny 1] imidazo [ 1 ,2- b]pyridazin~3-yl) phenyl) - l,2-dihydro-3H~ l,2,4-triazol-3-one;

Cpd 159, l- {4-[8-M φhoj½-4-yΐ-2-(qumoli -2-ylethyΐlyl)imiclazo[l ,2-bJpyridazin-3- y 3 Jphenyl} ethanone;

Cpd 16(5, 4-[6-Chloro-8-mo holin-4-yl-2-(trans-3-qui ^" olm-2- ylcyclobutyl)imidazo[l,2-bJpyridazin-3-yl]benzoic acid;

Cpd 161, 2-[2-(8-Moφ3loli -4-ylimid zo[l ,2-b] yΓidazill-2-yl)cycΐo ro yl]qumo3me; Cpd 162, S-(2-F3uoro-4- {8-moφholi -4--yl-2-[(E)-2--qui ol ^" in- ^■ 2- ^■ ylethe ^" l]imidazo[l,2- b]pyridazin~3-yl} phenyi)-2,4-d ^" ihydro-3H~ l,2,4-triazol-3-one;

Cpd 163, 5-(2-Fluoro-4- {8-moφholi -4-y3-2-[(E)-2-qui olm-2-yΐethellyl]imid zo[l ,2- b]pyridazin-3-y3}phenyi)-2-methyl-2,4-dihydro-3FI-l,2,4-tria zol-3-one;

Cpd 164, 4--[8-Mo holm--4- ^■ yl-2- ^■ (tra s-3-qui oli -2-yίcyclobutyl)inlidazo[l,2- b]pyridazin-3 -yl]benzoic acid;

Cpd 165, 4- {6-Γ^1θΓθ-8-ιηοφ3ιοΗη-4^1-2-[(1Κ,2 )-2^υϊηοΗη-2- ylcyclopropyl]imidazo[l,2--b]pyridazm-3-yl}-2-fluorobenzoic acid;

Cpd 166, 1 - {4-[8-Moφholin-4-yl ^■ -2-(cis-3-qu ^■ inolill-2-ylcyclobutyl)imidazo[l,2- b]pyridazin-3 -y3 Jphenyl } piperidine-4-carboxyiic acid;

Cpd 167, 4-[8-Mo holin-4-yi-2-(cis-3-qumolΐ -2-y3cyclobutyl)imidazo[l,2- b]pyridazin-3-yl]benzoic acid;

Cpd 168, l-- {4-[8-Moφholi -4-yi- ^■ 2-(trans-3-quiJlolin-2-ylcyciobutyl)ilnidazo[l,2- ^■ b Jpyri dazin- 3 -yljphenyl } iperi dme-4-carboxylic acid;

Cpd 169, 3- {4-[8-Moφholm-4-yi-2-(tra s-3-qui oli -2-ylcyciobutyl)imidazo[ϊ,2- bJpyridazin-3-ylJphenyHpropanoic acid;

Cpd 170, (lR,28)-2- {4-[8-Moφholm-4-yl-2-(ίrans-3-quinolin-2- y3cyclobutyl)imidazo[l,2-bJpyridazin-3-ylJphenyl}cyclopropan ecarboxylic acid; Cpd 171, 2-Methyl-2- (4- 8-ηιο ο1ϊη- ^1-2- Ιτ3η8-3^ηΐηο1τη-2- y icy clobutyl) imidazo [ 1 ,2-b Jpyridazin- 3 -yljphenyl) propanoic acid;

Cpd 172, 3-Methy3-3- {4-[8-moφholi -4-yΐ-2-(tr s-3-qui oΐm-2- ylcyc-3 obutyljimi dazo [ 3 ,2-b]pyridazm-3 -yljphenyl } butanoic acid; Cpd 173, (4- {6-ChloTO-8-moipholin-4-y3-2-[(l R,2 )-2-quinolin-2- ylcyclopropyl]imidazo[l,2-b]pyridazin-3-yl phenyl)acetic acid:

Cpd 174, (3-{4-[8-Moφho -4-y{-2-(trans-3-qumo{in-2-ylcyc{obutyl)imidazo[l,2- b]pyridazm-3-yl]phenyl}oxetan-3-y3)acetic acid;

Cpd 175, l- H-[8-Mo holm-4-yl-2-(trans-3-quinoli ^" n-2-ylcyclobut l)imidazo[l,2- b]pyridazin~3-yl]phenyl}cyclopiOpanecarboxylic acid:

Cpd 176, 2 (E)-2- {8-Moφboli -4-y]-3-[4-(lH-tetrazoj-5-yl)pbe yl]imidazo[l,2- b]pyridazin~2-yl } ethenyljquinoline;

Cpd 177, 2- {(E)-2-[8-Mo holin-4- l-3-(6-pipeΓazm-l-ylp τ^din-3-yl)i ^" midazo[l ,2- b]pyridazin-2-yl] ethenyi} quinoline;

Cpd 178, L-Ala yl-L-leucy3-L-alaΏyl- ~6~-({4-[8-moφholm-4-yl-2-(qumoliΏ-2- ylethynyl)imidazo[l,2-b]pyTidazm-3-yl]phenyl}carbonyl)-L-lys mamide;

Cpd 179, L-Alanyi-N~-6-— ( {4-[8-mor hoH^^^

b]pyridazin-3-y3]phenyl}carbonyl)-L-3ysmamide;

Cpd 180, N~6~-({4-[8-Mo holίn-4-y3-2-(quinolin-2-y3ethyn l)imidazo[l,2- b]pyridazin-3-yl]phenyl} carbonyl)-L-lysinamide;

Cpd 181, Glycyl-N-~6—( {4--[8-4ποφΚοίϊη-4·-ν1-2-( υίηο1ίΐΓ-2-^46ί1^ιιν1)ίΐιΐίί¼ζο[1 ,2- b]pyridazin-3-yl]plieny3}carbonyl)-L-lysmamide;

or a pharmaceutically acceptable salt form thereof.

For use in medicine, salts of compounds of Formula (I) refer to non-toxic "pharmaceutically acceptable salts." Other salts may, however, be useful in the preparation of compounds of Formula (1) or of their pharmaceutically acceptable salt forms thereof. Suitable pharmaceutically acceptable salts of compounds of Formula (1) include acid addition salts that can, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as, hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compounds of Formula (I) carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali meial salts such as, sodium or potassium salts; alkaline earth metal salts such as, calcium or magnesium salts; and salts formed with suitable organic ligands such as, quaternary ammonium salts. Thus, representative

pharmaceutically acceptable salts include acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, diliydroehloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate,

liexyiresorciiiate, bydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, metliyibromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N- methylgiucamine ammonium salt, oleate, pamoate (embonate), pabnitate, pantothenate, phosphate/dipbosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosyiaie, triethiodide, and valerate.

Representati ve acids and bases that may be used in the preparation of pharmaceutically acceptable salts include acids including acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartie acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, (+)- camphoric acid, camphorsulfonic acid, (+)-(lS)-eamphor-l 0-suJfonic acid, capric acid, caproic acid, capryfic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane- 1 ,2-disulfonic acid, ethanesuifonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D- glucoronic acid, L-giutamic acid, a-oxo-glutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, (+)-L-i.actic acid, (±)-DL-lactic acid, lactobionic acid, maleic acid, (-)-L-malic acid, malonic acid, (±)-DL-mandelic acid,

methanesulfomc acid, naphthalene-2- sulfonic acid, naphthalene- 1, 5 -disulfonic acid, 1- hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, L-pyroglutamic acid, salicylic acid, 4- amino-salicylic acid, sebaic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L -tartaric acid, thiocyanic acid, p-toluenesulfonic acid and undecylenic acid; and bases including ammonia, L-arginine, benethamine, benzathine, calcium hydroxide, choline, deanol, diethanoiamine, dietliylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylenediamine, N-methyl-glucamine, hydrabamine, IH-imidazole, L-lysine, magnesium hydroxide, 4-(2~hydroxyethyl)-niorphoIine, piperazine, potassium hydroxide, l -(2-hydroxyethyl)-pyrrolidine, sodium hydroxide, triethanolamme, tromethamine, and zinc hydroxide.

Embodiments of the present inv ention include prodrugs of compounds of Formula (i). In general, such prodrugs will be functional derivatives of the compounds that are readily convertible in vivo into the required compound. Thus, in the methods of treating or preventing embodiments of the present invention, the term

"administering" encompasses the treatment or prevention of the various diseases, conditions, syndromes and disorders described with the compound specifically disclosed or with a compound that may not be specifically disclosed, but which converts to the specified compound in vivo after administration to a patient.

Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.

Where the compounds according to embodiments of this invention have at least one chiral center, they may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixiitres thereof are encompassed within the scope of the present inv ention. Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended io be encompassed within the scope of this invention. The skilled artisan will understand that the term compound as used herein, is meant to include solvated compounds of Formula (I).

Where the processes for the preparation of the compounds according to certain embodiments of the invention give rise to mixture of stereoisomers, these isomers may be separated by conventional techniques such as, preparative chromatography. The compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may, for example, be resolved into their component enantiomers by standard techniques such as, the formation of diasiereomeric pairs by salt formation with an optically active acid such as, (-)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diasiereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.

One embodiment of the present invention is directed to a composition, including a pharmaceutical composition, comprising, consisting of, and/or consisting essentially of the (+)-enaniiomer of a compound of Formula (I) wherein said composition is substantially free from the (-)-isomer of said compound. In the present context, substantially free means less than about 2.5 %, preferably less than about 10 %, more preferably less than about 5 %, even more preferably less than about 2 % and even more preferably less than about I % of the (-)-isomer calculated as

, _/ , , . ( ^' maw (+) - enantiomer)

% (+) - enantiomer ^: ™ ^: x 11)0

{mass (+) - enantiomer) + (mass(-) - enantiomer)

Another embodiment of the present invention is a composition, including a pharmaceutical composition, comprising, consisting of, and consisting essentially of the (-)-enantiomer of a compound of Formula (I) wherein said composition is substantially free from the (+)-isomer of said compound. In the present context, substantially free from means less than about 2.5 %, preferably less than about 10 %, more preferably less than about 5 %, even more preferably less than about 2 % and even more preferably less than about 1 % of the (+)-isomer calculated as

, . . (mass (-) - enantiomer)

% (--) - enantiomer ^{■ ■'■} x 100

(mass (+)■■ enantiomer) + (mass{~) - enantiomer)

During any of the processes for preparation of the compounds of the various embodiments of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achie ved by means of conventional protecting groups such as those described in Protective Groups in Organic Chemistry, Second Edition, J.F. W, McOmie, Plenum Press, 1973; T.W. Greene & P.G.M. Wufs, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons, 1999. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.

Even though the compounds of embodiments of the present invention (including their pharmaceutically acceptable salts and pharmaceutically acceptable solvates) can be administered alone, they will generally be administered in admixture with a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient and/or a pharmaceutically acceptable diluent selected with regard to the intended route of administration and standard pharmaceutical or veterinary practice. Thus, particular embodiments of the present invention are directed to pharmaceutical and veterinary compositions comprising compounds of Formula (I) and at least one pharmaceutically acceptable carrier, pharmaceutically acceptable excipient, and/or pharmaceutically acceptable diluent.

By way of example, in the pharmaceutical compositions of embodiments of the present inv ention, the compounds of Formula (I) may be admixed with any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), soiubilizing agent(s), and combinations thereof.

Solid oral dosage forms such as, tablets or capsules, containing the compounds of the present inv ention may be administered in at least one dosage form at a time, as appropriate. t is also possible to administer the compounds in sustained release formulations.

Additional oral forms in which the present inventive compounds may be administered include elixirs, solutions, syrups, and suspensions; each optionally containing flavoring agents and coloring agents.

Alternatively, compounds of Formula (I) can be administered by inhalation (intratracheal or intranasal) or in the form of a suppository or pessary, or they may be applied topically in the form of a lotion, solution, cream, ointment or dusting powder. For example, they can be incorporated into a cream comprising, consisting of, and/or consisting essentially of an aqueous emulsion of polyethy lene glycols or liquid paraffin. They can also be incorporated, at a concentration of between about 1 % and about 10 % by weight of the cream, into an ointment comprising, consisting of, and/or consisting essentially of a wax or soft paraffin base togeiher with any stabilizers and preservatives as may be required. An alternati ve means of administration includes transdermal administration by using a skin or transdermal patch.

The pharmaceutical compositions of the present invention (as well as the compounds of the present invention alone) can also be injected parenterally, for example, intracavernosally, intravenously, intramuscularly, subcutaneously,

intradermaily, or intrathecally. In this case, the compositions will also include at least one of a suitable carrier, a suitable excipient, and a suitable diluent.

For parenteral administration, the pharmaceutical compositions of the present invention are best used in the form of a sterile aqueous solution that may contain other substances, for example, enough salts and monosaccharides to make the solution isotonic with blood. For buccal or sublingual administration, the pharmaceutical compositions of the preseni invention may be administered in ihe form of tablets or lozenges, which can be formulated in a conventional manner.

By way of further example, pharmaceutical compositions containing at least one of the compounds of Formula (I) as the active ingredient can be prepared by mixing the compound(s) with a pharmaceutically acceptable carrier, a pharmaceutically acceptable diluent, and/or a pharmaceutically acceptable excipient according to conventional pharmaceutical compounding techniques. The carrier, excipient, and diluent may take a wide variety of forms depending upon the desired route of administration (e.g., oral, parenteral, etc.). Thus, for liquid oral preparations such as, suspensions, syraps, elixirs and solutions, suitable carriers, excipients and diluents include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents and the like; for solid oral preparations such as, powders, capsules, and tablets, suitable carriers, excipients and diluents include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Solid oral preparations also may be optionally coated with substances such as, sugars, or be enterically coated so as to modulate the major site of absorption and disintegration. For parenteral administration, the carrier, excipient and diluent will usually include sterile water, and other ingredients may be added to increase solubility and preservation of the composition. Injectable suspensions or solutions may also be prepared utilizing aqueous carriers along with appropriate additives such as, solubilizers and preservatives.

A therapeutically effective amount of a compound of Formula (I) or a pharmaceutical composition thereof includes a dose range from about 0.1 mg to about 3000 mg, or any particular amount or range therein, in particular from about 1 mg to about 1000 mg, or any particular amount or range therein, or, more particularly, from about 10 mg to about 500 mg, or any particular amount or range therein, of active ingredient in a regimen of about 1 to about 4 times per day for an average (70 kg) human; although, it is apparent to one skilied in the art that the therapeutically effective amount for a compound of Formula (I) will vary as will the diseases, syndromes, conditions, and disorders being treated.

For oral administration, a pharmaceutical composition is preferably provided in the form of tablets containing about 1.0, about 10, about 50, about 100, about 150, about 200, about 250, and about 500 milligrams of a compound of Fonnuia (T).

Advantageously, a compound of Formula (I) may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three and four times daily.

Optimal dosages of a compound of Formula (I) to be administered may be readily determined and will vary with the particular compound used, the mode of administration, the strength of the preparation and the advancement of the disease, syndrome, condition or disorder. In addition, factors associated with the particular subject being treated, including subject gender, age, weight, diet and time of administration, will result in the need to adjust the dose to achieve an appropriate therapeutic level and desired therapeutic effect. The above dosages are thus exemplary of the average case. There can be, of course, individual instances wherein higher or lower dosage ranges are merited, and such are within the scope of this invention.

Compounds of Formula (I) may be administered in any of the foregoing compositions and dosage regimens or by means of those compositions and dosage regimens established in the art whenever use of a compound of Formula (I) is required for a subject in need thereof.

As PDEl Oa inhibitors, the compounds of Formula (I) are useful in methods for treating or preventing a disease, a syndrome, a condition or a disorder in a subject, including an animal, a mammal and a human in which the disease, the syndrome, the condition or the disorder is affected by the modulation, including inhibition, of the PDElOa enzyme. Such methods comprise, consist of and/or consist essentially of administering to a subject, including an animal, a mammal, and a human in need of such treatment or prevention, a therapeutically effective amount of a compound, salt or solvate of Formula (I).

In an embodiment, the present invention is directed to treating or preventing Type Π diabetes; comprising administering to a subject, including an animal, a mammal, and a human in need thereof, a therapeutically effective amount of a compound, salt, or solvate of Formula (I).

GENERAL SYNTHETIC METHODS

Representative compounds of the present invention can be synthesized in accordance with the general synthetic methods described below and illustrated in the schemes and examples that follow. Since the schemes are an illustration, the invention should not be construed as being limited by the chemical reactions and conditions described in the schemes and examples. The various starting materials used in the schemes and examples are commercially available or may be prepared by methods well within the skill of persons versed in the art. The variables are as defined herein.

Abbreviations used in the instant specification, particularly the schemes and examples, are as follows:

ACN aceionitrile

AcOH glacial acetic acid

aq. aqueous

Bn or Bzi benzyl

BINAP 2,2'-bis(diphenylphosphino)- 1 , 1 '-binaphthyl

Boc tert-butyloxyearbonyl

BPO benzoyl peroxide

cone. concentrated

dba dihenzylideneacetone

DBU l ,8-diazabicyclo[5.4.0]undec-7-ene

DCC N,N'-dicyclohexyl-carbodiimide

DCE 1 ,2- -dichloroethane

DCM dichloro methane

DIBALH diisobutylaiummum hydride

DIPEA or D1EA diisopropyl-eihyl amine

DMA dimethyl aniline

DMAP 4-dimetliylammopyridine

DMF N, N-dimetby If ormamide

DMSO dimethy Isulfoxide

DPPA diphenylphosphoryl azide

dppf 1 , 1 '-bis(dipheny lphosphino)ferrocene

EA ethyl acetate

EDCI l-ethyl-3-(3-dimethylaminopropyl) carbodiimide

EGTA ethylene glycol tetraacetic acid

ESI eiec trospray ionization

EtOAc o EA ethyl acetate

EtOH ethanoi

h or hr(s) hour or hours

HEK human embryonic kidney HEPES (4-(2-hydroxyethyl)- 1 -piperazineethane sulfonic acid

HOBt hydroxybenzotriazole

HPLC high performance liquid chromatography

LAH lithium aluminum hydride

LDA lithium diisopropylamide

LHMDS lithium bi sftriirtethyl si lyl)amide mCPBA w;<?ia~chioroperoxyhenzoic aci d

MEK methyl ethyl ketone

meq miiliequivaients

MeOH methanol

MHz megahertz

min minute or minutes

MS mass spectrometry

Ms methanesulfonyl

Mtt 4-methyltrityl

NBS N-bromosuecinimide

NMM N-methylmorphohne

NMP N-methylpyrrolidone

NMR nuclear magnetic resonance

PCC pyridinium cblorochromate

RP reverse-phase

rt or RT room temperature

R _t retention time

Sec second or seconds

SEM-C1 2-(trimethylsilyl)ethoxymethy3 chloride

TBAF tetrabuty lammoni um fluoride

TBDMS t-butyldimethyisilyl

TEA or Etj triethyiamine

TFA trifiuoroacetic acid

THF terrahydrofuran

TIPS rriisopropylsilyl

TEC thin layer chromatography

TMS tetramethyisilane Ts 4-toluenesulfony3

General Schemes

One of ordinary skill in the art will recognize that conventional protec ting groups may be utilized in certain synthetic sequences in order to protect functional groups that may be sensitive to a particular set of reaction conditions. Such protecting groups may be subsequently removed at an appropriate stage using conventional deprotection reagents.

Scheme A. illustrates a method for the preparation of certain compounds of Formula 0-A) of the present invention wherein L is cyclopropyf or cyclobuty].

Scheme A

A compound of formula (II), wherein X ¹ is chloro or bromo, is either commercially available or may be prepared according to methods described in the scientific literature. A compound of formula (II) may be treated with a conventional brominating agent, such as NBS, Br ₂ and the like, in a solvent such as CH ₃ CN, DCM, DCE, MeOH, DMF, THF or diethyl ether, to provide a compound of formula (III).

A compound of formula (III) may be reacted with morpholine in the presence or absence of a solvent such as DMF, DMA, DMSO, MeOH, DCE, EtOH and the like, preferably at a suitable temperature in the range of from about room temperature to about 180 °C to obtain a compound of formula (IV). The preferred conditions for this transformation include the reaction of compound (111) with excess morpholine at 100 °C for 12 h. A compound of formula (IV) may be transformed to a compound of formula (VI) by reaction with a compound of formula (IVa), wherein L is as defined herein, and X ² is a leaving group such as CI, Br, iodo, and the like, preferably Ci or Br. This reaction may be carried out in a solvent such as DMF, THF and the like, at a suitable temperature in the range of from about room temperature to about 180 °C, in the presence or absence of a base. When present, preferred bases for this reaction include, but are not limited to, inorganic bases such as K2CO3 and Na^HPC^. If a compound of formula (IVa) is not commercially available, it may be prepared according to methods described in the scientific literature. One known method for the preparation of compounds of formula (IVa) involves conversion of an appropriately substituted methyl ketone of formula Q-L-COCH ₃ (wherein L is as defined herein), either directly or indirectly, into its corresponding a-bromomethyl ketone of formula (IVa) wherein X ² is bromo. A preferred method for this transformation includes the conversion of an appropriately substituted ketone of formula Q-L-COCH3 to its corresponding silyl enol ether, followed by reaction with a bromine source such as Br ₂ or NBS and the like, in a solvent such as CH3CN, DCM, DCE, MeOH, DMF, THF or diethyl ether, in the presence of a base such as Na >( ^' () ; at a suitable temperature in the range of from about -78 "C to about room temperature. One of ordinary skill in the art will recognize that certain ketones of the formula Q- 1. -( ^" (.)( ^' ί h may not be

commercially available, but instead may be prepared using known conventional methods described in the scientific literature.

Another known method for the preparation of compounds of formula (IVa ) involves conversion of an appropriately substituted carboxylic acid of formula

Q-L-COOH to its corresponding acyl halide, preferably an acyl chloride of formula Q-L-COC1. The acyl chloride may then be converted to its corresponding diazoketone before final conversion to a compound of formula (IVa) wherein X ^" is bromo. The acyl chloride may be prepared using any of a number of conventional chlorinating agents such as thionyl chloride or, preferably, oxalyl chloride, in a solvent such as DCM, and preferably in the presence of DMF as a catalyst. A preferred method for the preparation of the diazoketone intermediate is the interception of the acyl chloride with TMSCHN ₂ , in a solvent such as DCM, at a suitable temperature in the range of from about -78 °C to about room temperature. A preferred method for the conversion of the diazoketone into a compound of formula (I Va) wherein X ² is bromo is by the action of HBr in HOAc, in a solvent such as DCM, diethyl ether, THF, acetonitrile and the like, at a suitable temperature in the range of from -20 °C to about room temperature.

Alternatively, a compound of formula (III) may undergo an initial reaction with a compound of formula (IVa) to obtain a compound of formula (V), followed by treatment with morpholine as previously described, to afford a compound of formula (VI).

To obtain certain compounds of the present invention wherein R.' is hydrogen, a compound of formula (VI) may be subjected to hydrogenoiysis. Preferred methods for this transformation include, but are not limited to, catalytic hydrogenoiysis at a suitable temperature and pressure, over an appropriate catalyst such as Pd/C and the like. More preferably, a compound of formula (VI) may be heated in the presence of HCOO H4 and Pd/C, in a solvent or a mixture of solvents such as EtOAc, MeOH or TTiF, at about room temperature to 65 °C to obtain a compound of formula (VII) wherein R ¹ is H. A compound of formula (VII) may be treated with a reagent of formula R ^? -X ^"* , wherein R: ^: is an optionally substituted phenyl or heteroaryl group as defined herein, and X ⁴ is a leaving group such as chloro, bromo, iodo, or the like, preferably bromo or iodo to obtain the compounds of formula 1-A. Suitable solvents include DMA, dioxane, THF, toluene and the like, and a suitable temperature is one in the range of from about room temperature to about 180 °C. The reaction is preferably run in the presence of a transition-metal catalyst such as Pd(OAc) ₂ , (PhsP^Pd and the like, and a base such as KOAc, in an inert atmosphere, and in the presence or absence of a suitable metal catalyst ligand such as PI13P and the like. Preferred conditions for this transformation include treatment of a compound of formula (VII) with a compound of formula R ² -X ⁴ while heating at a temperature of about 1 10 °C, in DMF solvent, and in the presence of either (1) (Ph ₃ P) ₄ Pd and KOAc; or (2) Pd(QAe) ₂ , Ph . P. KOAc in DMA; under an inert atmosphere, such as an argon gas atmosphere.

Alternatively, a compound of formula (VII) may be halogenated by using one of a number of conventional halogenating agents to obtain a compound of formula (VIII) wherein X ^" ' is halogen, preferably bromo. The preferred method of halogenation includes, but is not limited to, treatment of a compound of formula (VII) with an electrophilic bromine source, such as NBS, in a solvent such as DCM, C¾CN and the like, at a temperature ranging from about -20 °C to room temperature. A compound of formula (VIII) may be reacted with a suitably substituted compound of formula R'-M ¹ , wherein M ¹ is a suitably selected activating group, under suitable coupling conditions, to yield the corresponding compound of formula (I- A). A compound of formula R ² -M' may be (a) a boronic acid to form a compound of formula R ² -B(OH) ₂ ; (b) a suitably selected boronic ester such as pinacolatoboryl, neopentylglycoiatoboryl, and the like; (c) a suitably selected trialkylstannyl such as tri(«-butyl)tin, and the like; (d) a suitably selected trialk lsilyl such as triallylsilyl, and the like; or (e) a suitably selected aryldialkyisilyl such as 2-(hydroxymethyl)phenyl-dimethylsiiyl, and the like.

For example, a compound of formula R: ^: -M ¹ where M ¹ is -B(OH) ₂ or a suitably selected R ² -substituted boromc ester may be reacted with a compound of formula (VTTI) under Suzuki coupling conditions, more particularly in the presence of a suitably selected palladium catalyst such as palladium (II) acetate, palladium (II) chloride,?i ^' v(acetonitrile)-dichloro-palladium(lI), allylpalladiuni (II) chloride dimer, frjs(dibenzylidineacetone) dipalladium (0) (Pd ₂ (dba)3), 2-{A\-iert- butylphosphinoibiphenyl, dichloro-^»'(di-teri-butylphenylphosphme)-palladium (II), [l, -6/s-(diphenylphosphino)-ferrocene]-palladium (II) dichloride dichloromethane adduct ((dppf)PdCl ₂ .DCM), tefrflfeitriphenylpliosphine) palladium(O) (Pd(PPh ₃ )4), (l,r-/, ^, r ^' ₁ v(di-ter/-buiylphosphino)ferrocene palladium (II) chloride, and the like;

optionally in the presence of a. suitably selected ligand such as triphenylphosphine, tri - o-tolyiphosphine, tri(ieri-butyl)~phosphine, tricyclohexylphosphine, 1 ,Γ~

bis(diphenylphosphino)-ferroceiie, 2-(dicycf ohexylphosphino)-2 ' ,4 ',6' -tri-i-propyl- Ι,Γ-biphenyl, S-Phos, Ru-Phos, v[2-(diphenyl-phosphino)phenyl] ether, 2- dicyclohexylphosphino-2',6'-dimethoxybiphenyl, tris(2-furyI)phosphine, l-butyl-3- met ylimidazolium hexafluorophosphate, and the like; in the presence of a suitably selected inorganic base such as cesium carbonate, potassium carbonate, sodium carbonate, cesium fluoride, potassium fluoride, tetrabutylammonium fluoride, potassiu teri-butoxide, sodiu ieri-butoxide, sodiu hydroxide, sodium bicarbonate; potassium phosphate or preferably sodium carbonate; in a suitably selected solvent such as eihanol, THF, DMF, toluene, benzene, DME, water, 1 ,4-dioxane, and the like, or a combination thereof; preferably at a temperature in the range of from about room temperature to about 180 °C.

It is understood that when R ² contains a functional group that may be sensitive to the coupling reaction conditions described herein, the functional group may be suitably protected and, subsequently deprotected under appropriate conditions upon comple tion of the coupling reaction.

The following protocol may be used to prepare certain compounds of formula (I -A) wherein R is attached to the central bicyclic ring via a nitrogen atom, A compound of formula (VIII) may be treated with a suitable amine or monoprotected amine under transition metal -catalyzed animation conditions to obtain a compound of formula (I- A). Preferred reaction conditions include treatment of a compound of formula (VIII) with a suitable amine in the presence of a transition metal-catalyst such as Pdui dba ;} and the like, a base such as sodium tert-butoxide or CS2CO3, and a suitable metal catalyst ligand such as BINAP and the like, under an inert atmosphere, at a temperature range of from about room temperature to about 180 °C.

Scheme B illustrates a method for the preparation of certain compounds of Formulae (I-B l), (I-B2), and (I-B3), of the present invention.

A compound of formula (IX) may be obtained from a compound of formula (III) and a compound of formula (IVb) using the synthetic methods described in Scheme A. At this stage, the ² substituent may be installed as previously described in Scheme A to yield a compound of formula (X). The ester functionality of a compound of formula (X) may be saponified using one of various conventional methods known to one of ordinary skill in ihe art to produce the corresponding carboxylic acid of formula (XI). Such methods include the use of sodium hydroxide in water with a suitable co- solvent such as methanol, ethanol, THF, dioxane, or a co-solvent combination thereof. Various L linkers of the present invention may be incorporated using the common intermediates of formulae (XI) and (XIII). For example, a compound of formula (XI) may be reacted with an amino-substituted Q-ring, H?N~Q, utilizing standard amide formation conditions to obtain a compound of formula (I-B3) wherein Q-L- is

Q-IslHC(Q)-. Preferred reaction conditions include the conversion of a compound of formula (XI) to its corresponding acid chloride, as previously described in Scheme A, and reaction of the resultant acid chloride with H ₂ N-Q in the presence of a

trialkylamine base such as Et N, DIEA and the like, in a solvent such as DCM at temperatures ranging from about 0 °C to room temperature.

A compound of formula (XI) may be converted to its corresponding amine of formula (XIII) by one of numerous methods. For example, a compound of formula (XI) may be converted to its corresponding acid chloride, followed by reaction with sodium azide to obtain the corresponding acyl azide. The aeyl azide may undergo a Curtius rearrangement in the presence of water to obtain a compound of formula (ΧΓΠ), If the reaction is arned out in the presence of an alcohol, preferably feri-BuOPI, the amine compound of formula (XIII) may be obtained as its ί -butyl carbamate, which may then be subjected to suitable deprotection conditions to unmask the desired amino compound of formula (ΧΊΠ).

A compound of formula (XIII) may be reacted with a compound of formula Q- C(0)X ^J (wherein X ^J is chloro or hydroxy), under standard amide bond formation conditions to yield a compound of formula (I-Bl ) wherein Q-L- is Q-C(0)NH-. A. preferred method for amide bond formation includes reaction of a compound of formula (XIII) with Q-C(0)C1 in the presence of an organic base such as DIEA, in a solvent such as DCM, at room temperature.

Reductive alkylation of a compound of formula (XIII) with a compound of formula Q-CHO may provide a compound of formula (I-B2) wherein Q-L- is

Q-CH ₂ NH-. Preferred reaction conditions include treatment of a compound of formula (XIII) with an aldehyde of formula Q-CHO, in the presence of a reducing agent such as sodium triacetoxyborohydride and the like, in a suitable solvent such as DCM, DCE, HO Ac, or a combination thereof, at a suitable temperature in the range of from about -20 "C to about room temperature.

Scheme C illustrates a method for the preparation of certain compounds of Formulae (I-Cl), (I-C2), and (I-C3) of the present invention.

A compound of formula (X) may be reduced to the corresponding alcohol of formula (XII) using a suitable reducing agent such as LAH and the like, in a solvent such as THF, diethyl ether, or DME, at a temperature ranging from about -78 °C to about room temperature. The primary alcohol of formula (XII) may be reacted with a compound of formula Q-X°, wherein X ⁶ is a leaving group such as fluoro, chloro, bromo, trifiate, and the like, to afford a compound of formula (1-C3) wherein Q-L- is Q-OCH2-. A compound of formula Q-X ⁶ is either a known compound or a compound that may be prepared by known methods disclosed in the scientific literature. Preferred synthetic meihods include the reaction of a metal salt of a compound of formula (XII), preferably the potassium or sodium salt, which may be generated via treatment of a compound of formula (XII) with either potassium-ieri-butoxide or NaH, respectively, in a solvent such as THF or DMF, at a temperature in the range of from about room temperature to about 70 °C, optionally in the presence of an additive such as a crown ether. Most preferred is the reaction of a potassium salt of a compound of formula (XII) with a compound of formula Q-X ⁶ , in the presence of 18 -crown- 6, in THF solvent, at a temperature of about 60 °C.

A compound of formula (I-Cl) wherein Q-L- is Q-SCH ₂ - may be prepared via a compound of formula (XII). The primary alcohol functionality of the compound of formula (XII) may be converted to a leaving group such as a mesylate, tosylate, CI, Br, or I and the like, followed by reaction with a thiol of formula HS-Q to produce a compound of formula (I-Cl ). For example, the compound of formula (XII) may be activated by reaction with MeSO?Ci, in a solvent such as DCM, at about room temperature, in the presence of an organic base such as 1¾Ν, DTEA or pyridine and then be treated with a thiol of formula HS-Q, in a suitable solvent such as acetonitrile, in the presence of a base such as N ₂ C0 ₃ , at a suitable temperature in the range of from about -20 °C to about 100 °C, preferably at about room temperature.

The thioether of formula (I-Cl) may be oxidized to its corresponding sulfone using conventional oxidation methods to afford a compound of formula (I-C2) wherein Q-L- is Q-S0 ₂ CH ₂ -. Preferred reaction conditions include the treatment of a compound of formula (I-Cl) with an oxidant such as m-CPBA, in DCM, at room temperature. In certain instances, undesirable oxidation may occur within the molecule at other functional groups susceptable to oxidation. Such oxidized moieties may be converted back to their original form using conventional reduction methods. For example, if R ² is a pyridinyl group, the pyridine is susceptible to convertion to its N-oxide during sulfone formation. Selecti v e reduction of the pyridine N-oxide may be carried out v ia treatment with Fe/NHUCl in EtOH solvent, at a temperature of about 80 °C.

Scheme D illustrates a method for the preparation of certain compounds of Formula (I-D) of the present invention wherein L is ethynyl.

An aldehyde of formula (XIX) may serve as a central intermediate for the preparation of compounds of the present invention wherein L is ethynyl, ethenyi, and ethyl. Oxidation of the primary alcohol of formula (XII) with a suitable oxidizing agent such as PDC, NaOCl, active Mn0 ₂ , Dess-Martin periodinane, and the like, affords an aldehyde of formula (XIX). Preferred oxidation methods include treatment of a compound of formula (XII), in a solvent such as DCM or DCE, with active Mn0 ₂ or Dess-Martin periodinane, at about room temperature. Alternatively, the order of these transformations can be changed such that, from a compound of formula (IX), an alcohol of formula (X V) may be obtained, followed by oxidation to an aldehyde of formula (XVTII). A compound of formula (XVIII) may undergo a transition metal- catalyzed coupling reaction as described in Scheme A to install the R substituent and thus provide a compound of formula (XIX),

To prepare compounds of formula (I-D), the aldehyde functionality of a compound of formula (XTX) may be converted to a terminal acetylene. For example, an aldehyde of formula (XIX) may be reacted with dimethyl- l-diazo-2- oxopropylphosphonate , in the presence of an inorganic base such as K. C ^' i) ; and the like, in a solvent such as MeOH, at about room temperature, to obtain a compound of formula (XX). The compound of formula (XX) may then be arylated to obtain a compound of formula (I-D). A preferred synthetic method involves the reaction of a compound of formula (XX) with a compound of formula Q-X' (wherein X' is a halide, preferably an iodide) in the presence of a Pd catalyst, Cul, and an organic base such as EtjN or DIEA, in a polar aprotic solvent such as DMF or DMA, at an elevated temperature. More preferred reaction conditions include, but are not limited to, heating a compound of formula (XX) with a compound of formula Q-X' in DMF solvent, at a suitable temperature ranging from about 25 °C to about 120 °C, most preferably at a temperature of 25 °C, in the presence of Cul, and DIEA, under an argon atmosphere.

Scheme E illustrates a method for the preparation of certain compounds of Formula (I-E), (I-El), (I-E2), and (I-E3) of the present invention wherein L is ethenyl, - HCH ₂ -, -N( ⁴ )CH ₂ -, and ethyl, respectively.

Oiefination of an aldehyde of formula (XLX) may produce a compound of formula (l-E) wherein L is ethenyl. Preferred synthetic methods include, but are not limited to, Wittig or Honier-Emmons oiefination with an appropriate Wittig reagent i QC l N ^{5 '} Pb ;X s or Homer-Emmons reagent (QCH2P(=0)(OEt) ₂ ) derived from the corresponding compounds of formula C¾-Q, prepared by known methods. For example, a compound of formula QCH ₂ P(=0)(OEt) ₂ may be reacted with an aldehyde of formula (XIX), in the presence of a suitable base such as NaH, in a suitable solvent such as THF, at a suitable temperature in the range of from about 0 °C to about 70 °C, preferably at about 55 °C.

Alternatively, a Knoevenagel condensation between a compound of formula ( i with an aldehyde of formula (XIX), in the presence of an activating agent such as acetic anhydride or TMSC1, may also provide a compound of formula (I-E).

Preferred synthetic methods include heating an aldehyde of formula (XIX) with an 2 -methyl substituted Q ring (methyl substituent next to the heteroatom of the Q ring), at a temperature ranging from about 35 °C to about 120 °C, preferably at about 90 °C, in the presence of excess TMSC1, in a solvent such as DMF.

Compounds of formula (I-E) may be prepared by the halogenation of the alcohol functional group of a compound of formula (XIV) to afford a compound of formula (XV) where X'' is a halogen, preferably bromo. A compound of formula (XV) may then be oxidized as previously described to afford the corresponding aldehyde of formula (XVI). The aldehyde of formula (XVI) may serve as a substrate for olefination, methods for which have been described herein above, to obtain a compound of formula (XVIT). A compound of formula (XVTT) may subsequently undergo a Suzuki-type coupling reaction, as described for the preparation of compounds of formula (I- A) from a compound of formula (VIII), to provide a compound of formula (I-E).

The ethenyi linker in compounds of formula (I-E) may be reduced using an appropriate reducing agent, such as ft/Pd/C, in a solvent such as ethyl acetate or diimide, to obtain a compound of formula (I-E3) wherein L is ethyl. Preferred reaction conditions for this transformation include heating a compound of formula (I-E) with diimide generated in-situ from tosyihydrazide, in the presence of sodium acetate, in a water- DME co-solvent system, at a temperature of about 80 °C.

The aldehyde of formula (XIX) may undergo a reductive amination using an adaptation of the reductive alkylation reaction conditions used for the reaction of a compound of formula (XIII) with a compound of formula H ₂ N-Q to furnish compounds of formula (I-El ) wherein Q-L- is Q-NHCH ₂ -. Compounds of formula (1-El) may be Λ'-alkylated on the linker nitrogen using a conventional alkylation method to obtain compounds of formula (I-E2) wherein Q-L- is Q-N(R ⁴ )CH ₂ - and R ⁴ is methyl or ethyl. A preferred method for this transformation includes treatment of a compound of formula (i-El) with a base such as NaH, in a solvent such as DMF, and a Ci _-2 a]kyl halide such as methyl or ethyl iodide, at a suitable temperature ranging from about 0 °C to about 60 °C.

Scheme F illustrates an alternate route for the preparation of compounds of Formula (I-D) of the present invention .

(XV (XX!) (XX! I) (l-D)

An aldehyde of formula (XV) may be converted to a terminal acetylene, as previously described in Scheme D, to obtain a compound of formula (XXI). A compound of formula (XXI) may then be subjected to Suzuki cross-coupling reaction conditions to install the R substituent to yield a compound of formula (XXII). The terminal alkvne of a compound of formula (XXII) may then be ary iated as has been previously described to obtain a compound of formula (I-D).

Scheme G illustrates a method for the preparation of certain compounds of Formula (I-G) of the present invention wherein L is azetidin-3-yl.

(XXVI) (XXVIT)

Compounds of formula (XXIV) may be obtained via the reaction of either a compound of formula (III) or formula (IV) with a compound of formula (XXVTII) wherein P ¹ is a protecting group on the azetidinyl nitrogen. Reductive removal of the X ¹ substituent as previously described in Scheme A yields a compound of formula (XXV) which may be deprotected to obtain a compound of formula (XXVI). For example, when P ¹ of a compound of formula (XXVllI) is a Boc group, deprotection may be accomplished by treatment with an acid such as TFA, in a suitable solvent such as DCM, to obtain a compound of formula (XXVI). A compound of formula (XXVII) may be prepared from a compound of formula (XXV I) and a compound of formula Q-X ⁶ (wherein X" is a leaving group such as a CI, Br, I, triflate, and the like), by using a transition metal-catalyzed animation procedure as previously described in Scheme A. The R ² substituent may also be installed as previously described.

Scheme H illustrates a method for the preparation of certain compounds of Formula (I-TI) of the present invention wherein Q-L- is Q Oi l i■( ! ! ·-.

A compound of formula (XXVffl) may be obtained from a compound of formula (III) and a compound of formula (TVe) using the synthetic methods described in Scheme B. A compound of formula (XXVTU) may be converted to a compound of Formula (1 -Ti) using the synthetic methods described in Scheme C for the preparation of a compound of Formula (1-C3).

The Q and/or R ^" substituents illustrated herein may be further functionalized. In some mstances, when either the Q or R ^z -substituent contains an ester functionality, the ester may be converted to its corresponding carboxylic acid using conventional methods, and the resultant carboxylic acid may then be further derivatized. For example, a carboxylic acid may be converted to an amide by direct coupling with an amine, in the presence of a suitable coupling agent such as DCC, in the presence or absence of an activating agent such as HOBt. One of ordinary skill in the art will recognize that this transformation may be achieved following other conventional amide bond formation protocols. The carboxylic acid may also be coupled with a

functionalized amine such as an acylated amine or an alkyl-sulfonamide to obtain compounds wherein either R ^7' or 0 is substituted with an acylaminocarbonyl or alkylsulfonylaminocarbonyl groups, respectively. Additionally, the amine employed in the coupling may contain other non-interfering functionalities such as esters, afkyl sulfones and others. It is also understood that the amide product may be further derivatized. For example, an amido-ester may be converted to its corresponding acid to obtain an ami do- acid.

An amino group may be sulfonylated or acylated using conventional methods to obtain the corresponding sulfonamides or amides. An amino group may also be alkylated using a suitable alkylating agents under conventional alkylation conditions to obtain the corresponding alkylated amines. Similarly, an amino group may be treated with a suitable acyl halide or sulfonyl halide to afford an amide or sulfonamide, respectively. A nitrile substituent on either a Q or R ring may serve as an important intermediate group for the construction of heterocycles. For example, a nitrile can be reacted with an azide, preferably sodium azide in polar aprotic solvents such as DMF, to obtain a tetrazole. The intermediate obtained from the reaction of hydroxylamine with a nitrile (a hydroxyamidine), may be reacted with a carbonyl source such as ethylchloroformate to obtain hydroxyoxadiazole.

Specific Examples

Example 1

4-(6-CUoro-8-mo holmo-2-((lr,3r)-3-(quinolin-2~yl)cyclobutJd)im ^■ idazo[l ,2- d 160)

To a solution of ethyl 3-hydroxycyclobutanecarboxylate (10.2 g, 78.4 mmol) in dry pyridine (56.5 mL) at 0 °C, TsCl (14.9 g, 78.4 mm!) was added portion-wise. The resulting mixture was stirred at rt overnight. The reaction mixture was concentrated in vacuo and the residue obtained was dissolved in EtOAc (100 mL) and sequentially washed with 2 N HC1 (100 mL), saturated NaHCQ ₃ (100 mL) and water ( 100 mL). The organic layer was dried over Na ₂ S0 , filtered, and concentrated to obtain ethyl 3- (tosyloxy)cyclobutanecarbox late as a pale yellow oil, which was used in the next step without further purification.

To a solution of ethyl 3-(tosyloxy)cyclobutanecarboxylate (6.0 g, 20 mmol) in anhydrous MEK (20 mL), NaT (7.5 g, 50 mmol) was added. The resulting mixture was heated at 120 °C for 4 h in a microwave reactor. The reaction mixture was concentrated and water (50 mL) was added. The mixture was extracted with ether (100 mL) and washed with 1 (50 mL) and water (50 niL), The organic layer was separated, dried over Na^SC and concentrated. The residue was distilled under reduced pressure to obtain compound l a as a cis and trans mixture. Ή-NMR (400 MHz, CDC1 ₃ ) δ ρριη): 4.66 (quiii, J - 7.2 Hz, H), 4.30 - 4.48 (m, 2H), 4.02 - 4.24 (m, 6H), 3.30 - 3.49 (m, IH), 3.03 - 3.21 (m, 2H), 2.64 - 3.02 (m, 12H), 1.18 - 1 .34 (m, 9H).

B. (Ir,3r)-ethyl 3-(quinolin-2~yl)cyclobutanecarboxylate (lb) and (is,3s)-ethyl 3- (quinolin-2-yl)cyc]obutanecarboxylate (lb-1)

To a solution of naphthalene (1.9 g, 15 ramol) in dry THF (10 mL) under an argon atmosphere, was added finely cut Li metal (104 mg, 15,0 mmol) in portions and the resulting green mixture was stirred for 2 h. A solution of 0.5 M ZnCL in THF (16 mL, 8.0 mmol) was then added dropwise and the resulting mixture was stirred at rt for 3 h. The stirring was stopped and the supernatant was removed and replaced with compound la (762 mg, 3.00 mmol) in THF (TO mL). The reaction mixture was stirred for 20 h and the stirring was stopped to let the remaining Zn metal settle. The resulting solution was then transferred to a dry flask via a 1 μ PTFE filter and treated with a mixture of 2-iodo-quinoiine (382 mg, 1.53 mmol), i\U db;! > . (27.0 mg, 0.030 mmol) and trifurylphosphine (56.0 mg, 0,24 mmol). The mixture obtained was stirred at rt for 16 h and diluted with EtOAc (50 mL) and filtered through a pad of diatomaceous earth. The filtrate was concentrated and the residue obtained was purified by normal phase chromatography on silica gel (0- 100% F ) Ac-heptane) to obtain the desired products. Compound lb: Mass Spectrum (LCMS, ESI pos.): Caicd. for (: ₁₆ Η] ₇ Ν0 ₂ : 256.1 (M -H); found: 256.3. Compound lb-1: Mass Spectrum (LCMS, ESI pos.): Calcd. for C ₁₆ H ₁₇ N02: 256.1 (M+H); found: 256.3.

C. 4-(6-Chloro-2-((lr,3r)-3-(quinolin-2-yl)cyclobutyl) m dazo[l ,2-6]pyridazin-8- yljmorphoiine, lc

To a solution of compound lb (863 mg, 3.38 mmol) in EtOH (21.6 mL) was added 1 M aOH (6.76 mL, 6.76 mmol). The reaction mixture was stirred at rt overnight, treated with 1 N HC1 (6.76 mL, 6.76 mmol), and concentrated in vacuo. To the resultant residue, water (10 mL) and DCM (10 mL) were added. The organic layer was separated, dried over Na2S04, and concentrated to obtain 3-(quinolin-2- yLjcyclobutanecarbox iic acid which was used in the next step without further purification.

A solution of 3-(quinolin-2-yl)cyclobutanecarboxylic acid (200 mg, 0.800 mmol) in DCM was cooled to 0 °C and treated with 10 _, uL of DMF followed by addition of oxalyl chloride (154 uL, 1.76 mmol). The resulting mixture was stirred at rt for 30 min and concentrated. The resultant residue was dried in vacuo for 15 min, dissolved in C1¾CN (5 mL), and treated with a 2 M solution of TMSCFIN ₂ in hexanes (0.88 mL. 1.76 mmol). The resulting mixture was stirred for 1 h, cooled to 0 °C and treated with 33 wt % HBr in acetic acid (0.35 mL, 1.76 mmol), dropwise. After stirring for 30 min, the reaction mixture was diluted with DCM (25 mL) and washed with saturated NaHCOj (2 x 25 mL). The organic layer was separated, dried over Na^SC , and concentrated. The residue obtained was dried in vacuo for 15 min to obtain 2- bromo-l-(3-(quinolin-2-yl)cyclobutyl)ethanone as a viscous oil which was used without further purification in the next step.

A solution of 2-bromo-l -(3-(quinolin-2-yl)cyclobutyl)ethanone (426 mg, 1.40 mmol) in DMF (1 mL) was added to a solution of 6-chioro-4-morpholinopyridazin-3- amine (299 mg, 1.40 mmol, as prepared in the Example 19, step A) in DMF (5 mL). The resulting mixture was stirred at rt overnight. The reaction mixture was concentrated in vacuo and the residue obtained was purified by flash column chromatography on silica gel (0- 100% EiOAc/heptanes) to obtain compound lc. Mass Spectrum (LCMS, ESI pos.): Calcd. for C ₂₃ H ₂₂ F ₃ C1N ₅ 0: 420.2 (M+H); found: 420.4. D. 4-(3-Bromo-6-ch3oro-2-((lr,3r)-3-(quino]m-2-yl)cyclobutyl)im idazo[l,2- &]pyridazin-8- yl)morpholine, Id

To a solution of compound lc (298 mg, 0,710 mmol) in DCM (5 niL), NB8 (126 mg, 0.710 mmol) in DCM (3 mL) was added dropwise at -15 °C. The resulting mixture was stirred at -15 °C for 1 h and saturated NaHC03 (10 ml.) was added. The organic layer was separated and the aqueous layer was washed with DCM (2 x 20 mL). The combined DCM layers were dried over Na ₂ S0 ₄ , filtered, concentrated, and the residue obtained was purified by normal phase chromatography on silica gel (0-100% EtO Ac/heptanes) to obtain compound Id. Ή-NMR (400 MHz, CDCI ₃ ) 8(ppm) : 8.1 1 (dd, J= 8.6, 6.1 Hz, 2H), 7.79 (d, J 8.1 Hz, 1 H), 7.66 - 7.74 (m, 1H), 7.47 - 7.53 (m, 1H), 7.42 (d, J - 8.6 Hz, IH), 6.12 (s, 1H), 4.04 - 4.16 (m, 5H), 3.85 - 3.97 (m, 5H), 2.94 (t, 4H).

E. ferf-Butyl 4-(6-chloro-8-morpholino-2-((lr,3r)-3-(quinolin-2- yl)cyclobutyl)imidazo[l,2- ?Jpyridazin-3-yl)benzoate (3-bromo-6-chloro-2- ((lr,3r)-3-(qumolm-2-yl)cyclobutyl)imidazo [l,2- ?]pyridazin-8- yl)morpholine, le

To a solution of compound Id ( 100 mg, 0.710 mmol) and (4-(tert- butoxycarbonyl)phenyl)boromc acid (66.7 mg, 0.301 mmol) in dioxane (5 m ^' L) was added 2 M Na ₂ C0 ₃ (0.5 mL, 1 mmol) and Pd(Ph ₃ P)4 (23 nig, 0.020 mmoi) under an argon atmosphere. The resulting mixture was stirred at 90 "C for 3 h. The reaction mixture was allowed to cool to rt, diluted with EtOAc (10 mL) and filtered through a pad of diatomaceous earth. The filtrate was diluted with water (10 mL) and the organic layer was separated, dried over Na ₂ S0 ₄ , filtered, and concentrated to obtain a residue which was purified by normal phase chromatography on silica gel (0- 100%

EtO Ac/heptanes) to obtain compound le. Mass Spectrum (LCMS, ESI pos.): Caicd. for C34H34CIN5O3: 596.3 (M+H); found: 596.3.

F. 4-(6-chloro-8-morpholmo-2-(( lr,3r)-3-(quinolin-2-yl)cyclobutj4)-imidazo[ l,2- jjpyridazin~3-yl)benzoic acid trifluoroacetic acid salt, Cpd 1 Θ

To a solution of compound le (31 mg, 0.050 mmol) in DCM (1 mL), TFA (1 mL) was added. The resulting mixture was stirred at rt for 1 h and concentrated. The residue obtained was dried in vacuo and suspended in ether (10 mL) and sonicated for 5 min. The mixture was concentrated and the solid obtained was dried in vacuo overnight and dissolved in 1 : 1 MeOH/DCM (10 mL). The resulting solution was concentrated to obtain a white solid. The solid was placed under reduced pressure for 12 h to obtain the title compound 160. ^! H- NMR (400 MHz, CD3OD) δ (ppm): 9.04 (d, J = 9.1 Hz, I H), 8.25 - 8.29 (m, 1 H), 8.08 - 8.22 (m, 4H), 7.89 - 7.94 (m, IH), 7.79 (s, 1H), 7.72 (d, ./ 8.6 Hz, 2H), 6.42 (s, I H), 4.48 - 4.60 (m, i l l ). 4.16 - 4.22 (m, 4H), 3.99 - 4.10 (m, IH), 3.93 - 3.99 (m, 4H), 3.08 - 3.18 (m, 1 1 1 ) . 3.02 (m, 2H). Mass Spectrum (LCMS, ESI pos.) Caicd. For C ^' , _: .i CfN ₅ 0 ₃ : 540.2 (M + H), Found 540.2.

Example 2

yl)benzoic acid trifluoroacetic acid salt (Cpd 164)

A. ( lr,3r) -Methyl 3-(quinolin-2-yl)cyclobutanecarboxyiate (2a) and (h\3s)-methyl 3-

To a solution of naphthalene (33,3 g, 260 mmol) in dry THF (100 mL) under an argon atmosphere, finely cut Li metal (1.80 g, 260 mmol) was added in portions and the resulting green mixture was stirred at rt for 2 h. A solution of 0.5 M ZnCl? in TFIF (277 mL, 138 mmol) was then added drop wise and the resulting mixture was stirred at rt for 3 h. The stirring was stopped and the supernatant (75 mL) was removed.

Compound la (12.0 g, 50.0 mmol) in THF (20 mL) was added slowly and the resulting mixture was stirred at rt for 16 h. A solid mixture of 2-iodo-quinoline (6.60 g, 25,0 mmol), Pd ₂ (dba)3 (475 nig, 0.500 mmol) and trifurylphosphine (1.00 g, 4.20 mmol) was added. The mixture was then stirred at rt for 16 h, and filtered through a pad of diatomaceous earth. The filtrate was concentrated and the obtained residue was purified by normal phase chromatography on silica gel (0-100 % EtO Ac/heptane) to obtain compounds 2a and 2b.

( lr,3r)-Methyl 3-(quinolm-2-yl)cyclobutanecarboxylate (2a): ! i-N. ^' vi R (400 MHz, CDCls) 5 (ppm): 8.04 ^■■ 8.1 1 (m, 2H), 7.78 (d, J= 8.1 Hz, 1H), 7.65 ^■ · 7.73 (m, S i n. 7.46 - 7.53 (m, 1H), 7.25 - 7.31 (m, 1 H), 3.93 - 4.05 (m, ΠΤ), 3.76 is, 3H), 3.26 - 3.36 (m, 1H), 2.70 ^■■ 2.85 (m, 4H);

( Lv,35)-Methyl 3-(quinolm-2-yl)cyclobutanecarboxylate (2b): 1 !-NA-!R (400 MHz, CDCI ₃ ) 5 (ppm): 8.1 1 (d, J= 8.6 Hz, 1H), 8.05 (d, J= 8.6 Hz, 1H), 7.78 (d, J= 8.1 Hz, IH), 7.64 - 7.72 (m, IH), 7.45 - 7.52 (m, 1H), 7.40 (d, J = 8.6 Hz, IH), 3.73 - 3.84 (m, IH), 3.71 (s, 3H), 3.22 (m, IH), 2.66■■ 2.79 (m, 4H).

13. 4-(6-Bromo-2-((lr,3r)-3-(qumo]m-2-yl)cyc]obutyl)imidazor ,2~Z?]pyridazin-8~ yl)niorphoiine, 2c

A solution of 2-bromo- 1 -(( lr,3r)-3-(quino1in-2-yl)cyc1obutyl)ethaiione (1.56 g, 4.62 mmol, prepared using the method described in Example 1, step C) and 4,6- dibromopyridazin-3-amine (1.17 g, 4.62 mmol) in DMF (10 mL) was stirred at rt for 3 days. The reaction mixture was poured into water (200 mL), and extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with saturated aHCCh and brine, dried over filtered, and concentrated. The residue obtained was purified by flash chromatography on silica gel (0-40 % EtO Ac/heptane) to obtain 2-((lr,3r)-3- (6,8-dibromoimidazo[l,2-6]pyridazin-2-yl)cyc]obutyl)quinolme as a yellow oil. ^J H- NMR (400 MHz, CDCL) δ (ppm): 8.10 (dd, J= 8.3, 4.8 Hz, 2H), 7.98 (s, IH), 7.79 (d, J= 8.1 Hz, I H), 7.70 (t, J = 7.8 Hz, IH), 7.47 - 7.53 (m, IH), 7.44 (s, IH), 7.38 (d, J = 8.6 Hz, IH), 4.01 - 4.10 (m, IH), 3.89 - 3.99 fm, IH), 2.96 - 3.08 (m, 2H), 2.75 - 2.86 (m, 2H).

2-((lr,3r)-3-(6,8-Dibroraoimidazo[l,2-6]pyrida¾n-2-yl)cyc{o bi!tyl)qumoline (1.04 g, 2.27 mmol) was suspended in acetonitrile (25 mL). To the mixture was added DIEA (0.710 mL, 4.09 mmol) and morpholine (0.240 mL, 2.72 mmol) and the resulting mixture was stirred at 60 °C for 3 h and then at rt overnight. EtO Ac (200 mL) was added, and the organic layer was washed with water (100 mL) and brine (100 mL). The organic layer was dried over N 2SO/|, filtered, and concentrated to yield a yellow solid, which was purified by flash chromatography on silica gel (0-40 %

EtO Ac/heptane) to obtain compound 2c as a white solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C _. : .M _. : ;HrVO: 464.1 (M+H); found: 464.0.

C. 4-(2-((lr,3r)-3-(Qumolin-2-yl)cyclobutyl)imidazo[l,2-0]pyrid azin-8- yljmorphoiine, 2d

Compound 2c (1.0 g, 2.2 mmol) and ammonium formate (0.69 g, 1 1 mmol) were placed in a 200 mL round bottom flask equipped with a stir bar and dissolved in a mixture of THF (40 mL) and MeOH (20 mL). A portion of 5 % Pd/C (ca. 50 % water, 0.23 g) was then added under an argon atmosphere, and the reaction was stirred at 60 °C for 3 h. The hot reaction mixture was filtered through a pad of diatomaceous earth. The filter cake was washed with MeOH (2 x 20 mL), and the combined filtrates were concentrated under reduced pressure. The obtained residue was dissolved in DCM (100 mL) and washed with water (2.5 mL) and brine (25 mL). The combined aqueous washings were extracted once with DCM (50 mL). The organic extracts were combined, dried over Na ₂ S04, filtered, and concentrated under reduced pressure. The obtained residue was purified by flash chromatography on silica gel (0-40 %

EtO Ac/heptane) to give compound 2d as a colorless oil . Mass Spectrum (LCMS, EST pos.): Calcd. for C2 ₃ H2 ₃ N ₅ O: 386.2 (M+H); found: 386.1.

D, 4-(3-Bromo-2-((lr,3r)-3-(qumolm-2-yl)cyclobutj4)imidazo[l,2- 0]pyridazin~8- yl)morpholine, 2e

A solution of compound 2d (0.37 g, 0.96 mmol) in acetonitrile (20 mL) was cooled in an ice-salt bath (-20 °C). A solution of NBS (0.16 g, 0.87 mmol) in acetonitrile (5 mL) was added dropwise over 20 min. Fifteen minutes post- addition, a 5% Ma ₂ S ₂ 0 ₃ solution (10 mL) was added and the reaction mixture was extracted with EtOAc (20 mL). The organic layer was washed with brine, dried over Na ₂ S04, filtered, and concentrated. The obtained residue was purified by flash chromatography on silica gel (0-70 % EtOAc/heptane) to give compound 2e as a yellow solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for ( i .U - .BrN _. -·.(). 464.1 (M+H); found: 464.0.

E. 4-(8-Moφho]mo-2-((l r,3r)-3-(qui1 olin-2-yl)cyclobutyΓ)ΐmidazo[l ,2- b]pyridazm-3-yl)benzoic acid trifluoroacetic acid salt, Cpd 164

A solution of compound 2e (0.25 g, 0,55 mmol) and fert-butyl 4-(4,4,5,5- tetramethy1~l ,3,2-dioxaborolan-2-yi)benzoate (0.33 g, 1.1 mmol) in dioxane (7 mL) was purged with argon. Dichloro(diphenyfphosphinoferrocene)palfadium (40 mg) was then added, followed by aqueous Na ₂ C<¾ (2 M, 1.4 mL). The reaction mixture was stirred at 80 °C for 1 h under an argon atmosphere, and allowed to cool to rt. EtOAc (100 mL) was then added. The organic layer was washed with water and brine, dried over Na ₂ S04, filtered and concentrated to give a residue, which was purified by flash chromatography on silica gel (0-40 % EtO Ac/heptane), The resultant white foamy solid was then treated with TFA/DCM (1 : 1 v/v, 4 mL) and the resulting mixture was stirred at rt for 1 h. The reaction mixture was concentrated in vacuo to obtain a residue, which was dissolved in DCM (100 mL). The organic layer was washed with saturated NaHCCh. A foamy mixture appeared. The suspension was filtered, and the filtrate was concentrated to leave a white solid, which was washed with water (2 x 20 mL), and dried in vacuo. Compound 164 was obtained as a white solid. Ή- MR (400 MHz, ΟΧΊ : · ( [) :()!)) 8 (ppm): 8.14-8.21 (m, 3H), 8.09 i d. ./ 8.1 Hz, i l l ). 8.04 i d. ./ 5.6 Hz, IH), 7.81 (d, J- 8.1 Hz IH), 7.69-7.76 (m, 3H), 7.46 - 7.56 (m, 2H), 6.17 (d, J = 5.6 Hz, IH), 4.16 ^■ 4.29 (m, IH), 3.90 - 4.14 (m, 9H), 2.97-3.07 (m, 2H), 2.83-2.95 (m, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C30H27N5O3: 506.2 (M+H), Found 506.1.

Example 3

4-(8-Morpholino-2-((Lv,3s)-3-^

yl)benzoic acid trifluoroacetic acid salt (Cpd 1 7)

The title compound was prepared from (Is, 3s) -methyl 3-(quinolin- yl)eyclobutanecarboxylate (as prepared in Example 2, step A, compound 2b) following the procedures described in Example 2, steps B-E, Ή-NMR (400 MHz,

CDCI ₃ +CD ₃ OD) δ (ppm): 8.69 (d, J= 8.6 Hz, 1H), 8.45 i d. ./ 9.1 Hz, 1H), 8.22 (d, J = 8.6 Hz, 2H), 8.14 (d, J= 9.1 Hz, I I I ;. 8.02 - 8.08 (m, 2H), 7.96 - 8.02 (m, 1H), 7.76 - 7.83 (m, lH), 7.72 (d, J= 8.6 Hz, 2H), 6.19 (d, J= 5.6 Hz, 1H), 4.27 - 4.39 (m, 1H), 3.94 - 4.07 (m, 9H), 3.00 - 3.1 1 (m, 2H), 2.89 - 3.01 (m, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C30H27N5O3: 506.2 (M+H), Found 506.1.

Example 4

l-(4-(8-Mo^hol no-2-((lr,3r)-3-(qmno]m-2-yl)cyclobutyl) m dazo[1 ,2-6]pyridazm-3- yl)phenyl Cpd 168)

Ethyl l-(4-(8-mo^holmo-2-((l r,3r)-3-(quinolin-2-yl)cyclobuty])imidazo[l Z?]pyridaz n-3-yl)phenyl)piperidine-4-carboxyiate, 4a

Compound 4a was prepared from compound 2e (Example 2, step D) and ethyl 1 -(4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)phenyl)piperidine-4-carboxylate (as prepared in Example 56, step C) following the procedure described in Example 2, step E.

B. l -(4-(8-Mo^holino-2-((lr,3r)-3-(quinolin-2-yl)cyclobutyl)irni da2:o[l,2- j]pyridazin-3-yl)phenyl)piperidine-4-carboxylic acid, Cpd 168

Compound 4a (54 mg, 0,088 mmol) was suspended in EtOH and THF (1 : 1 v/v, 4 mL), and treated with a solution of LiOH (1 , 2 mL). The reaction mixture was stirred at rt for 1 h. Water (10 mL) was then added, and the reaction mixture was extracted with EtOAc (10 mL). The pH of the aqueous solution was adjusted to ca. pH 6 using 1 N HC1 solution. The aqueous solution was extracted with DCM (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over Na ₂ S0 , filtered and concentrated to give a yellow solid. The solid was purified by preparative- TLC (7:4: 1 DCM:EtOAc:MeOH, v/v/v) to obtain compound 168 as an off-white solid. 'H-NMR (400 MHz, CDCL) δ (ppm): 8.12 (d, J - 8.6 Hz, 2H), 8.00 (d, J= 5.6 Hz, 1H), 7.79 (d, J = 7.1 Hz, IH), 7.70 (t, /= 7.6 Hz, 1H), 7.46 - 7.54 (m, 3H), 7.44 (d, J = 8.6 Hz, I H), 7.03 (d, ./ 8.6 Hz, 2H), 6.07 (d, J= 5.6 Hz, I H), 4.15 - 4.26 (m, I f 11 4.03 - 4.10 (m, 4H), 3.97 - 4.03 (m, 4H), 3.89 - 3.97 (m, IH), 3.68 - 3.77 (m, 2H), 2.98 (dd, ./ 9.1, 5.6 Hz, 2H), 2.80 - 2.94 (m, 4H), 2.44 - 2.56 (m, IH), 2.01 - 2.10 (m, 2H), 1.82 - 1.95 (m, 2H). Mass Spectrum (LCMS, EST pos.) Calcd. For C ₃ sH _{36 6} 0 ₃ : 589.3 (M+H), Found 589.3.

Following the procedures described in Example 4 above, and substituting suitably selected reagents, starting materials and conditions as would be readily apparent to those skilled in the art, the following representative compounds of the present invention were prepared.

Example 5

(i?)-4-(8-Mo^holino-2-(2-(qum^

acid trifiuoroacetic acid :

A, Ethyl 8-bromo-6-chloroimidazo[l,2-6]pyridazine-2-carboxylate, Sa

To a suspension of 5-bromo-3-chloro-6-aminopyridazine (15.7 g, 75.3 mmol) in dry DMF (80 mL) was added ethyl bromopyruvate (21.0 mL, 151 mmol) via a syringe. The resulting mixture was stirred at rt for 20 h. The reaction mixture was poured into ice water (300 mL), and the precipitated solid was isolated by filtration, and washed with water (2 x 50 mL) and Et ₂ 0 (3 x 50 mL). The residual solvents in the solid were removed under reduced pressure to give compound Sa as an off-white solid. H -X .vi R (400 MHz, CDCi ₃ ) δ (ppm): 8.50 (s, 1H), 7.47 (s, I I I ) . 4.49 (q, J = 7.1 Hz, 2H), 1.44 (t, J = 7.1 Hz, 3H).

B. Ethyl 6-chloro-8-morpholinoimidazo[l ,2- j]pyridazine-2-carboxy]ate, 5b

To a solution of compound Sa (10.6 g, 34.8 mmol) in acetomtrile (150 mL) was added DIEA (10.9 mL, 62.6 mmol) and morpholine (3.60 mL, 42.0 mmol). The reaction mixture was stirred at rt for 1 h, during which time the entire solution solidified. The resulting mixture w ^r as left at rt for 3 h, then was poured into ice water (200 mL), and the precipitates were collected by filtration, and dried under high vacuum. Compound 5b was obtained as a white solid. 'H-NMR (400 MHz, CDCI ₃ ) δ (ppm): 8.25 (s, IH), 6.10 (s, IH), 4.43 (q, J= 7.1 Hz, 2H), 3.99 - 4.17 (m, 4H), 3.86 3.96 (m, 41 1 1. 1.41 i i. ,/ 7.1 Hz, 31 1 ).

C. Ethyl 8-morpholinoimidaz -/ ]pyridazine-2~carboxylate, Sc

Compound 5b (8.6 g, 28 mmol) was suspended in THF (100 mL)/MeOH (50 mL). The reaction mixture was purged with argon, and 10 % Pd/C ( 1.5 g, 1.4 mmol) was added followed by solid ammonium formate (8.7 g, 140 mmol). The reaction mixture was stirred under reflux for 1 h, during which time some of the ammonium formate sublimed onto the reflux condenser. The solid was rinsed back into the reaction flask with dr MeOH. The reaction mixture was filtered through a pad of diatomaceous earth. The filtrate was concentrated in vacuo to obtain a solid, which was dissolved in DCM (200 mL), and washed with water (100 mL) and brine (100 mL). The organic layer was dried over a?804, filtered and concentrated to give compound Sc as a white solid. ^' Ή-ΝΜί (400 MHz, CDC1 ₃ ) δ (ppm): 8.34 (s, I H), 8.04 (d, J= 5.6 Hz, IH), 6.06 (d, ,/ 5.6 Hz, IH), 4.43 (q, J - 7.1 Hz, 2H), 3.98 ^■ 4.07 (m, 4H), 3.88 - 3.96 (m, 4H), 1 .42 (t, J= 7.1 Hz, 3H).

D, (8-Morpholinoimidazo[l ,2-0] anol, 5d

A stirred solution of compound Sc ( 14 g, 5 mmol) in THF (400 mL) was cooled in an ice-water bath under an argon atmosphere and treated with lithium aluminium hydride (IM in THF, 51 mL, 51 mmol) dropwise. After 1 h, saturated NH/jCl solution (20 mL) was added slowly to quench the reaction, followed by 200 mL of water. The reaction mixture was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine, dried over Na ₂ S0 ₄ , filtered and concentrated to give compound 5d as a white solid. ^J H-NMR (400 MHz, CDCL) δ (ppm): 7.98 (d, J= 5.6 Hz, 1H), 7.77 (s, 1H), 6.05 (d, J= 5.9 Hz, IH), 4.81 (s, 2H), 3.91 (s, 8H), 2.71 (br. s., 1H).

E. 8-Moφholi oimidazo[l,2-^')] yrϊdazine~2-carba dehyde, Se

To a solution of compound 5d (1.7 g, 7.3 mmol) in DCM (244 mL) was added manganese (TV) oxide (10 g, 1 16 mmol). The mixture was stirred at rt for 18 h, and filtered through a pad ofdiatomaceous earth. The filtrate was concentrated to give compound Se as an off-white solid. ^J H-NMR (400 MHz, CDCI ₃ ) δ (ppm): 10.08 (s, i 1 1 !. 8.37 (s, I H), 8.06 (d, J= 5.6 Hz, IH), 6.09 (d, J= 5.6 Hz, H), 3.99 - 4.18 (m, 4H), 3.78 - 3.99 (m, 4H). -Butyl 4~(2-fomiyl-8~ ]pyridazin-3~yl)benzoate, Sf

To a mixture of compound 5e (0.57 g, 2.5 mmol), ier/-buty1-4-bromobenzoate (0.97 g, 3.7 mmol), palladium acetate (38 mg, 0.17 mmol), triphenylphosphine (45 mg, 0.17 mmol) and potassium acetate (0.72 g, 7.3 mmol) were added while under an argon atmosphere and in dry N,N-dimethylacetamide (5 mL). The reaction mixture was stirred at 1 10 °C for 22 h, allowed to cool to rt, diluted with water (100 mL), and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine, dried over Na ₂ S04, filtered and concentrated. The obtained residue was purified by flash chromatography on silica gel (10-60 % EtG Ac/heptane) to give compound Sf as a pale yello solid. Ti-NMR (400 MHz, CDClj) δ (ppm): 10.13 ($, 1H), 8.13 - 8.21 (m, J - 8.1 Hz, 2H), 8.09 (d, J= 5.6 Hz, 1H), 7.85 (d, J - 8.3 Hz, 2H), 6.15 (d, J = 5.6 Hz, l l . 4.02 - 4.14 (m, 4H), 3.90 - 4.00 (m, 4H), 1.62 (s, 9H).

G. (£T)-teri-Butyl 4-(8-morpholino-2-(2-(quinolin-2-yl)vinyl)imidazo[l,2-

0jpyridazin-3-yl)benzoate, Sg

To a mixture of compound Sf (0.68 g, 1.7 mmol) and 2-methylquinolme (0.26 mL, 2.0 mmol) in DMF (5 mL) was added chlorotrimethylsilane (0.64 mL, 5.0 mmol) dropwise. The resulting mixture was stirred at 90 °C for 2 h. The reaction mixture was cooled, and water (20 mL) was added. The precipitated solid was collected by filtration, washed with MeOH (2 x 5 mL), and dried under high vacuum. Compound Sg was obtained as an orange solid. Mass Spectrum (LCMS, EST pes.): Calcd. for C ₃₂ H ₃ s N5O3: 534.2 (M+H); found: 534.4.

H, (^-4-(8-Morpholino-2~(2-(quinolm-2-yl)vinyI)imidazo[l ,2-0]pyridazrn-3- yl)benzoic acid trifluoroacetic acid salt, Cpd 40

To a suspension of compound Sg (0.26 g, 0.49 mmol) in DCM (8 mL) was added TFA (2 mL). The solution was stirred at rt for 3 h, and concentrated to obtain a residue that was washed with Et ₂ 0 (3 x 20 mL) and isolated as a yellow solid, compound 40. Ή-NMR (400 MHz, DMSO-i¾) δ (ppm): 8.52 - 8.63 (m, 1 H), 8.1 1 - 8.24 (m, 4H), 8.01 - 8.1 1 (m, 2H), 7.79 - 7.98 (m, 5Ή), 7.61 - 7.75 (m, IH), 6.49 (d, J= 5.6 Hz, IH), 4.1 1 (br. s., 4H), 3.83 - 3.96 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C2 ₈ H2 ₃ N ₅ O ₃ : 478.2 (M+H), Found 478.1.

Following the procedures described in Example 5 above, and substituting suitably selected and substituted reagents, starting materials and conditions as would be readily apparent to those skilled in the art, the following representative compounds of the present invention were prepared.

Cpd No. Characterization

(£)-2,6-Βίί1υοΓο-4-(8-ιηοΓρ1ιο1ΐηο-2-(2 -( υϊηοΗη-2- yl)vinyl)imidazo[l,2-0]pyridazir!-3-yl)pher!ol

Ή-NMR (400 MHz, CfX ^' l : · ( i):{)D) δ (ppni): 8,22. (d, J= 8.6 Hz, 1H), 8.10 id../ 8.6 Hz, 1H), 8.03 (d, J= 5.6 Hz, HI).7.95

88 (d, ./ 16 Hz, Hi}.7.84 (d, J = 7.1 Hz, 1H), 7.69 - 7.80 (m, 3H), 7.51 - 7.59 (m, IH), 7.29 (m, 1H), 7.27 (d,J= 7.1 Hz, 1H), 6.18 id, ./ 5.6 Hz, Hi).4.06 - 4.14 (m, 4H), 3.98 - 4.05 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Caled. For 486.2. (M+H), Found 486.4.

(£)-5-(8-Morpholino-2-(2-(qumolin-2-yl)v ^" inyl)imidazo[l,2- />]pyridazin-3 -yl)picolinic acid

H-NMR (400 MHz, ΟΧΊ . · ( ^' l).OO) δ (ppm): 9.06 (br. s., 1H), 8.35 - 8.47 (m, 3H), 8.16 - 8.23 (m, III).8.04 - 8.13 (ra,

92

2H), 7.92 (m, 2H), 7.81 - 7.89 (m, 2H), 7.60 - 7.70 (m, Itl), 6.23 - 6.30 (m, IH), 4.12 (br.s., 4H), 3.96 - 4.05 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. For (yH. N,,0: _: 479.2 (M+H), Found 479.4.

(£ ^' )-3-Methoxy-4-(8-morpholino-2-(2-(quinolm-2- yl)vinyl)imidazo[l,2-6Jpyridazin-3-yl)benzoic acid 'H-NMR. (400 MHz, CiX ^' i. CD.OD) δ (ppm): 8.49 (d, J= 8.6 Hz, 1H), 8.21 (d, J= 8.6 Hz, 1H), 7.98 - 8.03 (m, 2H), 7.96 -

98 7.98 (m, IH), 7.93 (d, J - 8.6 Hz, 2H), 7.85 - 7.90 (m, 1H), 7.83 is, 111·.7.68 - 7.75 (m, 2H), 7.56 (d, ./ 8.1 Hz, IH), 6.21 id. J = 5.6 Hz, IH), 4.08 -4.15 (m, 4H), 3.93 ^■■ 4.03 (m, 4H), 3.87 (s, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C2 ₉ H2 ₅ N ₃ O4: 508.2 (M+H), Found 508.4. Cpd No. Characterization

(£)-2-Fluoro-4-(8-raorpholino-2-(2-(quinolin-2- yl)vinyl)imidazo[l,2- j]pyri(lazin-3-yl)benzoic acid Ή-NMR (400 MHz, DMSO-<¾) δ (ppm)i 13.39 (br. s., 1H), 8.35 (d, J = 8.6 Hz, 1H), 8.19 (d, J = 5.6 Hz, 1H), 8.09 (t, J= 8.1 Hz,

1Θ3 1H), 7.90 - 8.03 (m, 3H), 7.82 (d, J = 4.2 Hz, 2H), 7.70 - 7.79 (m, 3H), 7.68 (d, J - 8.1 Hz, I H), 7.52 - 7.62 (m, 1H), 6.48 (d, J - ----- 5.9 Hz, I H), 4.10 (br. s., 4H), 3.88 (m, 4H). Mass Spectrum

(LCMS, ESI pos.) Calcd. For J i , >F\ ₃ G ;: 496.2 (M+H), Found 496.5.

(£)-6-(8-Morpholino-2-(2-(quinolin-2-yl)v ^" inyl)imidazo[l ,2- 6]pyridazin-3 -yl)nicotinic acid

Ή-NM (400 MHz, DMSO-da) δ (ppra): 9.28 (s, IH), 8.55 - 8.63 (m, IH), 8.51 (d, J = 8.6 Hz, IH), 8.36 - 8.45 (m, 2H), 8.23

113 (d, ./ 5.6 Hz, I H), 7.92 - 8.01 (m, 3H), 7.80 (d, ./ 16.2 Flz, IH), 7.71 - 7.77 (m, 1FI), 7.51 - 7.60 (in, ili), 6.43 - 6.52 (m, IH), 3.99 - 4.1 1 (in, 4H), 3.77 ^■■ 3.88 (m, 4H). Mass Spectrum (LCMS, EST pos.) Calcd. For C > i L AV.O ;: 479.2 (M+H), Found 479.4.

Example 6

^■ -Hydroxy-4- (8-ηιοφ1ιοϋηο-2- 2-(quinolin~2-yl)vinyl)irnidazo[l,2-6]pyridazin-3- yJ)benzoic acid (Cpd 63)

(ii)-Methyl 2-hydΓoxy-4-(8-moφhoΐmo-2-(2-(qumoli -2-yl)vi yl)imidazo[l olpyri dazin-3 -yl)benzoate, 6a

, 6a

Compound 6a was prepared as a yellow solid following the procedures described in Example 5, steps A-G. Mass Spectrum (LCMS, ESI pos.): Calcd. for C29H25 5O4: 508.2 (M+H); found: 508.5.

B. (£)-2-Hydroxy-4-(8-mo holino-2-(2-(qumol ^" in-2-yl)vm l)imidazo[l,2- 6]pyridazm-3 -yl)benzoic acid, Cpd 63

Compound 6a (80 mg, 0.16 mmol) was suspended in THF/MeOH (1 : 1 v/v, 8 mL) and treated with 1 N LiOH solution (0.8 mL, 0,8 mmol). The mixture was stirred at 90 °C for 30 min, allowed to cool to rt, and treated with water (20 mL). The pH of the mixture was adjusted to ca. pH 3 using 1 N HCT solution. The reaction mixtitre was then extracted with 20 % MeOH in DCM (4 x 200 mL). The combined organic layers were washed with brine, dried over Na2SC>4, filtered and concentrated to give the title compound 63 as an orange solid. Ή-NMR (400 MHz, DMSO-<¾) δ (ppm): 8.60 (br. s., i 1 1 !. 8.55 - 8.67 (m, I I I ⁾ . 8.20 (d, J = 5.6 Hz, IH), 8.12 - 8.18 (m, 1H), 8.04 - 8.12 (m, 2H), 8.00 (d, J= 8.1 Hz, IH), 7.88 (m, 3H), 7.69 (br. s., I H), 7.37 (d, ./ 1.2 Hz, IH), 7.31 (d, J = 8.3 Hz, I H), 6.49 (d, J= 5.9 Hz, IH), 4.10 (m 4H), 3.88 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Cafcd. For C28H23N5O4: 494.2 (M+H), Found 494.4.

Following the procedures described in Example 6 above, and substituting suitably selected and substituted reagents, starting materials and conditions as would be readily apparent to those skilled in the art, the following representative compounds of the present invention were prepared.

Example 7

(£)-3-(4~(8-Morpholino-2-(2-(quinolin-2-yl)vinyl)imidazo[l, 2-6]pjTidazi

y])b d 44)

(£)-Methyi 3-(4-(8-nlOφholino-2-(2-(quinoli -2-yl)vinyl)imidazo[l,

Zj]pyridazin-3-y])benz

To a solution of Compound 40 (0.21 g, 0.36 mmoi, Example 5) in DMF (3 ml.) was added methyl 3-aminopropanoate (0.12 g, 0.89 mmoi), HATU (0.20 g, 0.53 mmoi) and DIEA (0.37 mL, 2.1 mmoi). The resulting mixture was stirred at rt for 16 h and poured into water (20 mL). The aqueous layer was extracted with DCM (2 x 20 mL). The combined organic layers were dried over MgS<¾ and filtered. Upon removal of the solvent, the resultant residue was purified by flash chromatography on silica gel (40- 100 % EtOAc/heptane) to give compound 7a as a red solid. Ή- MR (400 MHz, ( IX h i δ (ppm): 8.12 (d, ./ 8.8 Hz, l i s }. 8.07 (d, ./ 8.6 Hz, H i s. 7.92 - 8.03 (m, 4H), 7.84 (d, J= 8.6 Hz, 2H), 7.78 (d, J= 8.1 Hz, 1H), 7.65 - 7.76 (m, 3H), 7.46 - 7.54 (m, 1H), 6.97 (t, J= 6.0 Hz, 1H), 6.13 (d, ,/ 5.6 Hz, 1H), 4.06 - 4.13 (m, 4H), 3.96 - 4.03 (m, 4H), 3.76 - 3.83 (m, 2H), 3.75 (s, 3H), 2.71 (f, J= 5.9 Hz, 2H).

B. (Z^-3-(4-(8-Moφholmo-2-(2-(qui o]i -2-yl)vΐ yi imidazo[l ,2-Z?]pyridazΐ -3- yl)benzamido)propanoic acid, Cpd 44 Compound 7a (0.20 g, 0,36 mmol) was suspended in THF/MeOH (4: 1 v/v, 5 inL), and treated with 1 N LiOH solution (2.0 inL). The resulting mixture was stirred at rt for 3 h, and treated with water. The pH of the mixture was adjusted to ca. pH 5 using 1 N HC1 solution. The resulting mixture was extracted with DCM (2 x 200 niL). The combined organic layers were washed with brine, dried over MgS0 ₄ , filtered and concentrated. The residue obtained was washed with MeOH, and dried under high vacuum to give the title compound 44 as a yellow solid. Ή-NMR (400 MHz, CDC ) 8 (ppm): 8.14 i d. ./ 8.6 Hz, I H i. 8.06 L 8.6 Hz, 1H), 7.97 - 8.03 (m, 3H), 7.94 (d, J= 15.6 Hz, IH), 7.76 - 7.86 (m, 3H), 7.64 - 7.76 (m, 3H), 7.46 - 7.55 (m, IH), 6.15 (d, ./ 5.6 Hz, i l l ;. 4.08 (d, J 3.4 Hz, 4H), 4.01 (d, J= 3.4 Hz, 4H), 3.74 (t, ./ 5.9 Hz, 2H), 2.70 (t, J= 5.9 Hz, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. For

C31H28N6O4: 549.2 (M+H), Found 549.2.

Following the procedures described in Example 7 above, and substituting suitably selected and substituted reagents, starting materials and conditions as would be readily apparent to those skilled in the art, the following representative compounds of the present invention were prepared.

Cpd No. Characterization E)-Λ ^Γ -(^[ethylsulfonyl)-4-(8-mo holi o-2-(2-(qumolm-2- yi)vinyl)imidazo [1,2- >]pyridazin-3-yl)benzamide

! i-NM R (400 MHz, CDCU) δ (ppm): 8.40 - 8.45 (m, IH), 8.19 - 8.23 (m, IH), 8.12 (d, J = 8.6 Hz, 21 ! s. 8.05 (d, J = 5.6 Hz,

39

IH), 7.98 (s, I H), 7.94 (m, 11 1 ). 7.87 (dd, ./ 10.8, 8.6 Hz, 4H), 7.61 - 7.70 fm, Hi), 6.24 (d, J = 5.6 Hz, IH), 4.07 - 4.15 (m, 4H), 3.99 - 4.04 (m, 4H), 3.45 (s, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C^Hy^CUS: 555.2 (M+H), Found 555.1. Cpd No. Characterization

(£)-4-((4-(8-Mo^holino-2-(2-(qumolin-2-yl)vinyl)imidazo[ 1 ,2- £»/pyridazin-3-yl)phenyl)ammo)-4-oxobutanoic acid "'H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 10.24 (s, 1H), 8.31 (d, J = 8.1 Hz, 1H), 8.13 (d, J = 8.6 Hz, 1H), 7.90 - 7.99 (m,

48 2H), 7.77 - 7.88 (m, 3H), 7.67 - 7.77 (m, 3H), 7.64 (d, J = 8.6 Hz, 2H), 7.50 - 7.58 (m, lH), 6.36 - 6.46 (m, 1 H), 4.03 - 4.16 (m, 4H), 3.83 - 3.93 (m, 4H), 2.60 - 2.67 (m, 2H), 2.57 (m, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C ₃ iH ₂ s ₆ 0 ₄ : 549.2 (M+H), Found 549.4.

3-(4-(8-Morpholino-2-(quinolin-2-ylethynyl)imidazo[l ,2- b]pyridazin-3-yi)benzainido)propanoic acid

: H-NMR (400 MHz, DM SO -,</.·.) δ (ppm): 8.69 (t, J = 5.3 Hz, 1H), 8.46 (d, J = 8.6 Hz, IH), 8.29 (d, J = 6.1 Hz, 1H), 8.21 (d,

82 J = 8.6 tlz, 21 Π. 7.99 - 8.10 (m, 4tl), 7.84 (t, J = 7.8 Hz, IB), 7.72 (d, ./ 8.6 Hz, IH), 7.68 (d, ./ 7.6 Hz, IH), 6.50 (d, ./ 5.6 Hz, IH), 4.03 (br. s., 4H), 3.79 ^■■ 3.88 (m, 4H), 3.47 - 3.57 (m, 2H), 2.56 ( 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C31H26N6O4: 547.2 (M+H), Found 547.5,

Cpd No. Characterization

N-(Methylsu]fonyl)-4-(8-morpholmo-2-(quinolm-2- ylethyiiyl)imidazo[ 1 ,2-0]pyridazm-3-yl)benzamide !I-VYJR (400 MHz, CDCh C ^' i);()i)S 6 (ppm): 8.34 i . J 8.6 Hz, 2H), 8.24 (d,J= 8.6 Hz, 1H), 8.14 (d, J= 5.6 Hz, 1H), 8.06

83 -8.11 (m, 3H), 7.87 (d, J= 8.1 Hz, IH), 7.76 - 7.82 (m, 1H), 7.73 (d, J = 8.1 Hz, IH), 7.58 - 7.65 (m, IH), 6.22 (d, J= 5.6 Hz, H), 4.00 - 4.06 (m, 4H), 3.93 - 4.00 (m, 4H), 3.44 (s, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C2 ₉ H2 _{4 0} O ₄ S: 553.2 (M+H). Found 5^ S.

(£)-2-Fluoro-N-(methylsulfonyl)-4-(8-morpholino-2-(2- (quinoim-2-yl)vinyl)imidazo[l,2~6]pyridazin-3-yi)benzainide :H-NMR (400 MHz, CDC! ₃ ) δ (ppm): 8.22 - 8.36 (m, H), 7.90

134 - 8.21 (m, 4H), 7.59 - 7.87 (m, 6H), 7.43 - 7.58 (m, IH), 6.13 - 6.24 (m, IH), 4.05 - 4.18 (m, 4H), 4.00 (br. s., All).3.49 (s, 3H). Mass Specirum (LCMS, ESI pos.) Calcd. For C29¾ ₅ FN ₆ Q ₄ S: 573.2 (M+H), Found 573.4.

Cpd No. Characterization

(£)-N-(Met ylsuΐfo yl)-l-(8-mo holi o-2-(2-(qumolm-2- yi)viiiyl)irnidazo[I,2-0]pyridazm-3-yl)piperidme-4- carboxamide

^! H-NMR (400 MHz, (ΊΧΊ .·( !) .()!)} δ (ppm): 8.18 {·:!../ 8.6 Hz, Hi}.8.09 (d, J= 8.6 Hz, IH), 7.98 (d, J= 5.6 Hz, III).7.82

153 (d, J - 4.5 Hz, 3H), 7.76 id. J= 8.6 Hz, IH), 7.69 - 7.74 (m, ill).7.47 - 7.56 (m, 1H), 6.05 id, ./ 5.6 Hz, IH), 3.99 - 4.05 (m, 4H), 3.93 ^■■ 3.99 (m, 4H), 3.52 ^■■ 3.61 (m, 2H), 3.39 - 3.42 (m, IH), 3.33 - 3.38 (m, 2H), 3.32 (s, 3H), 2.50-2.65 (m, IH), 2.07 - 2.23 (m, 2H), 2.01 (m, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C ₂ s¾ ;N ₇ 08: 562.2 (M+H), Found 562.3.

(£)-4-(4-(8-Moφ o]mo-2-(2-(qumoj.m-2-yΐ)vinyl)imidazo[l,2- 0]pyridazm-3-yi)piperaziii- 1 -yl)-4-oxobutanoic acid "'H-NMR (400 MHz, CDC1 ₃ ) 6 (ppm): 8.15 (d, . 8.6 Hz, 2\l). 7.96 (d, J= 5.6 Hz, IH), 7.68 - 7.89 (m, 5H), 7.45 - 7.54 (m,

155

IH), 6.02 (d, ./ 5.6 Hz, IH), 3.99 ^■ · 4.07 (m, 4H), 3.88 - 3.98 (m, 6H), 3.73 - 3.81 (m, 2H), 3.39 - 3.51 (m, 4H), 2.81 (s, 2H), 2.79 (br. s., 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C29H31 _N7 0 ₄ : 542.2 (M+H), Found 542.3.

Example 8

A mixture of Compound 4Θ (74 mg, 0.16 mmol, Example 5), 4- methyibenzenesuifonohydrazide (0.14 g, 0.78 mmol) and sodium acetate (64 mg, 0.78 mmol) in DME/water (2.5 mL, 10: 1 v/v) was heated at 85 °C for 18 h. The reaction mixture was allowed to cool to rt, and water (20 mL) was added. The mixtur was extracted with DCM (2 x 20 mL). The organic layers were combined, washed with brine, dried over Na ₂ S04, filtered and concentrated to leave a yellow solid. The title compound 41 was obtained as a pale yellow solid afier recrystaliization from MeOH. Ti-NMR (400 MHz, CDCI3) δ (ppm): 8.20 (d, J= 8.6 Hz, ! ! ! ;·. 8.1 1 (d, J = 8.3 Hz, 1H), 8.08 (d, J = 8.3 Hz, 2H), 8.00 (d, J= 5.6 Hz, 1H), 7.79 (d, J = 8.1 Hz, IH), 7.67 - 7.74 (m, 3H), 7.48 - 7.55 fm, I H i. 7.44 (d, J = 8.3 Hz, IH), 6.09 (d, ,/ 5.6 Hz, l i s }. 3.87 ^■ · 3.98 (m, 8H), 3.56 ^■■ 3.65 (m, 2H), 3.49 (m, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C28H25N5O3: 480.2 (M+H), Found 480.4.

Following the procedures described in Example 8 above, and substituting suitably selected and substituted reagents, starting materials and conditions as would be readily apparent to those skilled in the art, the following representative compounds of the present invention were prepared. Cpd No. Characterization

4-(8-Morpholino-2-C2-(quinolin-2-y])et yl)imidazo[I ,2- Z?]pyridazm-3-yi)beiizeiiesulfonaraide

¹ H-NMR (400 MHz, CDCi ₃ ) δ (ppm): 7,94 - 8.03 (m, 3H), 7.89 (d, J = 8.3 Hz, 2H), 7.76 (d, J = 8.1 Hz, 1H), 7.65 - 7.72 (m,

38

3H), 7.46 - 7.52 (m, 1H), 7.22 (d, J = 8.6 Hz, 1H), 6.09 (d, J = 5.6 Hz, IH), 5.03 (br. s., 2H), 3.88 (dd, J - 15.3, 5.3 Hz, 8H), 3.44 (d, ./ 6.6 Hz, 2H), 3.38 (m, 2H). Mass Spectrum (LCMS, ESI pos.) Caled. For C ₂₇ H ₂₆ N ₆ 0 ₃ S: 515.2 (M+H), Found 515.2.

N-((4-(8-Morpholino-2-(2-(quinolin-2-yl)ethyl)imidazo[l ,2- h] pyridazin-3 -y l)pheny 1) sul fony l)acetamide

Ή-NMR (400 MHz, CDC1 ₃ ) δ (ppm): 8.05 (d, .1 8.6 Hz, 2H), 7.94 ^■■ 8.03 (m, 3H), 7.73 ^■■ 7.80 (m, 3H), 7.64 - 7.71 (m, IH),

42

7.45 - 7.52 (m, IH), 7.24 - 7.29 (m, IH), 6.09 (d, J = 5.6 Hz, IT ), 3.89 - 3.96 (m, 4H), 3.81 - 3.89 (m. A l l ). 3.47 - 3.53 (m, 2H), 3.40 - 3.47 (m, 2H), 1.98 (s, 3H). Mass Spec! i inn (LCMS, ESI pos.) Calcd. For C ₂ 9H ₂ s ₆ 0 ₄ S: 557.2 (M+H), Found 557.5.

3-(4-(8-Morpholino-2-(2-(quino{in-2-yl)ethy1)iraidazo[l,2 - j ]pyridaziri-3-yl)benzamido)propanoic acid

1 H-NMR (400 MHz, CDCI3) δ (ppm): 8.03 i d. J = 8.3 Hz, IH), 7.94 ^■■ 8.01 (m, 2H), 7.74 ^■■ 7.81 (m, 3H), 7.68 (s, IH), 7.56 (d, ./

46

= 8.6 Hz, 2H), 7.47 - 7.53 (m, I H), 7.24 (d, J= 8.6 Hz, IH), 6.09 (d, J = 5.6 Hz, ITT), 3.87 (br.s, 8H), 3.68 - 3.75 (m, 2H), 3.35 - 3.49 (m, 4H), 2.67 (t, ./ 5.9 Hz, 2H). Mass Spectrum (LCMS, ESI pos.) Caled. For C3jH3 ₀ N ₆ O ₄ : 551.2 (M+H), Found 551.2. Cpd No. Characterization

4-((4-(8-Mo^holino-2-(2-(qumolm-2-yl)ethyl)imidazo[l,2- 6]pyridazii-3-yl)phenyl)amino)-4-oxobu1anoic acid 1 H-NMR (400 MHz, CDC1 ₃ ) δ (ppm): 8.04 id. J= 8.3 Hz, III). 7.99 (d, J= 8.6 Hz, 1H), 7.95 (d, J= 5.6 Hz, 1H), 7.75 ^■■ 7.82 (m,

49 1H), 7.66 - 77? ( _m> 1H .7.57 - 7.63 (m.2H), 7.47 - 7.54 (m, III).7.40 - 7.46 (m, 2H), 7.27 (d, .7- 8.6 Hz, IH), 6.08 (d, ./ 5.6 Hz IH), 3.85 (s, 8H), 3.31 - 3.47 (m, 4H), 2.70 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C31H30N6O4: 551.2 (M+H), Found 551.5.

1,1,1,3,3,3-Η6Χ3ΑυοΓο-2-(4-(8-ιηοφ1ιο1ίηο -2-(2-(ςιιίηο1ίη-2- yl)ethyl)imidazo[l,2-6]pyridazin-3-yl)phenyl)propan-2-ol 1 H- MR (400 MHz, CDCI3) δ (ppm): 7.94 - 8.04 (m, 3H), 7.72 - 7.82 (m, 3H), 7.62 - 7.70 (m, Ml).7.43 - 7.51 (m, IB), 7.28 (d,

S3

J= 8.6 Hz, 1H), 6.05 (d, J - 5.6 Hz, IH), 4.82 (br. s., !Fi), 3.86 - 3.92 (in, 4H), 3.81 - 3.86 (m, 4H), 3.46 - 3.54 (m, 2H), 3.37 - 3.45 (m, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C30H25F6 5O2: 602.2 (M+H), Found 602.5.

5-(8-Morpholino-2-(2-(quinolin-2-yl)ethyl)imidazo[l,2- 0]pyridazin-3-yl)furan~2-carbox lic acid

¹ H-NMR (400 MHz, CDCI3+CD3OD) δ (ppm): 8.24 - 8.34 (m, 2H), 8.11 - 8.18 (m, IH), 7.84 - 7.91 (m, IH), 7.76 - 7.84 (m,

68

IH), 7.65 - 7.73 (m, IH), 7.57 - 7.65 (m, IH), 7.35 (m, 2H), 6.15 - 6.24 !H!. IH), 3.87 (br. s., 8H), 3.54-3.68 (m 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C26H23N5O4: 470.2 (M+H), Found 470.4. Cpd No. Characterization

5-(8-Morpholino-2-C2-(quinolin-2-y])et yl)imidazo[l,2- 6]pyridazm-3-yl)thiopbene-2-carboxylic acid

1 H-NMR (400 MHz, CDCI ₃ +CD ₃ OD) δ (ppm): 8.26 ^■■ 8.38 (m, 111:.8.12 (d, J - 5.6 Hz, Mb.7.83 - 7.95 (m, 2H), 7.73 ^■ 7.81

61 (m, 2H), 7.65 - 7.71 (m, IH), 7.56 (d, J= 3.9 Hz, 1H), 7.47 (d, J = 8.3 Hz, ill).7.14 (d, J= 7.8 Hz, 1H), 6.16 (d, J= 5.6 Hz, IH), 3.70 - 3.84 (m, 10H), 3.60 - 3.67 (m, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C> _; J L:N,i>:S: 486.2 (M+H), Found 486.4.

2-Hydroxy-4-(8-morpholmo-2-(2-(quinolin-2- yl)ethyl)imidazo[l,2-6]pyridazin-3-yl)benzoic acid

1 H- MR (400 MHz, CDC! ₃ +CD ₃ QD) 8 (ppm): 8.07 id. J = 8.3 Hz, 1H), 8.03 (d, J= 8.6 Hz, IH), 7.99 (d, J = 5.6 Hz, 1H), 7.87 (d, J= 8.1 Hz, 1H), 7.79 id../ 8.1 Hz, ill}.7.67 - 7.73 (m,

64

IH), 7.49 - 7.55 (m, IH), 7.30 (d, J- ----- 8.6 Hz, IH), 7.17 (d, ./

1.7 Hz, IH), 7.06 (dd, J= 8.2, 1.6 Hz, IH), 6.11 (d, J= 5.6 Hz, IH), 3.84 (br. s., 8H), 3.46 (dd, J = 8.8, 5.1 Hz, 4H). Mass Spectmm (LCMS, EST pos.) Calcd. For C28H25N5O4: 496.2 (M+H), Found 496.5.

Cpd No. Characterization

2-Methoxy-4-(8-moφholino-2-(2-(qumo{in-2- yl)ethyl)imidazo[l ,2~6]pyridazm-3~yl)benzoic acid

1 H-NMR (400 MHz, C ^' iX i . · CO .OD ) δ (ppm): 8.16 (d, J = 8.1 Hz, 1H), 7.92 ^■■ 8.02 (m, 3H), 7.73 ^■■ 7.77 (m, 1H), 7.65 ^■ 7.70

69 (m, 1H), 7.46 - 7.54 (m, 1H), 7.34 (dd, J = 8.1 , 1.5 Hz, 1H), 7.26 (ra, 1H), 7.22 (d, J = 8.6 Hz, 1H), 6.10 (d, J = 5.6 Hz, 1H), 3.99 (s, 3H), 3.90 - 3.96 (m, 4H), 3.84 - 3.89 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C29H27N5O ₄ : 510.2 (M+H), Found 510.4.

2,6-Difluoro-4-(8-morphoiii j-2-(2-(qumolm-2- y l)ethyl)imidazo [ 1 ,2-6]pyridazin- 3 -y l)phenol

1 H- MR (400 MHz, CDCU) 8 (ppm): 8.10 (d, ./ 8. 1 Hz, ! ! ! }. 8.02 (d, J = 8.6 Hz, 1H), 7.96 (d, J = 5.6 Hz, 1 H), 7.78 (d, J =

81 8.1 Hz, 1H), 7.61 - 7.69 (m, 1H), 7.46 - 7.52 (m, I H), 7.41 (d, J = 8.6 Hz, 1H), 6.97 (d, ./ 9.1 Hz, 2H), 6.05 (d, ./ 5.6 Hz, 1H), 3.85 (br. s., 8H), 3.47 ^■ 3.56 (m, 2H), 3.37 (m, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C27H23F2N5O2: 488.2 (M+H), Found 488.4.

I l l Example 9

Λ-(Metllylsυlfonyl)-4-(8-mo holmo-2-(2-(quinoiin~2-yl)eίhyi)imidazo[l ,2- 6]p 43)

To a suspension of Compound 41 (0.1 1 g, 0.22 mmolExample 8) in DCM (20 mL) was added oxalyl chloride (1.1 mL, 2.2 mmol) dropwise followed by one drop of DMF. The mixture was stirred at rt under an argon atmosphere for 2 h. The reaction mixture was concentrated to obtain an orange solid, which was re-dissolved in DCM (10 mL), and treated with methanesulfonamide (43 mg, 0,45 mmol) and triethylamme (0.10 mL, 0.68 mmol). The reaction mixture was stirred at rt for 16 h, then was washed with 1 N HC1 solution (10 mL) and brine. The organic layer was separated, dried over MgS0 ₄ , and concentrated to obtain a residue, which was purified by preparative-TLC (1 : 1 :0.1 EtOAc/DCM/MeOH, v/v/v) to give the title compound 43 as a yellow solid. Ή-NMR (400 MHz, CDCh) δ (ppm): 7.79 ^■■ 8.04 (m, 5H), 7.51 ^■■ 7.77 (m, 4H), 7.40 · ^■ 7.51 (m, 1H), 7. 16 i d. ./ 8.1 Hz, IH), 5.99 (br. s., Hi), 3.82 (br. s., 8H), 3.48 (s, 3H), 3.26 ^■■ 3.44 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C2 H28N6O4S: 557.2 (M+H), Found 557.1.

Example 10

(£)·-ΛΗ4- (8--Morph^

yl)phenyl)methanesuifonamide (Cpd 47)

A. (ZT)~4-(3-(4~Ni†rophenylV^

yl)morphoiine, 10a

Compound 10a was prepared according to the methods described in Example 5, steps A-G. ¹ H-NMR (400 MHz, DMSO-i¾ 6 (ppm): 8.78 (hr. s., 1H), 8.46 (d, ,/ 8.8 Hz, 2H), 8.37 (br. s., 1H), 8.23 (d, J= 5.9 Hz, 1H), 8.13 - 8.20 (m, 2H), 7.92 - 8.13 (m, 5H), 7.70 ^■■ 7.84 (m, 1H), 6.53 (d, J= 5.9 Hz, 1H), 4.06 - 4.20 (m, 4H), 3.81 ^■ · 3.95 (m, 4H).

B. (£)-4-(8-Morpholino-2-(2-(qumolin-2-yl)vmyl)imidazo[l,2- ?]pyridazm-3- yi)a:niiine, Wb

To a suspension of compound 10a (0.85 g, 1.8 mmol) in acetic acid (20 mL) was added iron powder (0.50 g, 8.9 mmol). The reaction mixture was stirred at 80 °C for 2 h, and allowed to cool to rt. The reaction mixture was treated with water, and the pH of the solution was adjusted to ca. pH 7 using 3 N NaOH solution. The mixture was extracted with DCM (3 x 1 00 mL). The combined organic layers were dried over MgSO/j, filtered, and concentrated to obtain compound 10b as a dark red solid. Mass Spectrum (LCMS, ESI os.): Calcd. for 449.2 (M+H); found: 449.1.

C. (fi N-(4-(8-Mo^holmo-2-(2-(quinolin-2-yl)vmyj imi

y3)phenyl)methanesulfonamide, Cpd 47

To a mixture of compound 18b (66 mg, 0.15 mmol) and pyridine (24 L, 0.29 mmol) in DCM (5 mL) was added methanesulfonyl chloride (23 uL, 0,29 mmol). The resulting mixture was stirred at rt for 3 days. The mixture was then diluted with DCM (20 mL), and washed with 1 Ν HC1 solution and brine. The organic layer was dried over MgSCXi, filtered, and concentrated. The orange solid obtained was washed with methanol (2 x 5 mL), and dried in vacuo to give the title compound 47. Ti- MR (400 MHz, DMSO-d ^" ₆ ) δ (ppm): 10.09 - 10.17 (m, 1H), 8.64 - 8.83 (br.s. , 1H), 8.25 (br.s, 1H), 8.06 ^■ 8.22 (m, 3H), 7.83 - 8.06 (m, 3H), 7.63 ^■ · 7.80 (m, 3H), 7.36 ^■■ 7.48 (m, 2H), 6.46 (d, J = 5.9 Hz, 1 H), 4.04 - 4.18 (m, 4H), 3.79 - 3.97 (m, 4H), 3.14 (s, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C^eNeOsS: 527.2 (M+H), Found 527.1. Example 1 1

N-(4-(8-Morpholino-2-(2-(quinolin-2~yi)ethyl)imidazo[l ,2~ ?]pyridazin-3- yl)phenyl)methanesuifonarmde (Cpd 45)

A. fen-Butyl (4-(8-mo^holino-2-(2-(quinoHi -2-yl)ethyl)imidazo[ l,2-0]pyridazin- 3 -yl)pheny l)carbamate

^' TO a suspension of compound 41 (0.22 g, 0.45 mmol, Example 8) in teri-butanoi (5.0 mL) was added TEA (0.13 mL, 0.90 mmol), and DPPA (0.12 mL, 0.54 mmol). The reaction mixture was stirred at ri for lh, then at 85 °C for 2 days. Water (20 mL) was added, and the mixture was extracted with EtOAc (2 x 20 mL). The combined organic layers were washed with brine, dried over NaaSO filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (20-60 % EtOAc heptane) to give compound 11a. Mass Spectrum (LCMS, ESI pos.) Caicd. For C ₃ 2H ₃ 4N ₆ O ₃ : 551.3 ( vl H i . Found 551.2.

B. (£ -4-(8-mo^hoHno-2-(2-(quinolin-2-yl)ethyl)imidazo[l,2-&]p yridazin^

yljaniline, lib

A solution of compound 11 (77 mg, 0.14 mmol) in DCM (2 mL) was treated with TFA (1 mL). The mixture was stirred at rt for 4 h. The reaction mixture was concentrated and the residue was re-dissolved in DCM (20 mL). The organic layer was washed with saturated NaHCOs (20 mL), brine, and dried over MgS0 . The mixture was filtered and concentrated to give compound l ib as a brown oil. Mass Spectrum (LCMS, ESI pos.) Calcd. For C ₂₇ H ₂₆ N ₆ 0: 451.2 (M+H), Found 451.5.

C. N-(4-(8-Morpholino-2-(2-(quniolin-2-y^^

y3)phenyl)methanesulfonamide, Cpd 45

Compound 45 was prepared using the method described in Example 10, Step C using compound lib. Ή- MR (400 MHz, CDC1 ₃ ) 5 (ppm): 7.93 · 8.07 (m, 3H), 7.77 (dd, J= 8.1, 1.2 Hz, 1H), 7.68 (d, . 1.5 Hz, 1H), 7.44 - 7.56 (m, 3H), 7.28 (m, 1H), 7.20 - 7.25 (m, 2H), 6.95 - 6.99 (m, 1H), 6.05 (d, J= 5.6 Hz, IH), 3.87 - 3.93 (m, 4H), 3.81 - 3.87 (m, 4H), 3.45 - 3.52 (m, 2H), 3.35 - 3.42 (m, 2H), 3.04 (s, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C _? . ₈ H2 _{8 6} 0 ₃ S: 529.2 (M+H), Found 529.2.

Example 12

(£)-N-((4-(8-Mo^holino-2-(2-(quinolm-2-yl)vinyl)imidazo[l,2 -6]pyiidazin-3- yl)phenyl)c e (Cpd 50)

A. Ethyl methyisulfonylcarbainate, 12a

To a mixture of methanesulfonamide (1.0 g, 1 1 mmol), trietliylamme (1.9 mL, 14 mmol), and DMAP (0.13 g, 1.1 mmol) in DCM (20 mL) cooled in an ice-water bath was added ethyl carbonochloridate (1.1 mL, 12 mmol) dropwise via a syringe under an argon atmosphere. The mixture was allowed to warm up to rt overnight. The reaction mixture was concentrated, and the residue obtained was dissolved in EtOAc (100 mL). The solution was washed with 1 N HCl (20 mL) and brine, and dried o ver MgS0 ₄ . The mixture was filtered and concentrated to give compound 12a as a yellow oil. Ή- MR (400 MHz, CDCh) 8 (ppm): 7.86 (br. s., i l l ). 4.28 (q, J= 7.25 Hz, 2H), 3.30 (s, 31 0. 1.33 (t, J = 7.25 Hz, 3H).

B. (i^-N-((4-(8-Mo^kolmo-2-(2-(qumolm^

yl)phenyi)carbamoyl)methanesuifonamide, Cpd 58

To a mixture of compound 18 (82 mg, 0.18 mmol) and compound 12a (0.14 g, 0.86 mmol) in DMF (2 mL) was added DIEA (0.16 mL, 0.91 mmol). The mixture was stirred at 100 °C for 2 h. The solution was cooled down, and diluted with DCM (10 mL). The organic layer was washed with 1 N HCl solution ( 10 mL) and brine, dried over MgS0 ₄ , filtered and concentrated. The resulting residue was purified by flash column chromatography on silica gel (0- 10 % CH ₃ OH/DCM) to give the title compound 50 as a red solid. I i- N .Y' R (400 MHz, DM SO-/,) δ (ppm): 8.96 (s, IB), 8.31 (d, J= 8.6 Hz, IH), 8.12 (d, J = 5.6 Hz, 1H), 7.94 (dd, J= 13.6, 8.2 Hz, 2H), 7.83 (d, J = 8.6 Hz, I H), 7.66 - 7.77 (m, 5H), 7.57 - 7.63 (m, 2H), 7.51 - 7.57 (m, IH), 6.40 (d, ./ 5.9 Hz, I H), 4.03 - 4.14 (m, 4ϊί), 3.83 - 3.92 (m, 4H), 3.17 (s, M l ). Mass Spectrum (LCMS, ESI pos.) Calcd. For C2 ₉ H2 ₇ N ₇ O4S: 570.2 (M+H), Found 570.4.

Following the procedures described in Example 12 above, and substituting suitably selected and substituted reagents, starting materials and conditions as would be readily apparent to those skilled in the art, the following representative compound of the present invention were prepared. Cpd No. Characterization

N-((4-(8-Mo^holino-2-(2-(qumolm-2-yl)ethyl)imidazo[l,2-

6]pyridazm-3-yi)pheiiyl)carbamoyl)raethanesulfoiiamide

¹ H-NMR (400 MHz, CDCi ₃ ) δ (ppm): 8.00 id. J= 8.6 Hz, III).

7.96 (d, J= 8.6 Hz, 1H), 7.89 (d, J =5.4 Hz, 1H), 7.75 (d, J =

51 8.3 Hz, 1H), 7.63 - 7.70 (m, IH), 7.52 (d, J= 8.6 Hz, 2H), 7.45 -

7.50 (m, 1H), 7.37 (d, J= 8.8 Hz, 2H), 7.24 (d, J= 8.3 Hz, IH),

6.02 (d, J------ 5.6 Hz, IH), 3.76 - 3.89 (m, 8H), 3.33 - 3.41 (m,

2H), 3.25 - 3.32 (m, 2H), 3.08 (s, 3H). Mass Spectrum (LCMS, ESI pos.) Caicd. For (\,iU,N O S: 572.2 (M+H), Found 572.5.

Example 13

-(4-(lH-Tetrazol-5-yl)phenyl)-2-(2-(qumolm-2-yj vmyl)imidazo[l,

6]pyr 176)

A. (Z^-4-(8-M φhoii o-2-(2-(quinolm-2-y3)vmyl)imidazo[l,2-6] ridazin-3- yl)benzonitrile, 13a

The title compound was prepared following the procedures described in Example 5, Steps A-G. Mass Spectrum (LCMS, ESI pos.) Calcd. For C28H ₂₂ N ₆ 0: 459.2 (M+H), Found 459.4.

B. (^-4-(3-( -(lH-TetrazoI-5-yl)phenyl)~2-(2-(quinolin-2~yI)vinyl)iinidaz o[l,2- Z>]pyridazin-8-yl)morpholme, 13to

A mixture of compound 13a (95 mg, 0.2.1 mmol), sodium azide (20 mg, 0.31 mmol) and ammonium chloride (16 mg, 0.31 mmol) in DMF (3 niL) was heated at 130 °C overnight. The reaction mixture was cooled to rt and water (20 mL) was added. The mixture was extracted with DCMTMeOH (9: 1 v/v, 2 x 100 mL). The combined organic layers were washed with brine, and dried over N ₂ SO/|. The mixture was filtered and concentrated to obtain a residue, which was washed with MeOFI (2 x 2 mL). The resulting solid was purified by flash column chromatography on silica gel (()■■ 20 % MeOH/DCM.) to give compound 13b as an orange solid. Ή-NMR. (400 MHz, ( IX h CThOD s δ (ppm): 8.27 (d, ,/ 8.3 Hz, 2FI), 8.09 - 8.14 (m, ill), 8.02 - 8.07 (m, IFI), 8.00 (d, J= 5.6 Hz, 1H), 7.84 - 7.92 (m, 3H), 7.73 - 7.80 (m, 2H), 7.65 - 7.72 (m, 2FI), 7.46 - 7.53 (m, 1H), 6.12 (d, 5.6 Hz, 1 H), 4.04 - 4.1 1 (m, 4H), 3.96 - 4.02 (m, 4H). Mass Spectmm (LCMS, ESI pos.) Calcd. For C28H23N9O: 502.2 (M-i-H), Found 502.5.

Example 14

(£)-4-(3-(Piperidin-l-yl)-2-(2-(quinolm-2-yl)vinyl)imidazo[ l,2-6]pyri

yl)morpholine (Cpd 1S4)

A. (3-Bromo-8-morpholi yl)methanol, 14a

A suspension of compound Sd (1 .0 g, 4.3 mmol) in acetonitrile (100 mL) was stirred at - 10 °C (in an ice/salt water bath) for 10 min, followed by addition of NBS (0.68 g, 3.8 mmol) in acetonitrile (20 mL) dropwise via an additional funnel. After the mixture was stirred in the ice-water bath for 2 h, 5 % a?S?0 ₃ solution (10 mL) was added to quench (he reaction. The aqueous layer was extracted with DCM (2. x 100 mL). The combined organic layers were washed with brine, and dried over Na ₂ S0 ₄ . The mixture was filtered, and the filtrate was concentrated to leave compound 14a as a white solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for CuHisBrNtCfe: 313.0 (M+H); found: 313.1.

B. 3-Bromo-8-morpholinoimidazo[l,2- j]pyridazine-2-carbaldehyde,14b

To a solution of compound 14a (3.1 g, 9.9 mmol) in DCM (200 mL) was added Dess-Martin periodinane (4.6 g, 1 1 mmol). The reaction mixture was stirred at rt for 16 h, diluted with DCM ( 100 mL), and washed with 10 % Na ₂ S ₂ 03 solution (50 mL) and aq Na ₂ C03 solution (2M, 100 mL). The organic layer was separated, dried over MgS0 ₄ , filtered and concentrated to give a residue, which was washed with MeOH (2 x

20 mL) and Et ₂ 0 (2 x 20 ml.) to afford compound 14b as an off-white solid. 'H-NMR

(400 MHz, CDCl-i) 8 (ppm): 10.13 (s, IH), 8.19 (d, J= 5.56 Hz, 1H), 6.15 (d, J = 5.56 Hz, l l . 4.01 - 4.10 (m, 4H), 3.86 - 3.97 (m, 4H).

C. (iT)-4-(3-Bronio-2-(2-(qum^

y])morphofine (14c) and ( _J E -4-(3-(piperidin- l -yl)-2-(2-(quinolm-2- yl)vinyi

To a suspension of compound 14b (5.4 g, 17 mmol) in toluene ( 150 mL) was added 2-methylquinofine (3.6 mL, 26 mmol) and piperidine (1.7 mL, 17 mmol). The mixture was refluxed at 1 15 °C for 16 h, and allowed to cool to rt. The reaction mixture was treated with water (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine, and dried over Na ₂ S0 ₄ . T he mixture was filtered, and the filtrate was concentrated to obtain a residue, which was purified by- flash column chromatography on silica gel (20-70 % EtO Ac/heptane) to obtain compound 14c as a pale yellow solid and compound 154 as a yellow solid. Compound 14c: ^J H-NMR (400 MHz, CDC1 ₃ ) 8 (ppm): 8.1 1 (t, J = 7.8 Hz, 11 1 ). 8.06 (d, J = 5.6 Hz, 1H), 7.87 (d, J = 1 6 Hz, I H), 7.67 - 7.80 (m, 4H), 7.50 (t, J = 7.6 Hz, 1H), 6.06 (d, J= 5.6 Hz, I H), 4.00 - 4.07 (m, 4H), 3.91 - 3.98 (m, 4H).

Compound 154: Ή-NMR (400 MHz, CDCI ₃ ) δ (ppm): 8.10 (t, J = 7.8 Hz, 2H), 7.86 - 7.99 (m, 2H), 7.63 - 7.82 (m, 4H), 7.43 - 7.52 (m, IH), 5.98 (d, J 5.6 Hz, I H), 3.98 ^■ · 4.06 (m, 4H), 3.93 ^■■ 3.98 (m, 4H), 3.34 ^■■ 3.44 (m, 4H), 1.77 ^■■ 1.87 (m, 4H), 1.63 - 1.77 (m, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C ₂ 6H ₂ gN ₆ 0: 441.2 (M+H), Found 441.2. Example 15

(i?)--5- 8-Morphomio-2-(2--(qum^

yl)thi d 57)

To a stirred solution of compound 14c (0.15 g, 0,34 mmol), 5-boronothiophene- 2-carbox.ylic acid (88 mg, 0.51 mmol) and

dichlorobis(triphenyfphosphine)paUadium(n) (24 mg, 0.034 mmol) in degassed DMF (5 mL), was added 2M Na ₂ C03 solution (0.85 mL, 1.7 mmol). The reaction mixture was purged with Argon before heating at 1 1 0 °C for 2 h. After cooling down, the reaction mixture was neutralized with 1 N HC 1 solution. The resulting red solution was extracted with DCM/MeOH (10: 1 v/ ^' v, 4 x 20 ml.). The combined organic layers were washed with brine, and dried over Na ₂ S0 ₄ . The mixture was filtered, and the filtrate was concentrated to give a residue, which was washed with MeOH (2 x 5 mL), and dried in vacuo to give the title compound 57 as an orange solid. 'H-NMR (400 MHz, CDCI ₃ +CD ₃ OD) 8 (pptn): 8.13 - 8.19 (m, 1H), 8.05 - 8.1 1 (m, 2H), 7.94 - 7.99 (m, 2H), 7.75 - 7.83 (m, 3H), 7.69 - 7.75 (m, 1 H), 7.62 - 7.65 (m, I I I ⁾ . 7.48 - 7.55 (m, 1H), 6.13 - 6.19 (m, 1H), 4.03 - 4.1 1 fm, 4H), 3.98 (m, 4H). Mass Spectrum (LCMS, ESI os.) Caled. For ί '.ν,Π > i _N5 0 ₃ S: 484.1 i. M I I I Found 484.3.

Following the procedures described in Example 15 above, and substituting suitably selected and substituted reagents, starting materials and conditions as would be readily apparent to those skilled in the art, the following representative compounds of the present invention were prepared. Cpd No. Characterization )-5-(8-Moφhoΐmo-2-(2-CqlJi olm-2-yl)vmyj imidazo[l ,2- 6]pyridazin-3-yl)furan-2-carboxylic acid

Ή-NMR (400 MHz, CDCI ₃ +CD ₃ OD) δ (ppm): 8.61 (d, .1 15.9 Hz, 1H), 8.23 (d, J = 8.6 Hz, 1H), 8.10 ^■ 8.17 (m, 2H), 8.00 ^■ · 8.04

58 (m, 1H), 7.95 - 8.00 (m, 1H), 7.81 (d, J = 8.1 Hz, 1H), 7.71 - 7.77 (m, IH), 7.50 - 7.57 (m, 2H), 7.40 (d, J - 3.7 Hz, 1H), 6.20 (d, J - ----- 5.9 Hz, IH), 4.05 - 4.13 (m, 4H), 3.97-4.02 (m, 4H).

Mass Spectrum (LCMS, ESI pos.) Calcd. For C ₂₆ H ₂ , _N5 0 ₄ : 468.2 (M+H), Found 468.4.

5-(8-Morpholii j-2-(quinolin-2-yleth_v¾yl)nmdazo[l,2- b]pyridazin-3-yl)fhiophene-2-carboxy}ic acid

H-NM R (400 MHz, DMSO-rf*) δ (ppm): 8.51 (d, ./ 8.6 Hz, 1H), 8.44 (d, J = 5.6 Hz, IH), 8.39 (d, J = 4.0 Hz, 1H), 8.07 (dd, J

85

- 7.8, 4.8 Hz, 2H), 7.81 - 7.93 (m, 3H), 7.69 (t, J= 7.3 Hz, I H), 6.57 i d. ./ 6.1 Hz, IH), 4.13 (br. s., IH), 4.05 (br. s., 4H), 3.76 - 3.89 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C2 ₆ H1 _{9 5} O ₃ S: 482.1 (M+H), Found 482.4.

Example 16

(E)~ 1 -(8-Morpholino-2-(2~(quinolm-2.-yl)vir!yl)ir!iidazo[ 1 ,2- ?]pyridazin-3- yl)piperidme-4-carboxyiic acid trifiuoroacetic acid salt (Cpd 131 )

(E)-tert-Butyl l -(8"morpholino-2-(2"(qumolin-2-yi)vrnyl)miid:

bjpyri daziii-3 -yl)piperi

, 16a

A mixture of compound 14c (0.10 g, 0.23 mmol), tert-butyl piperidine-4-carboxylate (61 mg, 0.28 mmol), 2,2'-bis[diphenylphosphmo]- l, -bmaphihaleiie (14 mg, 0.023 mmol), tris(dibenzylideneacefone)dipa}iadium (0) (10 mg, 0,01 1 mmol) and sodium ieri-butoxide (66 mg, 0.69 mmol) in toluene (2 mL) in a vial was purged with Argon. The sealed vial was heated at 80 °C for 18 h. The reaction mixture was allowed to cool to rt, and diluted with EtOAc (10 mL). The organic layer was washed with water and brine, and dried over Na ₂ S0 . The mixture was filtered and concentrated to give a residue, which was purified by flash coiumn chromatography on siiica gei (10-60 % EtO Ac/heptane) to give the compound 16a as a yellow solid. Mass Spectrum (LCMS, EST pos.) Calcd. For CsiHseNeOs: 541.3 (M+H), Found 541.6. B. (^)- l -(8-Mo^holino-2-(2-(qumolm-2-yl)vinyI)imidazo[l ,2- j]pyridazin-3- yl)piperidine-4-carboxylic acid trifluoroacetic acid salt, (Cpd 131)

To a solution of compound 16a (0.10 g, 0.19 mmol) in DCM (2 ml.) was added TFA (1 niL). The mixture was stirred at rt for 2 h, and concentrated to a red oil. Et ₂ 0 (5 mL) was added, and the resulting mixture was stirred at rt for 6 days. A precipitate was collected by filtration, washed with water, and dried in vacuo to obtain the title compound 131 as a dark red solid. ^] H~NMR (400 MHz, CDCI ₃ ) δ (ppm): 8.56 (d, J = 8.8 Hz, 1H), 8.34 (d, J = 8.6 Hz, 1H), 8.03 - 8.14 (m, 2H), 8.00 (d, J = 6.6 Hz, 2H), 7.94 (t, J = 7.7 Hz, IH), 7.86 (d, J= 15.7 Hz, 1H), 7.69 - 7.78 (m, I H), 6.07 (d, J= 5.4 Hz, 1H), 4.03 (br. s., 4H), 3.96 (br. s., 4H), 3.49 - 3.60 (m, 2H), 3.39 - 3.47 (m, 2H), 2.54 ^■ · 2.66 (m, 1H), 1.95 ^■■ 2.19 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C27H28N6O3: 485.2 (M+H), Found 485.5.

Following the procedure described in Example 16 above, and substituting suitably selected and substituted reagents, starting materials and conditions as would be readily apparent to those skilled in the art, the following representative compounds of the present invention were prepared.

Cpd No. Characterization

(i£)-3-Fluoro-4-((8-morpholmo-2-(2-Cqumolin-2- yl)vinyl)imidazo[l,2-6]pyridazin-3-yl)ammo)benzoic acid 1 H-NMR (400 MHz, CDG ₃ +CD ₃ GD) δ (ppm): 8.15 (d, J = 9.1 Hz, 1H), 8.04 (d, J= 8.1 Hz, 1H), 8.01 (d, J= 5.6 Hz, IH), 7.78 -

139

7.84 (m, 3H), 7.66 - 7.74 (m, 3H), 7.59 - 7.64 (m, 1H), 7.48 - 7.54 (m, ! ! ί :·. 6.41 (t, ./ 8.3 Hz, IH), 6.16 (d, J = 5.6 Hz, IH), 4.07 - 4.13 (m, 4H), 3.97 - 4.04 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Caled. For C > J d- ^' NV.O ;: 511.2 (M+H), Found 51 1.2.

(£)-4-((8-Mo^holmo-2-(2-(qumo]m-2-yl)vinyl)imidazo[l ,2- ft]pyridaziR-3-yl)amirio)cyclohexariecarboxylic acid

Ή-NMR (400 MHz, CDCI . · C i> :(>D) δ (ppm): 8.15 (d. ./ 8.6 Hz, IH), 8.06 (d, J = 8.6 Hz, IH), 7.95 (d, ./ 5 6 Hz, IH), 7.75 ^■■ 7.82 (m, 2H), 7.66 - 7.74 (m, 3H), 7.46 - 7.52 (m, I H), 5.99 (d, J

152

- 6.1 Hz, i l l }. 4.00 - 4.08 (m, 4H), 3.94 - 4.00 (m, 4H), 3.43 - 3.53 (m, IH), 2.32 (tt, IH), 2.20 (d, J 10.6 Hz, 2H), 2.08 fbr. s., 2H), 1.49■■ 1.64 (m, 2H), 1.31 - 1.45 (m, 2H). Mass Spectrum (LCMS, EST. pos.) Calcd. For C.gHjo gO _? : 499.2 (M+H), Found 499.2.

(£)-2-(1 -(8-Mo^ho{ino-2-(2-(qumolin-2-yl)vinyl)imidazo[l ,2- 0]pyridazii -3-yl)piperidin-4-yl)acetic acid

¹ H-NMR (400 MHz, CDC1 ₃ ) 8 (ppm)i 8.13 (d, J = 8.6 Hz, 2H), 7.97 i d. ./ 5.6 Hz, 1H), 7.84 - 7.92 (m, 1H), 7.67 ^■■ 7.82 (m, 4H),

156 7.44 - 7.51 (m, 1H), 5.99 (d, J= 6.1 Hz, 1H), 3.99 - 4.06 (m, 4H), 3.91 - 3.98 (m, 4FI), 3.47 - 3.57 (m, 2H), 3.35 (d, J = 1 1.1 Hz, 2H), 2.45 (d, ./ = 6.6 Hz, 2H), 2.06 - 2.17 On. 1H), 1.94 i d. ./ 12.1 Hz, 2H), 1.65 (m, 2H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C ₂ 8¾ ₀ N ₆ i¾: 499.2 (M+H), Found 499.2.

Example 17

-(8-Morpholmo-2-(qumolin-2-ylethyny^ ae

(Cpd 77)

ter/-Butyl 4-(2- ;thynyl-8-morpholinoimidazo[l,2-0]pyridazin-3-yl)benzoate, 17a

To a suspension of compound Sf (0.30 g, 0.73 mmol, Example 5) in MeOH (5 mL) was added K2CO ₃ (0.30 g, 2.2 mmol) and a solution of dimethyl (l-diazo-2- oxopropy])phosphonate (0.18 g, 0.96 mmol) in MeOH (2. mL). The reaction mixture was stirred at rt for 2 days, and concentrated under reduced pressure. The residue obtained was dissolved in DCM (20 mL) and washed with water (20 mL). The aqueous layer was extracted with DCM (3 x 10 mL). The combined organic extracts were washed with brine, and dried over MgS0 ₄ . The mixture was filtered and concentrated to give a residue, which was purified by flash column chromatography on silica gel (20-60 % EtOAc/heptane) to give the compound 17a as an off-white solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C23H24N4O3: 405.2 (M+H); found: 405.2.

B. 4-(8-Moφholmo-2-(qumolm-2- leth nyl)imidazo[l,2-/ ] ridazin-3- l)berlzoic acid (Cpd 77)

A. mixtur of compound 17a (0.23 g, 0.57 mmol) and 2-bromoquinoline (1.0 g, 4.8 mmol) in a vial was evacuated and back flushed with Argon, Dry DMF (5 mL) and DIEA (0.99 mL, 5.7 mmol) were added via syringe and the mixture was deoxygenated by bubbling Argon gas through the stirred solution for 5 min. To the mixture were added Cui (5.4 mg, 0.028 mmol) and dichlorobis(triphenylphosphine)palladium(II) (40 mg, 0.057 mmol). The resulting mixture was stirred at rt for 1 h, and was poured into water (50 mL). The mixture was extracted with EtOAc (3 x 30 mL). The combined organic extracts were washed with water (2.0 mL) and brine (2 x 20 mL). The organic layer was concentrated, and the resulting residue was purified by flash column chromatography on silica gel (20-60 % EtO Ac/heptane) to give ier(-huiyl 4-(8- morpholmo-2-(qumoiin-2-yleihynyl)i^ as a yellow solid. To a solution of ferf-butyl 4-(8-moTpliolmo-2-(quinoHn-2- ylethynyi)imidazo[L2- 0]pyridazin-^-yl)benzoate (231 mg, 0.435 mmoi) in DCM (2 mL) was added TFA (2 mL). The mixture was stirred at rt for 3 h, and concentrated in vacuo. The residue obtained was stirred in ether (5 mL) for 1 h. The solid obtained was collected by filtration, and dried in vacuo to give the title compound 77 as a yellow solid. i l-\ \l R (400 MHz, CDCI ₃ +CD ₃ OD) δ (ppm): 8.26 (m, 4H), 8.21 (d, J= 8.6 Hz, IH), 8.13 i d. ,/ 5.6 U/. 1H), 8, 10 (d, J = 8.6 Hz, 1H), 7.85 (d, J= 8.1 Hz, 1H), 7.77 (m, IH), 7.64 (d, J= 8.6 Hz, I H), 7.60 (m, IH), 6.21 (d, J= 6.1 Hz, I H), 4.00 - 4.06 (m, 4H), 3.93 - 4.00 (m, 4H). Mass Spectrum (LCMS, EST pos.) Calcd. For C28H2 5O3: 476.2 ( vi · ! i !. Found 476.4.

Following the procedure described in Example 17 above, and substituting suitably selected and substituted reagents, starting materials and conditions as would be readily apparent to those skilled in the art, the following representative compounds of the present invention were prepared.

4-(8-Morpholino-2-(pyridin-2-ylethynyl)imidazo[l ,2- /jjpyridazin~3-yJ)benzoic acid

TI-NMR (400 MHz, DMSO-de) δ (ppm): 8.62 (d, ./ = 4.9

Hz, 1 H), 8.27 (d, J - 5.8 Hz, I H), 8.21 (d, J - 8.4 Hz, 2ίί), 8.1 1 (d, J = 8.4 Hz, 2H), 7.87 (dt, J - 7.8, 7.8, 1.7 Hz, IH), 7.66 (d, J = 7.8 Hz, IH), 7.43 (ddd, J = 7.5, 4.6, 0.7 Hz,

I H), 6.50 (d, J = 5.9 Hz, I H), 4.01 (m, 4H), 3.82 (m, 4H).

Mass Spectrum (LCMS, ESI pos.) Calcd. For C ₂ 4ii ₂ o ₅ 0 ₃ :

426.2 (M + H), Found 426.4.

Cpd No. Characterization

4-(2-(Benzo[i/]thiazol-2-ylethynyl)-8- morpholir!oirnidazo[I,2- ?]pyiidazm-3-yl)ber!zoic acid ¾H-NMR (400 MHz, DM80-d ₆ ) δ (ppm): 8.33 (d, J - 5.8

87 Hz, 1H), 8.23-8.10 (m, 6H), 7.67-7.55 (m, 2H), 6.56 (d, J =

5.9 Hz, 1H), 4.06 (m, 4H), 3.85 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C26H20N5O3S: 482.3 (M + H), Found 482.4,

4-(2- ((5 -Cyanopyridin-2~yl)ethynyi) - 8- inorpholinoiraidazofl ^.- ijpjT'idaziri-S-y besizoic acid 'H-NMR (400 MHz, DMSO-de) δ (ppin): 9.08 (d, J ------ i .4

Hz, I H), 8.40 f ili!. ./ 8.2, 2.0 Hz, H), 8.31 (d, J = 5.8 Hz,

96

Hi), 8.22 (d, J 8.4 Hz, 2H), 8.15 (d, ./ 8.4 Hz, 2H), 7.88 (d, J = 8.1 Hz, IH), 6.54 (d, J - 5.9 Hz, IH), 4.04 (m, U s. 3.85 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C25FL9 6O3: 451.2 (M + H), Found 451.3.

4-(8-Morpholino-2-((5-(trifluoromethyl)pyridin-2- yl)ethynyl)imidazo[l ,2- ?]pyridazin-3-yl)benzoic acid Ί-Ϊ-NM (400 MHz, DMSO-de) δ (ppm): 9.05 (s, I H), 8.34-8.28 (m, 2H), 8.24 (d, J - 8.4 Hz, 2H), 8.15 (d, J - 8.5

97

Hz, 2H), 7.90 (d, J ----- 8.2 Hz, IH), 6.54 (d, ./ = 6.0 Hz, IH), 4.05 (m, 4H), 3.85 (m, 4H).

Mass Spectrum (LCMS, ESI pos.) Calcd. For C25H19F3N5O3: 494.1 (M + H), Found 494.4. Cpd No. Characterization

4-(2-((lH-Benzo[<3i]imidazol-2-yl)et ynyl)-8- morpholir! irnidazo[i,2- ?]pyiidazm-3-yl)ber!zoic acid 1 H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.31 (d, J = 5.7 Hz, IH), 8.23 (d, J ----- 8.3 Hz, 2H), 8.15 (d, J = 8.4 Hz, 2H),

108

8.12 (s, IH), 7.62 (dd, J = 5.9, 3.1 Hz, 2H), 7.32 (dd, J = 6.0, 3.1 Hz, 2H), 6.54 i d../ 5.9 Hz, IH), 4.03 (m, 4H), 3.83 (s, 4H). Mass Spectram (LCMS, ESI pos.) Calcd. For C26H ₂ ]N ₆ 03: 465.2 (M + H), Found 465.4.

4-(2-((6-Methoxypyridin-2-yl)ethynyl)-8- morpho]moimidazo[l ,2-Z?]pyridazin-3-yl)bei zoic acid 'H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 13.12 ( br s, IH), 8.29 (d, ,/ 5.7 Hz, IH), 8.25 (d, ./ 8.3 FIz, 2H), 8.13 (d, J

109 - 8.4 Hz, 2H), 7.77 (t J = 7.8 Hz, IH), 7.27 (d, J = 7.2 Hz,

IH), 6.90 (d, J = 8.4 Hz, 1 H), 6.52 (d, J = 5.8 Hz, IH), 4.01 (m, 4H), 3.89 (s, 3H), 3.82 (m, 4H). Mass Spectrum

(LCMS, ESI pos.) Calcd. For C25H22N5O4: 456.2 (M + H), Found 456.4.

4-(2-((5-Methox ^r pyridin-2-yl)ethynyr)-8- morpholmo ^" irnidazo[l,2-i>]pyridazin-3-yl)benzoic acid 'H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 8.35 (d, J = 2.9

110 Hz, IH), 8.28 (d, J - 5.8 Hz, IH), 8.23 (d, J = 8.5 Hz, 2H),

8.12 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 8.6 Hz, IH), 7.46 (dd, ./ - 8.7, 3.0 Hz, IH), 6.50 (d, .7 - 5.9 Hz, I H), 4.01 (m, 4H), 3.88 (s, 3H), 3.82 (m, 4H). Mass Spectram (LCMS, ESI pos.) Calcd. For C^^NsC^: 456.2. (M + H), Found 465.4. No.

4-(8-Morpholino-2-((6-(trifluoromethyl)pyridm-2- yl)ethynyl)imidazo[l ,2-6]pyridazin-3-yl)benzoic add

¾H-NMR (400 MHz, DM80-d ₆ ) δ (ppm): 8.30 (d, J - 5.8

Hz, 1H), 8.24 (d, J ----- 8.6 Hz, 21 1 ;·. 8.19 (d, ./ = 7.9 Hz, IH), 8.14 (d, J = 8.6 Hz, 2H), 7.96 (dd, J = 7.8, 2.7 Hz, 2H),

6.52 (d, J = 5.9 Hz, IH), 4.03 (m, I H), 3.82 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C25H19F3N5O3:

494.1 (M + H), Found 494.4.

Example 18

3-(8-Mo^holino-2-(qumo]m-2-ylethy^^^ acid

)

A. 4-(3-Bromo-2-ethy morphoiine, 18a

To a suspension of compound 14b (0.78 g, 2.5 mmol) in MeOH (20 mL) was added K ₂ C0 ₃ (1.1 g, 7.5 mmol) and a solution of dimethyl (l-diazo-2- oxopropyl)phosphonate (0.53 g, 2.7 mmol) in MeOH (5 mL). The reaction mixture was stirred at rt overnight, diluted with DCM (200 mL), and washed with water (20 mL) and brine (20 mL). The organic layer was dried over MgS0 ₄ , filtered and concentrated. The residue obtained was purified by flash column chromatography on silica gel (0-20 % EtOAc/DCM) to give compound 18a as a white solid. 'H-NMR (400 MHz, CDCk) δ (ppm): 8.13 (d, J= 5.56 Hz, 1H), 6.1 1 (d, J= 5.56 Hz, 1H), 3.94 ^■■ 4.01 (m, 4H), 3.86 - 3.93 (m, 4H), 3.41 (s, 1H).

B. 4~(3-Bromo-2~(quinolin~2-ylethyny^

1. 8 lb

A mixture of compound 18a (0.74 g, 2.4 mmol) and 2-bromoquinoline (2.0 g, 9.6 mmol) in a vial was evacuated and back-flushed with Argon. Dry DMF (10 mL) and DIEA (1.7 mL, 9.7 mmol) were added via syringe and the mixture was

deoxygenated by bubbling Argon through the stirred solution for 5 min. To the mixture was added Cul (46 mg, 0.24 mmol) and dic orobis(triphenylphosphine)palladium(II) (0.17 g, 0.24 mmol). The reaction mixture was stirred at it overnight, and was poured into water (50 mL). The mixture was extracted with EtOAc (3 x 30 mL). The combined organic extracts were washed with water (20 mL) and brine (20 mL), and dried over Na ₂ S0 ₄ . The mixture was filtered, and the filtrate was concentrated to obtain a residue which was purified by flash column chromatography on silica gel (30- 70 % EtO Ac/heptane) to obtain compound 18b as a white solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C ₂₁ H ₁₆ Br ₅ 0: 434.1 (M-i-H); found: 434.2.

C. tert-Butyl 3-(8-mo hoii o-2-(qui olin-2-ylethy yl)imidazo[l ,2- ] yridazin-3- yl)benzoate, 18c

To a stirred solution of compound 18b (51 mg, 0.12 mmol), (3~(tert- butoxycarbonyl)phenyl)boromc acid (39 mg, 0.18 mmol), and cesium carbonate (0.12 g, 0,36 mmol) in degassed 1,4-dioxane (4 mL) and water (0.5 mL) under Argon was added dichloro(diphenylphosphinoferrocene)palladium (II) (4.3 mg, 0.0059 mmol). The resulting mixture was heated at 80 °C for 2 h, allowed to cool to rt, and treated with EtOAc (10 mL). The organic layer was washed with waf er (10 mL) and brine (10 mL), and dried over Na ₂ S0 . The mixture was filtered, and the filtrate was concentrated. The resulting residue was purified by flash column chromatography on silica gel (20- 100 % EtOAc/heptane) to give compound 18c as a brown oil Mass Spectrum (LCMS, ESI os.): Calcd. for C32H29N5O3: 532.2 ( +H); found: 532.5.

D. 3-(8-Mo holmo-2-(qumolm-2-yleth yl)imidazo[l,2-^] ridazm-3-yl)beIlzok acid (Cpd 88)

To a solution of compound 18c (53 mg, 0.10 mmol) in DCM (2 mL) was added TFA (2 mL). The resulting mixture was stirred at rt for 1 h, and concentrated. The residue obtained was stirred in Et¾0 (5 mL) for 1 h. The solid obtained was collected by filtration, and dried in vacuo to give the title compound 88 as an orange solid. ^] H- NMR (400 MHz, DMSO- ) δ (ppm): 8.81 (s, I H), 8.38 - 8.48 (m, 2H), 8.31 i d. J= 6.1 Hz, IH), 7.97 - 8.1 1 (m, 3H), 7.84 (t, J= 7.8 Hz, 1H), 7.71 - 7.79 (m, 2H), 7.61 - 7.71 (m, I H), 6.51 (d, J= 6.1 Hz, IH), 4.04 (br. s., 4H), 3.85 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C ₂ gH _2! N ₅ 0 ₃ : 476.2 (M+H), Found 476.4. Example 19

4-(8 -Morpholino-2 -(i- (qirmolin-2 -yl)azeiidin-'3-yl)m

yljbenzoie acid (Cpd 57}

A, 6-Chloro-4-morpholi

4-Bromo-6-chloropyridazin-3-amine (2.0 g, 9.6 mmol) was placed in an 8 ml, vial equipped with a stir bar, and ACN (5 niL) and morpholine (8.3 mL, 96 mmol) were added. The mixture was stirred at 70 °C for 18 h. The reaction was cooled to rt, the suspension obtained was filtered, and the filtercake was washed with ACN (10 mL). The filtrate was concentrated under reduced pressure and the residue obtained was dissolved in DCM (50 mL) and washed with saturated NaHCOj solution (2. x 30 mL). The aqueous washings were combined and extracted with DCM (3 x 30 mL). The combined organic extracts were dried over MgS0 ₄ and filtered. The solvent was removed under reduced pressure. The crude residue was triturated with EtOAc (30 mL) then the solid was isolated by filtration to give compound 19a. Mass Spectmm (LCMS, ESI pos.): Calcd. for C ₈ H _n ClN ₄ 0: 215.1 (M+H); found: 215.1.

B. iert-Butyl 3-(6-chloro-8-morpholinoimidazo[l,2-0]pyridazin-2-yl)azetidi ne-l- carboxylate, 1 to

A solution of ter/~butyl 3-(2-bromoacetyi)azetidine-l -carboxylate (207 mg, 0.744 mmol) in DMF ( i mL) was added to a solution of compound 19a (99.8 mg, 0.465 mmol) and Na ₂ HP0 ₄ (165 mg, 2.50 mmol) in DMF (20 mL). The resulting mixture was stirred at rt overnight. The reaction mixture was concentrated in vacuo and the residue obtained was purified by normal phase column chromatography on silica gel (0- 100% EtO Ac/heptane) to obtain compound 19b. Mass Spectrum (LCMS, ESI pos.): Calcd. for d^ClN^O?: 393.2 (M+H); found: 393.3.

C. iert-Butyl 3-(8-morphoiinoimidazo[I,2-0]p Tidazm-2-yl)azetidme-I- carboxylate, 19c

Compound 19b (430 mg, 1.09 mmol) and ammonium formate (344 mg, 5.45 mmol) were placed in a 20 mL vial equipped with a stir bar and dissolved in a mixture of THF (8 mL) and MeOH (4 mL). 10 % Pd/C ( 1 16 mg, 0.109 mmol) was then added. The reaction mixture was stirred at 70 °C for 3 h, cooled to rt, and filtered through a pad of diatomaceous earth. The solids were washed with MeOH (2 x 1 0 mL). The combmed filtrates were concentrated under reduced pressure and the residue obtained was dissolved in EtOAe (100 mL) and washed with water (2 x 25 niL) and brine (25 mL). The combined aqueous washings were extracted once with EtOAe (25 mL) and the organic extracts were combined, dried overMgS0 ₄ , and filtered. The solvent was removed under reduced pressure to obtain compound 19c. Mass Spectrum (LCMS, ESI pos.): Calcd. for CJ ₉ H25N ₅ 0J: 360.2 (M+H); found: 360.3.

D. ten-Butyl 3-(3-bromo-8-morpholinoimidazo[I,2- ?]pyridazin-2-yl)azetidine-I- carbox late, 19d

Compound 1 c was brominated as described in the Example 1 , Step D to obtain compound 19d. Mass Spectrum (LCMS, ESI pos.): Calcd. for ¾Η24ΒΓΝ ₅ <¾: 438.1 (M+H); found: 438.3. ieri-Butyl 3-(3-(4-(ethoxycarbonyl)phenyl)-8-morpholinoimidazo[l ,

Zjjpyridazm-2-y1)az

Compound 19d was coupled with (4-(ethoxycarbonyl) phenyi)boronic acid under Suzuki reaction conditions as described in Example 1 , Step E, to obtain compound 19e. Mass Spectmm (LCMS, ESI pos.): Calcd. for C^HwlSkOs: 507.2 (M+H); found: 507.3.

F. Ethyl 4-(8-mo hol ^" ino-2-(l -(qumolm-2-yl)azetidin-3-yl)imidazo[ l,2- 6]pyridazin-3-yl)benzoate, 19f

To a solution of compound 19e ( 170 mg, 0.335 mmol) in DCM (2 mL), TFA (2 mL) was added. The resulting mixture was stirred at rt for 1 h and concentrated. The resulting residue was dried in vacuo for 4 h and suspended in ether. The mixture was concentrated and the resulting residue was dried in vacuo overnight to obtain ethyl 4- (6-( azetidin-3 -yl)-4-morpholinopyrrolo[ 1 ,2-&]pyridazin-7-yI)benzoate trifluoro acetic acid salt (19g), which was used without further purification in the next step.

To a solution of compound 1 g (222.4 mg, 0.35 mmol) in toluene (2.5 mL), ( s .( () : (570 mg, 1.75 mmol) was added. The resulting mixture was stirred at rt for 30 min under argon and Pd?(dba)3 (32. mg, 0.035 mmol), BINAP (43 mg, 0.07 mmol) and 2-bromoquinoline (146 mg, 0.700 mmol) were added. The reaction mixture was stirred at 80 °C for 6 h. The reaction mixture was allowed io cool to rt and filtered through a pad of diatomaceous earth. The filtrate was concentrated and the residue obtained was purified by normal phase column chromatography on silica gel (0-100%

EtO Ac/heptane) to obtain compound 191 Mass Spectrum (LCMS, ESI pos.): Calcd. for CjiHjoN ₆ Oj: 535.2 (M+H); found: 535.4.

G. 4-(8-Morpholino-2-(l -(qumo]in-2-yl)azetidin-3-yl)imidazo[l,2-6]pyri.dazin-3- yl)benzoic acid, Cpd J 57

To a solution of compound 19f ( 98 mg, 0.18 mmol) in EtOH (2 mL) and THF (2 ml . ) was added 1 M NaOH (0.90 mL, 0.90 mmol). The resulting mixture was stirred at 50 °C for 3 h and allowed to cool to rt, and then treated with 3 mL of HO Ac. Saturated NaCl solution (5 mL) was added and the mixture was extracted with DCM (3 x 30 mL). The DCM layers were combined, dried over MgSO^ filtered, and concentrated. The residue obtained was dried under reduced pressure, suspended in ether (50 mL), and sonicated for 10 min. The white solid obtained was collected by suction filtration to obtain the title compound 157. Ή-NMR (400 MHz, CD ₃ QD) δ (ppm): 8.28 (d, J= 9.6 Hz, 1H), 8.2.1 (d, J = 8.6 Hz, 2H), 8.10 (d, J= 5.6 Hz, 1H), 7.95 (d, J= 8.6 Hz, 1H), 7.84 i d. ./ 8.1 Hz, 1H), 7.78 (t, J = 7.8 Hz, IH), 7.72 (d, J= 8.6 Hz, 2.H), 7.47 - 7.54 (m, I H), 6.89 (d, /= 9.6 Hz, IH), 6.32 (s, 1H), 4.80 - 4.98 (m, 4H), 4.46 - 4.57 (m, I H), 3.97 - 4.05 (m, 4H), 3.86 - 3.94 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. For CaiHaeNeOj: 507.2 (M + H), Found 507.4. Example 20

8-Morpholino - 3 -(6-(piperazin- 1 -yl)pyridin- 3 -yl) -N-(quinoiin-2-yl)imidazo[l,2- 6]pyridazine-2-carboxamide trifluoroacetic acid salt (Cpd 3)

A. Ethyl 3-(6-chloro yridi -3-yl)-8-mo holinoimidazo[l,2-i>] yridazme-2- carboxylate, Ida

Compound 5c, 5~bromo~2-chloropyridine (12.7 g, 64.1 mmol), Pd(OAc)? (671 nig, 2.99 mmol), PPh¾ (784 mg, 2.99 mmol), and KOAc (12.6 g, 128 mmol) were placed in a 250 mL pressure vessel equipped with a stir bar and then the flask was flushed with Argon. Dry DMA (150 mL) was added and then the vessel was capped under an argon purge. The reaction was stirred at 110 °C for 8 h. The reaction was cooled to rt, diluted with water (300 mL), and filtered. The precipitate was washed with water (2 x 200 mL), and then the solid was dissolved in DCM (500 mL). To this solution was added 50 g SiO? and the solvent was removed under reduced pressure. The material was dry-loaded onto a 240 g Si0 ₂ pre-packed column and eluted with 0- 60 % EtOAc/DCM. The fractions containing (he product were pooled and concentrated to afford a residue that was triturated with EtOAc. The solid was isolated by filtration, washed with EtOAc (2 x 50 mL), and then dried under reduced pressure to afford compound 28a, H-NMR (400 MHz, CDCL) 8 (ppm): 8.65 (d, J - 2.0 Hz, 1H), 8.04 (d, J - 5.9 Hz, IH), 7.97 (dd, J = 8.2, 2.3 Hz, 1H), 7.47 (d, J = 8.3 Hz, 1H), 6.14 (d, J = 5.9 Hz, IH), 4.34 (q, J - 7.1 Hz, 2H), 4.01 - 4.1 1 (m, 4H), 3.90 - 3.99 (m, 4H), 1.29 (t, J - 7.1 Hz, 3H).

B. Ethyl 3-(6-(4-(Zer/-hutoxycarbonyl)piperazm- 1 ~yl)pyridin~3-yl)~8- morpholino 0b

Compound 20a (12.0 g, 30.9 mmol), K ₂ C(¾ (4.28 g, 30.9 nimol), and \ -tert- butoxypiperazine ( 1 1.5 g, 61.9 mmol) were placed in a 250 mL pressure vessel equipped with a stir bar. The vessel was flushed with argon and then dry NMP was added via cannula. The capped vessel was stirred at 130 °C for 72 h and then cooled to rt and poured into water (300 mL). The precipitate was isolated by filtration and washed with water (3 x 50 mL). The solid was dissolved in DCM and

chromatographed on a 160 g Si0 ₂ pre-packed column eluting with 0-60 %

EtOAc/DCM to afford compound 20b. Ή-NMR (400 MHz, CDC ^' ! ; ! δ (ppm): 8.45 (s, IH), 8.03 {·:!. J - 5.4 Hz, H), 7.80 (d, J - 7.8 Hz, I H), 6.75 (d, J - 8.8 Hz, IH), 6.09 (d, J = 5.4 Hz, i l l ). 4.35 fq, J = 7.0 Hz, 2H), 3.99 - 4.09 fm, 4H), 3.89 - 3.99 (m, 4H), 3.60 - 3.70 (m, 4H), 3.50 - 3.60 (m, 41 ! ) 1 .50 (s, 9H).

C. 3-(6-(4-(ier/-Butoxycarbonyl)piperazin- 1 -yl)pyridin-3-yl)-8- morpholinoimidazo[i,2-6jpyridazine-2.-carboxyiic acid, 20c

Compound 20b (2,07 g, 3,85 mmol) was placed in a 100 mL round bottom flask equipped with a stir bar and then THF (35 mL) was added. 1M NaOH (7.7 mL) was added and the reaction was stirred at rt for 3 d. Additional 1 M NaOH (8 mL) was added follo wed by addiiion of MeOH until the reaction went homogeneous. The reaction was stirred for 4 h and then the solvent was removed under reduced pressure. The residue was dissolved in water (100 mL) and extracted with Et ₂ 0 (2 x 20 mL). The aqueous phase was acidified with 10 % citric acid resulting in a precipitate. The mixture was diluted with DCM (100 mL) and the organic phase was separated. The aqueous layer was extracted with DCM (3 x 50 mL) and then the combined organic extracts were washed with water (30 mL) and dried over MgS0 ₄ . The solution was filtered and the solveni was removed under reduced pressure to afford compound 20c.

Ή-NMR (400 MHz, CDCI3) δ (ppm): 8.58 (d, J = 2.0 Hz, 1H), 8.06 (d, J = 5,6 Hz, 1H), 7.91 (dd, J - 8.9, 2.3 Hz, IH), 6.76 (d, J = 8.8 Hz, 1H), 6.14 (d, J = 5.9 Hz, 1H), 3.97 - 4.06 (m, 4H), 3.90 - 3.97 (m, 4 S i s. 3.61 - 3.70 (m, 4H), 3.52 - 3.60 (m, 4H), 1.50

(s, 9H). ier, '-Butyl 4-(5-(8- o olino-2-(q i oίϊ ~2-ylcarbamoyl)i idazo[l

0jpyTidazin-3-yl)p\Tidm-2-yl)piperazine- 1 -carboxylate, 2iM

Compound 2(te (2.58 mg, 0.506 mmol) was placed in a 20 mL vial equipped with a stir bar and then DCM (4 mL) and DMF (10 iiL) were added. Oxalyl chloride (66.2 μί, 0.759 mmol) was added dropwise via syringe and the reaction was stirred for 20 min. The soivent was removed under reduced pressure. The residue was dissolved in DCM (25 mL) and then DIEA (440 _s uL, 2.53 mmol) and 2-aminoquinoline (87.5 mg, 0.607 mmol) were added sequentially. The reaction was stirred at ri for 16 h and then poured into water (20 mL) and separaied. The aqueous layer was extracted wiih DCM (3 x 10 mL) and the combined organic layers were dried over MgS0 ₄ and filtered. The solvent was removed under reduced pressure. The crude residue was chromatographed on a 12 g Si0 ₂ pre-packed column eluting with 0- 100 % EtOAc/DCM to afford compound 20d. Ή-NMR (400 MHz, CDC1 ₃ ) δ (ppm): 9.99 (s, 1 H), 8.59 - 8.64 (m, 2H), 8.16 (d, J = 9.0 Hz, 1H), 8.06 (d, J = 5.6 Hz, 1H), 7.96 (dd, J = 8.8, 2.4 Hz, 1H), 7.90 (d, j = 8.3 Hz, 1H), 7.78 (d, J = 8.1 Hz, I H), 7.65 - 7.71 (m, H), 7.42 - 7.48 (m, i l l }. 6.79 (d, J - 8.8 Hz, IH), 6.15 (d, J - 5.9 Hz, I H), 4.04 - 4.10 (m, 4H), 3.98 - 4.04 (m, 4H), 3.63 ^■■ 3.70 (m, 4H), 3.54 - 3.60 (m, 4H), 1.50 (s, 9H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C3 ₄ H37N9O ₄ : 636.3 (M + H), Found: 636.4.

E. 8-Mo^holino-3-(6-(piperazm- l -yl)pyridin-3-yl)-N-(qumolin-2-yl)imidazo[l ,2- 6]pyridazine-2~carboxamide trifluoroaceiaie saii, Cpd 3

Compound 20d (191 mg, 0.300 mmol) was placed in an 8 mL vial equipped with a stir bar and then DCM (4 mL) was added. Once the solution was homogeneous, TFA (1 mL) was added dropwise. The mixture was stirred at rt for 4 h. The solvent was removed under reduced pressure. The residue was dissolved in DCM ( 10 mL) and then the solvent was removed under reduced pressure again. The residue was triturated with Et?0 (20 mL), resulting in a yellow precipitate, which was isolated by filtration and washed with Et?0 (2 x 1 0 mL). The residual solvent was removed under reduced pressure to afford the title compound 3. Ή-NMR (400 MHz, DMSQ-ifc) δ (pprn): 10.35 (s, 1 H), 8.78 (br. s., 2H), 8.50 (d, J = 2.2 Hz, lH), 8.41 (d, J - 9.0 Hz, 1H), 8.35 (d, J = 9.0 Hz, IB), 8.21 (d, J = 5.9 Hz, 1H), 7.92 - 8.00 (m, 2H), 7.89 (d, J = 8.6 Hz, lH), 7.70 - 7.79 (m, lH), 7.48 - 7.58 (m, IH), 7.07 (d, J - 9.0 Hz, i ff), 6.50 (d, J - 5.9 Hz, Iff), 4.04 - 4.16 (m, 4H), 3.80 - 3.91 (m, 8H), 3.20 - 3.29 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C29H29N9O2: 536.3 (M + H), Found: 536.3.

Example 21

iV-((8-Moipholino-3-(6-(piperazin- 1 -yl)pyridin-3-yl)imidazo[ 1 ,2-5]pyridazm-i yl)methyl) salt (Cpd 4)

A. ter t-Butyl 4-(5-(2-(hydroxymethyl)-8-morpholmoimidazo[l ,2- )]pyridazm-3- yl)pyridin-2-yl)piperazine- 1 -carboxylate, 21a

Compound 20to (2.07 g, 3.85 mmol) was placed in a 100 mL round bottom flask equipped with a stir bar and then the flask was evacuated and backfiushed with argon. Dry THF (40 mL) was added via syringe and then the solution was cooled to 0 °C in an ice bath. 1 M L1AIH4 in THF (3.85 mL, 3.85 mmol) was added via syringe and then the ice bath was removed and the reaction was allowed to warm to rt. The reaction was stirred at rt for 1 h and then poured into saturated NH4CI solution (100 mL). The aqueous mixture was extracted with EtOAc (4 x 50 mL) and then the combined organic extracts were dried over MgSQ ₄ and filtered. The solvent was removed under reduced pressure to afford compound 21a. ¹ H-NMR (400 MHz, CDCI3) δ ppm): 8.48 (d, J = 2.2 Hz, IH), 8.01 (d, J = 5.4 Hz, IH), 7.90 (dd, J = 8.8, 2.4 Hz, 1H), 6.77 (d, J = 9.0 Hz, 1H), 6.09 (d, J - 5.6 Hz, 1H), 4.83 (s, 2H), 3.93 (d, J - 3.4 Hz, 8H), 3.51 - 3.66 (m, 8H), 1.50 (s, 9H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C25H33N7O4: 496.3 (M+H), Found: 496.3.

13. tert-Butyl 4-(5-(2-fomiyl-8-mo^holinoiTnidazo[l,2-0]pyridazin-3-yl)pyri din-2- yl)piperazine- -carboxylate, 211)

Compound 21a (500 mg, 1.01 mmol) was placed in an 8 mL vial equipped with a stir bar and then DCM (2 mL) was added. Dess-Martin periodinane (471 mg, 1.1 1 mmol) was added as a solid and the reaction was stirred at rt for 20 min. The reaction was diluted with DCM (20 mL) and washed with saturated NaHCC solution (2 x 20 mL). The organic phase was dried over MgS0 ₄ and filtered. The solvent was removed under reduced pressure. The crude product was chromatographed on a 40 g SiO? prepacked column eiutmg with 0-60 % ACN/DCM to afford compound 21b. I i- N.VIR (400 MHz, CDCI ₃ ) δ (ppm): 10.12 (s, I H), 8.58 (d, J - 2.2 Hz, I H), 8.06 (d, J - 5.6 Hz, IH), 7.94 (dd, J = 9.0, 2.4 Hz, IH), 6.78 (d, J = 8.8 Hz, IH), 6.1 i (d, J = 5.9 Hz, IH), 4.03 - 4.11 (m, 4H), 3.91 - 3.97 (m, 4 S i s. 3.63 - 3.71 (m, 4H), 3.52 - 3.60 (m, 4H), 1.50 (s, 9H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C ₂₅ H3iN ₇ 04: 494.3 (M+H), Found: 494.3.

C. iert-Butyl 4-(5-(8-morpholino-2-((qumolin-2-ylamino)methyl)imidazo[ 1 - 6]pyridazin-3 -yl)pyridin-2-yl)piperazine- 1 -carboxylate, 21c

Crude compound 21b (140 mg, 0.284 mmol) was placed in a 50 ml. round bottom flask equipped with a stir bar and then 2-aminoquinoline (49.1 mg, 0.340 mmol) was added. DCE (10 mL) and AcOH (32.5 μ.Ε, 0.567 mmol) were added and then NaBH(QAe)3 (180 mg, 0.851 mmol) was added as a solid. The reaction was stirred at rt. for 20 h and then additional NaBH(OAc)j (60.0 mg, 0.2.83 mmol) was added. After 24 h, more NaBH(OAc)3 (60.0 mg, 0.283 mmol) was added and the reaction was stirred for an additional 20 h. The reaction was poured into saturated NaHCO solution (30 mL) and extracted with DCM (3 x 10 mL), and then the combined organic extracts were dried over MgS0 ₄ and filtered. The solvent was removed under reduced pressure. The crude product was chromatographed on a 12 g Si€>2 pre-packed column eluting with 0- 100 % ACN/DCM to afford compound 21c. Ή-NMR (400 MHz, CDC1 ₃ ) δ (ppm): 8.52 (d, J = 2.0 Hz, 1 H), 8.00 (d, J = 5.4 Hz, 1H), 7.88 (dd, j = 8.8, 2.2 Hz, 1H), 7.80 (d, J = 9.0 Hz, I H), 7.69 (d, J = 8.3 Hz, lH), 7.58 (d, J - 7.8 Hz, I H), 7.52 (t, j - 7.7 Hz, I H), 7.21 (t, j - 7.5 Hz, I H), 6.76 (d, J - 8.8 Hz, I H), 6.71 (d, J = 9.0 Hz, IH), 6.08 (d, J = 5.9 Hz, IH), 5.49 (br. s., IH), 4.87 (d, J = 4.9 Hz, 2H), 3.88 - 4.01 (m, 8H), 3.52. ^■■ 3.65 (m, 8H), 1.50 (s, 9H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C34H39N9O3: 622.3 (M+H), Found: 622.3.

D. Λ-((8-Mo holino-3-(6- piperazm- l -yl) yridin-3- l)irnidazo[l ,2-ό]pyridazm-2- yl)methyi)quinoiin--2-amine trifluoroacetic acid salt, Cpd 4

Compound 21 c was deprotected as described in Example 20, Step D, to obtain the title compound 4. Ή-NMR (400 MHz, DMSQ- ) δ (ppm): 13.04 (br. s., IH), 10.01 (br. s., IH), 8.93 (br. s., 2H), 8.22 - 8.44 (m, 2H), 8.15 (d, J = 5.6 Hz, IH), 7.86 - 7.99 (m, 3H), 7.81 (t, J = 7.2 Hz, IH), 7.53 (t, J = 7.0 Hz, IH), 7.02 ^■ 7.27 (m, 2H), 6.40 (d, J = 5.6 Hz, I H), 4.93 (br. s., 2H), 3.85 (br. s„ 4H), 3.79 (br. s., 4H), 3.53 - 3.57 (m, 4H), 3.22 (br. s., 4H). Mass Spectrum (LCMS, ESI pos.) Cafcd. For C29H31N9O: 522.3 (M+H), Found: 522.2.

Example 22

-(6-(Piperazm-l-yl)pyridm-3-yl)-2-((quinolin-2-ylthio)methyl )imidazo[l, / ]pyridazin-8 d salt (Cpd 6)

A. (ert-Butyl 4-(5-(8-moφholmo-2-((q^ΰnolin-2- lthio) ^" methyl)imidazo[l,2- 6]pyridazin-3 - a

A. Compound 21a (152 mg, 0.307 mmol) was placed in an 8 mL vial equipped with a stir bar and then DCM (2 mL) and D1EA (107 μ,Ε, 0.615 mmol) were added. The solution was cooled to 0 °C and MsCi (35.8 μΕ, 0.461 mmol) was added drop ise via microsyringe. The reaction was stirred at 0 °C for 1 min and then ihe solvent was removed under reduced pressure. The erode material was placed in a 50 mL round bottom flask equipped with a stir bar and then 2-qumoimeth ol (56.2 mg, 0.338 mmol) and K ₂ CO ₃ (63.7 mg, 0.461 mmol) were added. Dry ACN (10 mL) was added and then the reaction was stirred at rt for 20 h. The reaction was diluted with water (20 mL) and extracted with DCM (3 x 30 mL). The combined organic extracts were washed with brine (20 mL) and then dried over MgS0 ₄ and filtered. The solvent was removed under reduced pressure. The crude product was chromatographed on a 12 g Si0 ₂ pre-packed column eluting with 0-60 % ACN/DCM to afford compound 22a. U-Vvi R (400 MHz, CDC1 ₃ ) δ (ppm): 8.54 (d, J - 2.2 Hz, IH), 7.96 (d, J - 5.6 Hz, i 1 1 i. 7.84 (d, J - 8.6 Hz, 2H), 7.87 (d, J - 8.8 Hz, IH), 7.70 (d, J - 7.8 Hz, IH), 7.56 - 7.66 (m, I H), 7.38 - 7.47 (m, IH), 7.26 (d, J = 6.1 Hz, Hi), 6.69 (d, J = 8.8 Hz, IH), 6.03 (d, J = 5.6 Hz, I H), 4.85 (s, 2H), 3.89 - 3.98 (m, 4H), 3.81 ^■ 3.89 (m, 4H), 3.56 (d, J = 5.4 Hz, 8H), 1.49 (s, 9H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C _M H _?8 N ₈ i¾S: 639.3 (M+H), Found: 639.4.

B. 4-(3-{6-(Piperazin- l-yi)pyridin-3-

Z>]pyridazin-8-yi)morpholine trifiuoroacetie acid salt, Cpd 6

Compound 22 was deprotected as described in Example 20, Step D, to obtain the title compound 6. Ή-NMR (400 MHz, DMSO- ) δ (ppm): 8.79 (br. s., 2H), 8.48 (d, J = 2.2 Hz, IH), 8.17 (d, J - 8.6 Hz, IH), 8.09 (d, J - 5.9 Hz, IH), 7.87 ^■ 7.96 (m, 2H), 7.70 (d, J = 3.4 Hz, 2H), 7.47 - 7.56 (m, I H), 7.43 (d, J = 8.6 Hz, IH), 7.06 (d, J = 8.8 Hz, I H), 6.36 (d, J - 5.9 Hz, I H), 4.76 (s, 2H), 3.88 - 3.99 (m, 4H), 3.76 - 3.82 (m, 4H), 3.69 - 3.76 (m, 4H), 3.22 (br. s., 4FI). Mass Spectrum (LCMS, ESI pos.) Calcd. For C ₂ 9H ₃ oN _s OS: 539.2 (M+H), Found: 539.2.

Example 23

N-(8-Morpholino ^■ 3 ~(6-( piperazin- 1 -yl)pyridin- 3 -y l)imidazo [ 1 ,2-6]pyridazin-2- yl)quinoline-2-carboxamide trifluoroacetic acid salt (Cpd 8)

A, teri-Butyl 4-(5-(8-mo holino-2-(((2-(trimethylsilyl)ethoxy)c rbonyl)aImno) imidazo[l 23a

Compound 20c (250 mg, 0,491 rnmoi) was placed in a 20 mL vial equipped with a stir bar and then DCM (4 mL) and DMF (10 μΐ,) were added. Oxalyl chloride (100 μί, 1.15 mmol) was added dropwise via syringe and then the reaction was stirred for 20 min. The solvent was removed under reduced pressure. The residue was dissolved in DCM (25 mL) and then TMSNj (100 μϊ-, 0.760 mmol) was added. The reaction was stirred at rt for 16 h and then additional TM8N ₃ (100 μΐ-., 0.760 mmol) was added. The reaction was stirred at rt for 24 h and then the solvent was removed under reduced pressure. The residue was dissolved in toluene ( 10 mL) and then 2- (trimethylsilyl)ethanol (1 mL, 7 mmol) was added. The flask was fitted with a reflux condenser and heated to 100 °C for 3 h. The reaction was cooled to rt and then the solvent was removed under reduced pressure. The residue was chromatographed on a 12 g Si0 ₂ pre-packed column eluting with 0-80 % ACN/DCM to afford compound 23a. Ή-NMR (400 MHz, CDCI3) δ (ppm): 8.51 (d, J = 2.2 Hz, 1 H), 7.99 (d, J = 5.6 Hz, 1H), 7.90 (dd, J - 8.9, 2.3 Hz, IH), 6.73 (d, J - 8.8 Hz, IH), 6.70 (s, 1H), 6.09 (d, J - 5.6 Hz, IH), 4.10 ^■■ 4.20 (m, 2H), 3.84 - 3.96 (m, 8H), 3.50 - 3.62 (m, 8H), 1.49 (s, 9H), 0.00 (s, 9H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C30H44N8O5S1: 625.3 (M+H), Found: 625.3. tert-Butyl 4-(5-(2~amino-8-mo^holinoiniidazo[l,2~6]pyridazin-3-yi)pyrid in- yljpiperazine- 1 -carboxylate, 23b

Compound 23b (88.3 ing, 0.141 mmol) was placed in an 8 mL vial equipped with a stir bar and then TBAF (59.2 mg, 0.212 mmol) and KF (16.4 mg, 0.283 mmol) were added as solids. ACN (1 mL) was added and then the reaction was stirred at 50 °C for 8 h. The mixture was cooled to rt and filtered. The precipitate was washed with ACN (2 x 2 mL) and then the solid was dissolved in DCM (5 mL) and filtered. The solvent was removed under reduced pressure to afford compound 23b. Ή-NMR (400 MHz, CDCI ₃ ) δ (ppm): 8.54 (d, J - 2.2 Hz, IH), 7.96 (dd, J - 9.0, 2.4 Hz, IH), 7.92 (d, J = 5.6 Hz, I H), 6.79 (d, J = 8.8 Hz, IH), 6.08 (d, J = 5.6 Hz, IH), 3.99 (s, 2H), 3.89 - 3.94 (m, 4H), 3.82 - 3.88 (m, 4H), 3.52 - 3.63 (m, 8H), 1.49 (s, 9H). Mass Spectrum (LCMS, ESI pos.) Calcd. For CwifeNgOj: 481.3 (M+H), Found: 481.3.

C. ten-Butyl 4-(5-(8-morpholino-2-(quino]iiie-2-carboxamido)imidazo[l ,2- Z?]pyridazm-3-yl)pyridm-2- l)piperazine- 1 -carboxylate, 23c

Quinaldic acid (24.4 mg, 0.141 nimol) was placed in an 8 mL vial equipped with a stir bar and then DCM (1 mL) and DMF (10 uL) were added. Oxalyl chloride (20.5 jiL, 0.235 mmol) was added dropwise via syringe and then the reaction was stirred at rt for 1 h. The solvent was removed under reduced pressure. The resulting acid chloride was dissolved in DCM (5 mL).

Compound 23b (56.4 mg, 0.1 17 mmol) was placed in a 50 mL round bottom flask equipped with a stir bar and then DCM (10 mL) and DIEA (40.9 iL, 0.235 mmol) were added. The DCM solution of the acid chloride (as prepared above) was added dropwise via pipette and then the reaction was stirred at rt for 4 h. The solvent was removed under reduced pressure and then the residue was chromatographed on a 4 g SiO? pre-packed column eluting with 0-60 % ACN/DCM to afford compound 23c. Ή- NMR (400 MHz, DMSO- .) 8 (ppm): 10.87 (s, IH), 8.62 (d, J = 8.3 Hz, IH), 8.53 (s, IH), 8.10 ^■ 8.27 (m, 4H), 7.89 - 8.02 (m, 2H), 7.73 ^■ · 7.82 (m, 1H), 6.92 (d, J - 9.0 Hz, 1H), 6.44 (d, J = 5.6 Hz, 1H), 3.97 (br. s., 4H), 3.79 (br, s., 4H), 3.50 (br. s., 4H), 3.38 (br. s., 4H), 1.40 (s, 9H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C34H37N9O4: 636.3 (M+H), Found: 636.4.

D. N-(8-Morphoimo-3-(6-(p peraz n- 1 -y3)pyridm-3-yl)imidazo[ 1 ,2~.6]pyridazin~2~ yl)qumorine-2-carboxamide triffuoroacetic acid salt, Cpd 8

Compound 23c was deproteeted as described in Example 20, Step D, to obtain the title compound 8. ^J H-NM (400 MHz, DMSO- ) δ (ppm): 10.87 (s, I H), 8.72 (br. s., 2H), 8.62 (d, J = 8.6 Hz, IH), 8.56 (d, J = 2.4 Hz, IH), 8.09 - 8.25 (m, 4H), 8.02 (dd, J - 8.8, 2.4 Hz, I H), 7.89 - 7.98 (m, IH), 7.72 - 7.83 (m, IH), 7.01 (d, J - 8.8 Hz, IH), 6.46 (d, J = 5.9 Hz, IH), 3.93 - 4.03 (m, 4H), 3.76 - 3.83 (m, 4H), 3.67 - 3.76 (m, 4H), 3.12 - 3.20 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C2 ₉ H2 _{9 9} O2: 536.3 (M+H), Found: 536.2. Example 24

4-(3-(6-(Pip6razin- 1 -y!jpyridm^

0]pyridazm-8-yl)morpbolir!e trifluoroacetic acid salt (Cpd 9)

A, Lithium quinoline-2-sulfinate, 24a

2-Qumolinethiol (161 mg, 1.00 mmol) was placed in an 8 mL vial equipped with a stir bar and then the vial was evacuated and backflushed with argon. Dry THF (1.5 mL) was added via syringe and then the solution was cooled to -78 °C. BuLi (0.400 mL. of a 2.5 M hexane solution, 1.00 mmol) was added dropwise via syringe maintaining the internal temperature below -60 °C and then a THF solution (2 mL) of 3-phenyI-2-(phenylsulfonyI)- l,2-oxaziridine (661 mg, 2, 10 mmol) was added dropwise via syringe maintaining the internal temperature below -64 °C. After completion of addition, the reaction was allowed to warm to -40 °C and stirred for 15 min, and then warmed to -10 °C when a precipitate formed. The reaction was stirred for 15 min at -10 °C and then the cooling baih was removed and the reaction was stirred at rt for 18 h during which time a precipitate formed. The solid was isolated by filtration and then the solid was washed with EtOAc (3 x 5 mL). The residual solvent was removed under reduced pressure affording compound 24a. Ή-NMR (400 MHz, D ₂ 0) δ (ppm): 8,51 (d, J = 8.6 Hz, 1H), 8.01 (d, J = 8.6 Hz, 1H), 7.96 (d, J - 8.3 Hz, 1 1 h. 7.88 (d, J = 8.6 Hz, IH), 7.78 - 7.85 (m, 1H), 7.61 - 7.69 (m, 1H). Mass Spectrum (LCMS, EST. pos.) Calcd. For C ₉ H ₇ N0 ₂ 8: 194.0 (M+H), Found: 194.1. B, iert-Butyl 4-(5-(8-mo holino-2-((quinolin~2-ylsulfonyl)methyl)inlid zo[l ,2~ i>]pyridazin-3-y{)pyridin-2-yl)piperazine- 1 -carboxylate, 24b

Compound 21a ( 152 mg, 0.307 mmol) was placed in an 8 mL vial equipped with a stir bar and then DCM (4 mL) was added and the solid dissolved. Thionyl chloride (54.7 μΐ,, 0.750 mmol) was added dropwise via microsyringe and then the reaction was stirred at rt for 5 min. The solvent was removed under reduced pressure. The residue was placed in a 40 mL vial equipped with a stir bar and then acetone was added. Compound 24a (199 mg, 1 .00 mmol) was dissolved in water (5 mL) and added to the stirred acetone solution. The reaciion turned yellow immediately. The reaction was stirred at rt for 18 h and then diluted with EtOAc (30 mL). The organic layer was separated and then the aqueous layer was extracted with EtOAc (3 x 20 mL). The aqueous layer was then extracted with DCM (3 x 30 mL). The organic extracts were combined, dried over MgS0 , and filtered. The solvent was removed under reduced pressure. The crude residue was cnromatographed on a 12. g Si0 ₂ pre-packed column elut ng with 0-80 % ACN/DCM to afford compound 24b. l i -Wf R (400 MHz, D l -. ) 8 (ppm): 8.47 id, J = 2.2 Hz, ill), 8.33 (d, J = 8.6 Hz, Hi), 8.29 (d, J - 8.6 Hz, IH), 7.93 - 7.98 (m, 2H), 7.92 (d, J - 5.6 Hz, IH), 7.85 - 7.90 (m, IH), 7.83 (dd, J - 8.8, 2.4 Hz, IH), 7.72 - 7.78 (m, IH), 6.68 (d, J = 8.8 Hz, Hi), 5.93 (d, J = 5.6 Hz, I H), 5.07 (s, 2H), 3.59 ^■ 3.64 (m, 4H), 3.55 - 3.59 (m, 4H), 3.36 - 3.41 (m, 4H), 3.29 - 3.36 (m, 4H), 1.51 (s, 9H). Mass Spectrum (LCMS, ESI pos.) Cafcd. For Cj-iHsx xGsS : 671.3 (M+Ii), Found: 671.3. C. 4-(3-(6-(Piperazin- 1 -yl)pyridm-3-yl)-2-((quinolin-2- ylsulfonyl)methyl)imidazo[ 1 ,2-6]pyridazin- 8-yl)morpholine trifluoroacetic acid salt, Cpd 9

Compound 24b was deprotected as described in Example 20, Step D, and purified by RP HPLC to afford the title compound 9. Ή-NMR (400 MHz, DMSO-ifc) δ (ppm): 8.83 (br. s., 2H), 8.69 (d, J = 8.6 Hz, 1H), 8.44 (d, J = 2.2 Hz, 1H), 8.19 (d, J = 8.6 Hz, 1H), 8.23 (d, J - 8.3 Hz, 1H), 8.05 (d, J - 5.6 Hz, IH), 7.97 - 8.03 (m, 1H), 7.94 (d, J = 8.6 Hz, IH), 7.81 - 7.91 (m, 2H), 7.01 (d, J = 9.0 Hz, IH), 6.24 (d, J = 5.9 Hz, IH), 5.05 (s, 2H), 3.77 - 3.84 (m, 4H), 3.29 - 3.37 (m, 4H), 3.22 - 3.28 (m, 4H), 3.14 - 3.22 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C29H30N8O3S: 571.2 (M+H), Found: 571.3.

Example 2,5

8-Moφholϊ -3-(6~(piperazin ~yl py id ~3^

&jpyridazm-2--amine trifluoroacetic acid salt (Cpd 11)

tert-Butyl 4-(5-(8-morpholmo-2-((qu ^" inolin-2-ylmethyl)amino)imidazo[ l . Z)]pyridazin-3-yl)pyridin~2-yl)piperazine- 1 -carboxylate, 25a

Using the procedure described in Example 21 , Step C, the title compound was prepared from Compound 23b and 2-quinolinecarba.ldehyde. 'H-NMR (400 MHz, CDC1 ₃ ) δ (ppm): 8.66 (d, J = 2.2 Hz, 1H), 8.09 (d, J = 8.3 Hz, 1H), 7.97 - 8.07 (m, 2H), 7.89 (d, J = 5.6 Hz, 1H), 7.79 (d, J = 8.1 Hz, 1H), 7.70 (ddd, J = 8.4, 6.9, 1.3 Hz, 1 H), 7.46 - 7.56 (m, 2 \ \ . 6.81 (d, J - 9.0 Hz, I H), 6.03 (d, J - 5.6 Hz, 1 H), 5.30 (t, J - 5.3 Hz, l l . 4.91 (d, J = 5.4 Hz, 11 1 ). 3.81 (s, 8H), 3.49 - 3.69 (m, 8H), 1 .50 is, 9H). Mass Spectrum (LCMS, ESI pos.) Caicd. For C ₃ 4H ₃₉ N ₉ O ₃ : 622.3 (M+H), Found: 622.3.

13. 8-Morpholino-3-(6-(piperazin- 1 -yi)pyridin-3-yl)-N-(qumolm-2- ylmeihyl)imidazo[ l,2-£]pyridazm-2-amme trifluoroacetic acid salt, Cpd 11 Compound 25a was deproiected as described in Example 20, Step D, and purified by RP HPLC to afford the title compound 11. ¹ H-NMR (400 MHz, CD ₃ OD) δ (ppm): 9.04 (d, J = 8.8 Hz, I H), 8.71 (d, J = 2.2 Hz, LH), 8.27 - 8.37 (m, 3H), 8.13 - 8.21 (m, 2H), 7.90 - 8.01 (m, 2H), 7.25 (d, J - 9.3 Hz, I H), 6.23 (d, J - 5.9 Hz, H), 5.07 (s, 2H), 3.91 ^■■ 3.97 (m, 4H), 3.38 ^■■ 3.51 (m, 12H). Mass Spectrum (LCMS, ESI pos.) Caicd. For ί^Η,ιΝ,Ο: 522.3 (M+H), Found: 522.2.

Example 26

4-(3-(6-(Piperazm- l -yl)pyridm-3-yl)-2-(qum^

8-yl)mo (Cpd 12)

teri-Butyl 4-(5-(2-ethynyl-8-mo^holinoimidazo[ l ,2- ?]pyridazin-3-y])pyrid 2-yl)piperazine- 1 -carboxylate, 26a

Compound 21a (195 mg, 0.393 mmol) was placed in an 8 mL vial equipped with a stir bar and then DCM (2 mL) was added. The Dess-Mariin periodinane (184 sng, 0.433 mmol) was added and then the reaction was stirred at rt for 20 min. The reaction was diluted with DCM (20 mL) and washed with saturated NaHCCh solution (2 x 20 mL). The organic phase was dried over MgS0 and filtered. The solvent was removed under reduced pressure. The residue was placed in a 20 mL vial equipped with a stir bar and then MeOH (5 mL) was added. K ₂ C0 ₃ (163 mg, 1.18 mmol) was added and then dimethyl (1 -diazo-2-oxopropyi)phosphonate (1 13 mg, 0.590 mmol) dissolved in MeOH (2 mL) was added. The reaction was stirred at reflux for 3 h. Additional K2CO3 ( 163 mg, 1.18 mmol)) and diazophosphonate (1 13 mg, 0,590 mmol) were added and the reaction was reflux ed for 6 h. The reaction was cooled to rt and then the solvent was removed under reduced pressure. The residue was dissolved in DCM (20 mL) and washed with water (20 mL). The aqueous layer was extracted with DCM (3 x 10 mL) and then the combined organic extracts were washed with brine (20 mL), dried over MgS0 ₄ , and filtered. The solvent was removed under reduced pressure. The crude product was chromatographed on a 40 g SiO? pre-packed column eluting with 0-60 % ACN/DCM to afford compound 26a. i l - X M R (400 MHz, CDCI3) δ (ppm): 8.85 (d, J - 2.2 Hz, 1 H), 8.16 (dd, J - 8.8, 2.4 Hz, H), 8.03 i d. J - 5.6 Hz, 1H), 6.77 (d, J = 9.0 Hz, 1H), 6.08 (d, J = 5.6 Hz, 1H), 3.95 - 4.03 (m, 4H), 3.88 - 3.95 (m, 4H), 3.60 - 3.68 (m, 4H), 3.50 - 3.60 (m, 4H), 3.28 (s, H), 1.50 (s, 9H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C^ TOS: 490.3 (M+H), Found: 490.3.

B. iert- tyl 4-(5- 8-moφho]mo-2- qumolm-2-ylethynyI)imidazo[l ,2-Z?] yridazΐn- 3-yl)pyridin-2-yl)piperazine- 1 -carboxylate, 26b

Compound 26a (1 31 mg, 0.268 mmol) and 2-bromoqumoline (558 mg, 2,68 mmoi) were placed in an 8 mL vial equipped with a stir bar and then the vial was evacuated and backflushed with argon. Dry DMF (4 mL) and DIEA (0.468 mL, 2.68 mmoi) were added via syringe and then ihe mixture was deoxygenated by bubbling argon through the stirred solution for 5 mm. Cul (2.56 mg, 0.0134 mmoi) and

(Ph ₃ P) ₂ PdCl2 (18.9 mg, 0.0268 mmoi) were added and then the reaction was stirred at rt for 1 h. The reaction was poured into water (50 mL) and then the mixture was exiracted with EtOAc (3 x 30 mL). The combined organic extracts were washed with water (20 mL) and brine (2 x 20 mL) and then dried over MgS0 ₄ and filtered. The solution was concentrated under reduced pressure. The crude product was

chromatographed on a 40 g SiO? pre-packed column eluting with 0-60 % ACN DCM to afford compound 26b. l i -Wf R (400 MHz, ΠΧ Ί δ (ppm): 8.97 (d, J = 2.2 Hz, 1H), 8.27 (dd, J = 8.9, 2.3 Hz, IH), 8.12 (t, J = 8.6 Hz, 2H), 8.04 (d, J = 5.6 Hz, 1H), 7.80 (d, J - 8.1 Hz, 1H), 7.67 - 7.77 (m, 1 H), 7.62 (d, J - 8.6 Hz, I H), 7.49 - 7.59 (m, I H), 6.81 i d. J = 8.8 Hz, IH), 6.09 (d, J = 5.6 Hz, IH), 3.98 - 4.07 (m, 4H), 3.88 - 3.98 (m, 4H), 3.61 · ^■ 3.70 (m, 4H), 3.51 - 3.61 (m, 4H), 1.50 (s, 9H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C <i ! _; ,N>i ⁾ ^: 617.3 (M+H), Found: 617.3.

C. 4-(3- 6-(Piperazin- l -yl)pyridin-3-yl)-2-(quinolm-2-ylethynyi)imidazo[l ,2- 6]pyridazin-8-yl)morpholine trifluoroacetic acid saii, Cpd 12

Compound 26b was de-protected as described in Example 20, Step D to afford the title compound 12. Ή-NMR (400 MHz, DMSO- ) δ (ppm): 8.84 i d. J = 2,2 Hz, I H), 8.82 (br. s., 21 n. 8.46 (d, J - 8.6 Hz, I H), 8.28 (dd, J - 8.9, 2.3 Hz, i l l }. 8.24 i d. J - 5.9 Hz, IH), 8.03 (t, J - 8.9 Hz, 2H), 7.79 ^■■ 7.88 (m, I I I ). 7.71 (d, J = 8.6 Hz, IH), 7.64 - 7.69 (m, IH), 7.18 (d, J = 9.0 Hz, I H), 6.47 (d, J = 5.9 Hz, I H), 3.99 - 4.08 (m, 4H), 3.80 - 3.89 (ra, 8H), 3.17 - 3.31 (m, 4H). Mass Spectrum (LCMS, EST pos.) Calcd. For C ₃ oH _{28 8} 0: 517.3 (M-i-H), Found: 517.3.

Example 27

4-(3-(6-(Piperazin- l -yl)pyridin-3-yl)-2-(2-(qumolin-2-yl)ethyl)imidazo[l,2- 6]pyridazin-8-yI)morpholine trifluoroacetic acid salt (Cpd 13)

Compound 12 (50.0 nig, 0.0671 mmol, Example 26) was dissolved in MeOH (50 mL) and then treated with H ₂ over 10 % Pd on activated carbon using an H-Cube device with a flow rate of 1 mL/min at ambient temperature. The solvent was removed under reduced pressure and then the crude product was purified by RP HPLC to afford the title compound 13. 'H-NMR (400 MHz, DMSO- + TFA) δ (ppm): 9.02 (d, J = 8.6 Hz, IH), 8.91 (br. s., 2H), 8.35 (d, J = 2.2 Hz, 1H), 8.32 (d, J - 8.3 Hz, 1H), 8.09 - 8.21 (m, 2H), 8.02 - 8.09 (m, 2H), 7.90 - 7.99 (ra, IH), 7.84 (dd, J = 8.9, 2.3 Hz, 1H), 7.02 (d, J - 8.8 Hz, IH), 6.29 (d, J - 5.6 Hz, I H), 3.74 - 3.84 (m, 4H), 3.61 - 3.68 (m, 2H), 3.55 - 3.61 (m, 4H), 3.41 - 3.51 (m, 6H), 3.20 - 3.31 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. For CsoHw gO: 521.3 (M-i-H), Found: 521.2.

Example 28

- (3 ~(6-(Piperazin~ 1 -yl)pyridin-3 -yl)-2 - (2~(quinoiin-3 -yloxy)ethyl)imidazo [ 1 ,2 - 6]pyridazm-8-yi)morpholine trifluoroacetic acid salt (Cpd 14)

A. Ethyl 2~(8-bromo-6~cliloroimidazoil ,2~6]pyridazin-2~yi)acetate, 28a

Ethyl acetoacetate (2.55 mL, 20.0 mmol) was dissolved in CHCI ₃ (5 mL) and then the solution was cooled to 0 °C. Bromine (1.03 mL, 20.0 mmol) in CHCI ₃ (6 mL) was added dropwise and then the reaction was stirred at 0 °C for 2 h. The reaction was warmed to rt and stirred for 16 h. The headspace of the reaction vessel was purged with air to remove HBr, and then the reaction was stirred an additional 2 h open to air. The reaction was washed with ice-cold water (20 mL) and then the aqueous layer was extracted with DCM (10 mL). The combined organic layers were washed with brine and then dried over MgS0 ₄ and filtered. The solvent was removed under reduced pressure. The residue was placed in a 100 mL round bottom flask equipped with a stir bar and then dry DMF (10 mL) was added. 5-Bromo-3-chloro-6-ammopyridazine (2.08 g, 10.0 mmol) was added and then the reaction was stirred at rt for 4 d. The reaction was poured into water (50 mL) and then the mixture was extracted with EtOAc (3 x 30 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL), and then dried over MgS0 ₄ and filtered. The solvent was removed under reduced pressure. The crude product was chromatographed on an 80 g S 0 ₂ prepacked column eiuting with 0-20 % EtOAc/DCM to afford the title compound 28a. 'H-lslMR (400 MHz, CDCI ₃ ) δ (ppm): 8.05 (s, 1H), 7.35 (s, I H), 4.22 (q, J = 7.2 Hz, 2H), 3.95 (s, 2H), 1.30 (t, J - 7.1 Hz, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C nl !.;Br( ^' !.\ _; () .: 318.0 (M+H), Found: 318.0. B. Ethyl 2-(6-chioro-8-morpho]moimidazo[l ,2-&]pyridazin-2-yl)acetate, 28b

Compound 28a (1 .80 g, 5.66 mmol) was placed in a 2.0 ml. vial equipped with a stir bar and then ACN ( 1 1 mL) was added. Once the mixture was homogeneous, DIEA (1.79 mL, 10.3 minoi) was added. Morpholine (0.601 mL, 6.90 mmol) was added and then the reaction was stirred at rt for 3 h during which time the entire solution solidified. The solid was broken up and additional ACN (2 mL) was added. The reaction was stirred for an additional 2 h at rt. The reaction was poured into water (50 mL) and the resulting precipitate was isolated by filtration. The solid was washed with water (2 x 2.0 mi .) and then dried under reduced pressure to afford compound 28b. Ή-

NMR (400 MHz, CDC1 ₃ ) 6 (ppm): 7.73 (s, 1H), 6.05 (s, i l l ). 4.20 (q, J = 7.1 Hz, 2D ). 3.97 - 4.05 (m, 4H), 3.86 - 3.93 (m, 4H), 3.79 (s, 2H), 1.28 (t, J - 7.2 Hz, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For CWHJTCIN^: 325.1 (M-fH), Found: 325.1.

Ethyl 2-(8-moipholino l)acetat

Compound 28b (1.00 g, 3.08 mmol) and 10 % Pd on activated carbon (164 mg, 0.154 mmol) were placed in a 40 mL vial equipped with a stir bar and then the vial was evacuated and backflushed with argon. Dry THF (10 mL) was added followed by ammonium formate (388 mg, 6.16 mmol) and then the reaction was stirred at 70 °C for 1 h. The reaction was cooled to rt and diluted with DCM (200 mL). The solids were removed by filtration and then washed with DCM (2 x 50 mL). The combined filtrates % ^r ere concentrated under reduced pressure to affordcompound 28c. ¹ H-NMR (400 MHz, CDCI3) δ (ppm): 7.96 (d, J = 5.1 Hz, Hi), 7.80 (s, S i n. 6.02 (d, J = 5.1 Hz, i l l ). 4.21 (q, J - 6.8 Hz, 2H), 3.85 - 4.01 (ra, 8H), 3.83 (s, 2H), 1.29 (t, J - 6.8 Hz, M i ). Mass Spectrum (LCMS, ESI pos.) Calcd. For C14H18N4O3: 291.2 i M S O. Found:

291 .1.

D. Ethyl 2-(3-(6-chloropyridm-3-yl)-8-morpholinoimidazo[l ,2-6]pyridazin-2- yl)acetate, 28d

Compound 28c (867 mg, 2.99 mmol), 5-bromo-2-chloropyridine (888 mg, 4.48 mmol), Pd(OAc)2 (46.9 mg, 0.209 mmol), PPh ₃ (54.8 mg, 0.209 mmol), and KOAc (879 mg, 8.95 mmol) were placed in a 40 mL vial equipped with a stir bar and then the vial was evacuated and backtluslied with argon. Dry DMA (10 mL) was added via syringe and then the mixture was heated to 1 10 °C and stirred for 16 h. The reaction was cooled to rt, diluted with EtOAc (30 mL), and filtered. The solids were washed with EtOAc (30 mL) and then the combined filtrates were washed with water (2 x 20 mL) and brine (20 mL). The organic phase was dried over N ?S0 and filtered, and then the solvent was removed under reduced pressure. The crude product was chromatographed on a 40 g Sii¾ pre-packed column eluting with 0-60 % EtOAc/DCM to afford compound 28d. Ή-NMR (400 MHz, CDC1 ₃ ) δ (ppm): 8.68 (d, J = 2.2 Hz, S i n. 8.07 (dd, J - 8.3, 2.4 Hz, 1 H), 8.00 (d, J = 5.6 Hz, i l l ). 7.47 (d, J = 8.3 Hz, 1H), 6.1 1 (d, J = 5.6 Hz, 1H), 4.18 (q, J - 7.2 Hz, 2H), 3.96 ^■■ 4.03 (m, 4H), 3.89 - 3.95 (m, 4H), 3.84 (s, 21 ! ) . 1 .26 (t, J = 7.1 Hz, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C .,l i.,„n .V,0 ;: 402.1 (M+H), Found: 402.1.

E. itTi-Butyl 4-(5-(2.-(2~ethoxy-2-oxoethyl)-8-morpholinoimidazo[ 1 ,2- >]pyridazin- 3-yl)pyridin-2-yl)piperazine- 1 -carboxylate, 28e

Compound 28d (854 mg, 2.13 mmol), ■( () ; (323 mg, 2,34 mmol), Cu powder (27.0 mg, 0.425 mmol), and l-(ter/-buioxycarbonyl)piperazine (435 mg, 2.34 mmol) were placed in a 40 mL vial equipped with a stir bar. The vessel was evacuated and backflushed with argon and then dry DMF (4 mL) was added via syringe. The reaction was heated to 130 °C and stirred for 3 d. The solvent was removed under reduced pressure and then the residue was partitioned between wafer (50 mL) and DCM (70 mL). The organic phase was separated and then the aqueous layer was extracted with DCM (2 x 20 mL). The organic extracts were combined and % ^r ashed with brine (2 x 30 mL), and then dried over ajSC and filtered. The solvent was removed under reduced pressure. The crude product was chromatographed on a 40 g SiO? pre-packed column during with 0-80 % AC /DCM to afford compound 28c. ^] H-NMR (400 MHz, CDC1 ₃ ) δ (ppm): 8.42 (d, J = 1.7 Hz, 1H), 7.97 i d. J = 5.6 Hz, Hi), 7.83 (dd, J = 8.8, 2.4 Hz, i l l }. 6.78 (d, J - 9.0 Hz, ! ! ! }. 6.06 (d, J - 5.6 Hz, lH), 4.17 (q, J 7. 1 Hz, 2H), 3.94 - 4.01 (m, 4H), 3.87 - 3.94 (m, 4H), 3.83 (s, 2H), 3.59 - 3.67 (m, 4H), 3.50 - 3.59 (m, 4H), 1.50 (s, 9H), 1.25 (t, J - 7.1 Hz, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For Γ κΠ ; N ih: 552.3 (M+H), Found: 552.2.

F. teri-Butyl 4-(5-(2-(2-hydlΌxyethyl)-8-moφhoirnoi ^" midazo[l,2-6]pyridazm-3- yl)pyridm-2-yl)piperazine- 1 -carboxylate, 281 ^"

Compound 28e (260 mg, 0,471 mmol) was placed in an 8 mL vial equipped with a stir bar and then the vial was evacuated and backflushed with argon. Dry THF (4 mL) was added and then the solution was cooled to 0 °C in an ice bath. 1 M LiAlH ₄ in THF (0.471 mL, 0.471 mmol) was added and then the ice bath was removed and the reaction was allowed to warm to rt. The reaction was stirred at rt for 20 min and then poured into saturated NHsCl solution (20 mL). DCM (20 mL) was added and then the mixture was filtered. The filter cake was washed with DCM (2 x 10 mL) and then the organic phase was separated. The aqueous layer was extracted with DCM (3 x 10 mL) and then the organic extracts were combined, dried over a ₂ S0 ₄ , and filtered. The solvent was removed under reduced pressure. The crude product was chromatographed on a 12 g SiO? pre-packed column eiuting with 0-100 % ACN/DCM to afford compound 281 ^" . ^] H-NMR (400 MHz, CDCI ₃ ) δ (ppm): 8.38 (d, J = 2.2 Hz, IH), 8.00 (d, J - 5.4 Hz, IH), 7.81 (dd, J - 8.8, 2.4 Hz, IH), 6.78 (d, J = 8.8 Hz, IH), 6.10 (d, J = 5.6 Hz, IH), 3.97 - 4.07 (m, 3H), 3.92 (s, 8H), 3.52 - 3.65 (m, 8H), 3.05 (t, J = 4.6 Hz, 2H), 1.50 (s, 9H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C26H35N7O : 510.3 (M+H), Found: 510.2.

G, ten-Butyl 4-(5-(8-morphol no-2-(2-(quinolin-3-yIoxy)ethyl)imidazo[l,2- 0]pyridazin-3-yl)pyridin-2-y l)piperazine- 1 -carboxylate, 28g

Compound 28f (97.3 mg, 0.19.1 mmol), 3-hydroxyquinofine (38.8 mg, 0,267 mmoi), and PPI1 ₃ (70.1 mg, 0.267 mmol) were placed in an 8 mL vial equipped with a stir bar. DCM (2 mL) was added and the mixture was stirred at rt for 5 min. 40 % Diethyl azodicarboxylate in toluene (0.104 mL, 0.229 mmol) was added dropwise and then the resulting solution was stirred at rt for 30 min. The crude reaction was ehromatographed on a 12. g S1O2 pre-packed column and eluted with 0-80 %

AC /DCM to afford compound 28g. ! i-NM R (400 MHz, CDCI ₃ ) δ (ppm): 8.59 (d, J = 2.9 Hz, 1H), 8.47 (d, J = 2.2 Hz, 1H), 7.95 - 8.05 (m, 2H), 7.84 (dd, J = 8.8, 2.2 Hz, i 1 1 !. 7.67 (d, J - 7.8 Hz, IH), 7.45 - 7.59 (m, 2H), 7.37 (d, J - 2.7 Hz, IH), 6.77 (d, J -

8.8 Hz, IH), 6.07 (d, J = 5.6 Hz, IH), 4.51 (t, J = 6.7 Hz, 2H), 3.87 - 4.00 (m, 8H), 3.52 - 3.65 (m, 8H), 3.38 (t, J = 6.7 Hz, 2H), 1.50 (s, 9H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C35H40N8O4: 637.3 (M+H), Found: 637.3.

H. 4-(3 - (6-(Piperazin- 1 -yl)pyridin-3-yl)-2-(2 ^■ (quinolin-3 -yloxy)ethyl)imidazo [1,2- Zj]pyridazin-8-y])morphoIine trifluoroacetic acid salt, Cpd 14

Compound 28g was deprotected as described in Example 20, Step D to afford the title compound 14. Ή-NMR (400 MHz, DMSQ-i¾ + TFA) δ (ppm): 8.86 (d, J -

2.9 Hz, 3H), 8.44 (d, J = 2.0 Hz, IH), 8.28 (d, J - 2.4 Hz, IH), 8.13 (d, J = 5.9 Hz, IH), 7.96 - 8.10 (m, 3H), 7.67 - 7.83 (m, 2H), 7.18 (d, J = 9.0 Hz, IH), 6.42 (d, J = 5.9 Hz, IH), 4.64 (t, J = 6.2 Hz, 2H), 3.87 - 4.00 (m, 4H), 3.79 - 3.87 (m, 4H), 3.71 - 3.79 (m, 4H), 3.30 - 3.37 (m, 2H), 3.21 - 3.30 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C30H32N8O2: 537.3 (M+H), Found: 537.3. Example 29

N-Methyl-N-((3-(6-(4-methylpipei^in-l-yl)pyridin-3-yl)-8-m

0]pyridazin-2-yj.)met y])qumolin-2-amme trifluoroacetie acid salt (Cpd 15)

A. N-((3-(6-(4-MeihyIpiperazin-l -yl)pyridm^

Zj]pyridazin-2-yl)methyl)quinolin-2-amme, 29a

Compound 21d (201 mg, 0.268 mmol) was placed in an 8 mL vial equipped with a stir bar and then DCE (2 mL) was added. 37 % formaldehyde in water (99.8 μΐ,, 1.34 mmol) was added via syringe and then the reaction mixture was stirred for 5 min at rt. NaBH(OAc)3 (170 mg, 0.804 mmol) was added and then the reaction was stirred at rt for 16 h. The reaction was quenched with water (4 mL), diluted with DCM (30 mL), and then the mixture was washed with 1 M NaOH (20 mL). The aqueous phase was extracted with DCM (3 x 10 ml.) and then the organic extracts were combined, dried over Na?804, and filtered. The solvent was removed under reduced pressure to afford \ compound 29a. Ή-NMR (400 MHz, CDC1 ₃ ) δ (ppm): 8.50 (d, j = 2.0 Hz,

1H), 7.98 (d, J - 5.6 Hz, 1H), 7.86 (dd, J - 8.8, 2.2 Hz, 1H), 7.78 (d, J - 8.8 Hz, IH), 7.69 (d, J - 8.3 Hz, 1H), 7.57 (d, J - 8.1 Hz, I H), 7.49 - 7.54 (m, I H), 7.1 8 - 7.23 (m, 1H), 6.76 (d, J - 8.8 Hz, IH), 6.71 (d, J - 8.8 Hz, IH), 6.06 (d, J = 5.6 Hz, IH), 4.87 (d, j = 5.1 Hz, 2H), 3.88 - 3.97 (ra, 8H), 3.60 - 3.68 (m, 4H), 2.53 (t, J = 4.9 Hz, 4H), 2.36 (s, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C30H33N9O: 536.3 (M+H), Found: 536.3.

B. N-Methyl-N-((3-(6-(4-methylpiperazin- 1 -yi)pyridin-3-yl)-8- morpholinoimidazo[I,2-Z?]pyridazim^

trifluoroacetic acid salt, Cpd 15

Compound 29a (86,6 mg, 0.162 mmol) was placed in an 8 mL vial equipped with a stir bar and then the vial was evacuated and backflushed with argon. Dry DMF (2 mL) was added and then Nail (7.1 1 mg, 0.178 mmol, 60 wt % mineral oil dispersion) was added as a solid. The reaction was stirred at rt for 5 min and then Mel (10.1 μΕ, 0.162 mmol) was added. The reaction was stirred at rt for 1 h and then poured into water (25 mL). The suspension was extracted with EtOAc (3 x 20 mL) and then the combined organic extracts were washed with brine (2 x 25 mL), dried over Na^SC , and filtered. The solvent was removed under reduced pressure. The crude product was purified by preparative TLC on a 2000 μηι Si(¾ plate developed with 20 % MeOH/DCM. The product was further purified by RP HPLC to afford the title compound 15. Ή-NMR (400 MHz, DMSO-tfc + TFA) δ (ppm): 10.00 (br. s., IH), 8.41 - 8.56 (m, 2H), 8.12 id, J = 5.6 Hz, IH), 8.07 (d, J = 8.1 Hz, Hi), 8.00 (d, J = 7.3 Hz, 2H), 7.86 (t, J = 7.8 Hz, IH), 7.54 ^■■ 7.74 (m, 2H), 7.16 (d, J - 9.0 Hz, IH), 6.35 (d, J - 5.9 Hz, I H), 5.32 (s, 21 11 4.42 - 4.56 (m, 2F1), 3.68 - 3.77 (m, 4FI), 3.53 - 3.64 (m, 2H), 3.38 - 3.47 (m, 4H), 3.35 fs, 3H), 3.07 - 3.29 (m, 4H), 2.90 (s, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For 550.3 (M+H), Found: 550.3.

Example 30

(¾-4-(3-(6-(Piperazin -yl)pyridin^

?]pyridazin-8~ id salt (Cpd 177)

(E)-tert- Butyl 4-(5-(8-morpholino-2~(2-(quinolin-2-yl)vinyl)-irnida.zo[l Z>]pyridazin-3-yl)pyridin-2-yj.)piperazme- 1 -carboxylate, 30a

Compound 21a (195 nig, 0.393 mmol) was placed in an 8 mL vial equipped with a stir bar and then DCM (4 mL) was added. Dess-Martm persodinane (184 mg, 0.433 mmol) was added and then the reaction was stirred at rt for 20 mi . The reaction was diluted with DCM (20 mL) and washed with saturated NaHCCb solution (2 x 20 mL). The organic phase was dried over MgSC¾ and filtered. The solveni was removed under reduced pressure. The residue was placed in an 8 mL vial equipped with a stir bar and then dry DMF (4 mL) was added. 2-Methylquinoline (51.5 ^iL, 0.393 mmol) and TMSCi (150 ^iL, 1.18 mmol) were added sequeniially and then the mixture was heated to 80 °C and stirred for 3 h. The reaction was cooled to rt and then poured into water (50 mL) and neutralized wiih saturated NaHCCh solution (50 mL). The aqueous mixture was extracted with EtOAc (3 x 50 mL), and then the organic extracts were combined, washed with brine (2 x 50 mL), dried over Na ₂ S0 ₄ , and filtered. The solvent was removed under reduced pressure. The crude product was chromatographed on a 12 g SiO? pre-packed column eiuting with 0-80 % EtOAc/DCM to afford compound 30a. Ή- MR (400 MHz, CDC1 ₃ ) δ (ppm): 8.50 (d, J - 2.0 Hz, IH), 8.07 (dd, J = 8.4, 4.3 Hz, 2H), 7.88 - 7.98 (m, 3H), 7.65 - 7.78 (m, 4H), 7.44 - 7.51 (m, I H), 6.83 i d. J - 8.8 Hz, IH), 6.05 (d, J - 5.6 Hz, 1H), 4.02 - 4.10 (m, 4H), 3.92 - 4.01 (m, 4l . 3.63 - 3.71 (m, 4H), 3.57 - 3.63 (m, 4H), 1.51 (s, 9H). Mass Spectrum (LCMS, ESI pos.) Calcd. For Css&s sOs: 619.3 (M+H), Found: 619.3.

B. (¾i-4-(3-(6-(piperazin- 1 -yl)pyridin-3-yi)-2-(2-(qumolm-2-yl)vinyi)imidazo[ 1 ,2- &]pyridazin-8-yl)morphoIine trifluoroacetic acid salt, Cpd 177

Compound 30a was deprotected as described in Example 20, Step D, and purified by RP HPLC to afford the title compound 177. ^J H-NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 8.92 (br. s., 2H), 8.59 (d, J = 8.6 Hz, IH), 8.46 (d, J - 2.4 Hz, IH), 8.14 (d, J = 5.6 Hz, 2H), 8.02 - 8.1 1 (m, 2H), 7.99 (dd, J = 8.9, 2.3 Hz, IH), 7.90 - 7.96 (m, i l l ). 7.88 (t, j - 7.8 Hz, IH), 7.76 ^■■ 7.84 (m, IH), 7.68 (t, J - 7.5 Hz, IH), 7.17 (d, J - 8.8 Hz, IH), 6.44 (d, J = 5.9 Hz, IH), 4.05 - 4.14 (m, 4H), 3.84 - 3.91 (m, 8H), 3.2.0 - 3.33 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. For ( ^' .,,Π .,Λ ,Ο: 519.3 (M+H), Found: 519.2.

Example 31

4-(5 -(8-Morphoiino -2-((qum

yl)pyridin-2-yl)piperazine- -sulfonamide (Cpd 20)

/eri-Butyl (4-(5-(8-morpholino-2-((quii jiin-2-ylihio)methyl)hnidazo[l, b jpyridazin-3 -yl)pyridin-2. -yl)piperazin- 1 -yl)sulfon lcarbamate, 31a

Compound 6 (137 mg, 0,6 ! 2 mmol) was placed in an 8 ml, vial equipped with a stir bar and then DCM (1 mL) and DIEA (68.2 μΕ, 0.486 mmol) were added, (ter Butoxycarbonyl)((4-(dimethyl-iminio)pyridin-l(4H)~yi)sulfony l)amide (48.8 mg, 0.162 mmol) was added as a solid and the reaction was stirred at rt for 3 h and then the solvent was removed under reduced pressure. The crude product was chromatographed on a 12 g SiO? pre-packed column eluting with 0-100 % EtO Ac/heptane. The resulting product was chromatographed on a 12 g Si0 ₂ pre-packed column eluting with 0-80 % EtOAc/heptane to afford the title compound 31a. Ή- MR (400 MHz, CDCh) δ (ppm): 8.55 (d, J = 2.2 Hz, 1 H), 7.96 (d, J = 5.6 Hz, lH), 7.80 - 7.92 (m, 3H), 7.71 (d, J - 8.1 Hz, I H), 7.58 - 7.66 (m, I H), 7.29 - 7.48 (m, 2H), 7.24 (d, J - 8.8 Hz, IH), 6.70 id, J = 8.8 Hz, IH), 6.04 (d, J - 5.9 Hz, IH), 4.85 (s, 2H), 3.89 - 4.00 (m, 4H), 3.80 ^■ 3.89 (m, 41 ! ) 3.62 - 3.73 (m, ·! ! ! ). 1.47 (s, 9H).

B. 4-(5-(8-Moφholmo-2-((qumolm-2-yhhio)methyl)imidazo[l ,2-ό] yridazin-3- yl)pyridin-2-yl)piperazine- 1 -sulfonamide, Cpd 2Θ

Compound 31a was deprotected as described in Example 20, Step D to afford the title compound 2(5. Ή-NMR (400 MHz, DMSO- ) δ (ppm): 8.45 (d, J = 2,2 Hz, I H), 8.16 {·:!. J - 8.6 Hz, I H), 8.09 (d, J - 5.6 Hz, IH), 7.83 - 7.93 (m, 2H), 7.65 - 7.75 (m, 11 1 ). 7.50 (ddd, J = 8.0, 5.9, 2.2 Hz, I H), 7.42 (d, J = 8.6 Hz, IH), 7.02 (d, J = 9.0 Hz, IH), 6.85 (s, 2H), 6.35 (d, J - 5.9 Hz, IH), 4.76 (s, 2H), 3.87 - 3.99 (m, 4H), 3.71 ^■ 3.77 (m, 4H), 3.62 - 3.71 (m, 4H), 3.00 - 3.12 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C29H31N9O3S2: 61 8.2 (M+H), Found 618.2.

Example 32

4-(3-(6-(i/ -Tetrazol-5-yl)pyridm-3-yf)-2-((quinolin-2

i>]pyridazin-8-yi)morpholine trifluoro acetic acid salt (Cpd 32)

A. Ethyl 3-(6~cyanopyridin~3~yJ)-8~morpholinoimidazo[l ,2~ ?]pyridazine-2- carboxylate, 32a

Using the procedure described in Example 20, Step A, the title compound was prepared from Compound 5c (1.38 g, 5.00 mmol), 5-bromo-2-cyanopyridine (1.42 g, 7.50 mmol), Pd(OAc) ₂ (78.6 mg, 0.350 mmol), PPh ₃ (91.8 mg, 0.350 mmol), and KOAc (1.47 g, 15.0 mmol) in DMA (20 mL) at 1 10 °C for 16 h. Ή-NMR (400 MHz, CDC¾) δ (ppm): 9.00 (s, 1H), 8.20 (dd, J - 8.1, 1.7 Hz, 1H), 8.05 (d, J - 5.6 Hz, 1H), 7.83 (d, J - 8.1 Hz, I ! i :·. 6.17 (d, J = 5.6 Hz, H i s. 4.36 (q, J = 7.3 Hz, 21 1 ). 4.02 - 4.13 (m, 4H), 3.90 ^■■ 3.99 (in, 4H), 1.30 (t, J - 7.1 Hz, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For ¾Η ₁₈ Ν ₆ 0 ₃ : 379.2 (M+H), Found: 379.1.

B. Ethyl 3-(6-(iH-tetrazol-5-yl)pyridin-3-yl)-8-morpholinoimidazo[l,2 - 6]pyridazine-2-carboxylate

Compound 32a (378 mg, 1.00 mmol), NH ₄ CI (80.2 mg, 1.50 mmol), and NaN ₃ (97.5 mg, 1.50 mmol) were placed in an 8 mL vial equipped with a stir bar and then the vial was evacuated and backflushed with argon. Dry DMF (4 mL) was added and then the reaction was stirred at 110 °C for 1 h. The reaction was cooled to rt and poured into water (25 mL). The pH of the mixture was adjusted with 2 M HCJ to pH 2 and then the precipitate was isolated by filtration. The solid was dried under reduced pressure to afford compound 32b. Ή-NMR (400 MHz, DM80~< ₆ ) δ (ppm): 9.01 (s, 1 H), 8.29 - 8.40 (m, 2H), 8.23 (d, J - 5.6 Hz, 1H), 6.50 (d, J - 5.6 Hz, 1 H), 4.23 (q, J - 6.8 Hz, 2H), 4.01 - 4.1 i (m, 4H), 3.77 - 3.86 (m, 4H), 1.16 (t, J = 7.0 Hz, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For CJ9H19N9O3: 422.2 (M+H), Found: 422.2.

C. Ethyl 8-morpholino-3-(6-(l -((2-(trimethylsilyl)ethoxy)methyl)-/H-tetrazol-5- yl)pyrid ^" in-3 -yl)i ^" midazo[l ,2- ?Jpyridazine-2-carboxyla.te, 32c, and

Ethyl 8-moipholino~3 '6-(2~((2-(trimethy{silyl)ethoxy)ffi

Compound 32b (416 mg, 0.987 mmol) was suspended in DMF (5 mL) and then ^~ NaH. (43.4 mg, 1.09 mmol, 60 wt % mineral oil dispersion) was added. The mixture w ^r as stirred at rt for 15 min and then SEMC1 (0.210 mL, 1.1 8 mmol) w ^r as added. The reaction was stirred at rt for 1 h and then quenched with water (20 mL). The precipitate was isolated by filtration, and then the filtercake was washed with water (2. x 20 mL). The solid was dried under reduced pressure to afford a mixture of compound 32c and compound 32c-l. Mass Spectrum (LCMS, ESI pos.) Calcd. For C25H32N9O48 552.2 (Μ+Η), Found: 552.2.

D. (8-MoφhoIi o-3-(6-(l -((2-(trimethy3silyl)etho )methyl)- /H-tetrazol-5- yl)pyridm-3-yl)imidazo[l ,2-6]pyridazin-2-yl)methanol, 32d and (8-Mo^holmo-3-(6-(2-((2-(trimethylsilyl)ethoxy)methyl)-2H-te trazol-5-

Using the procedure described in Example 20, Step A, the mixture of compounds 32d and 32d~l were prepared from the mixture of compound 32c and compound 32c-l. Mass Spectrum (LCMS, ESI pos.) Calcd. For 5.10.2 (Μ+Η), Found: 510.2.

E. 4-(2-((Quinolm-2-yitmo)meth^^

iH-tetrazol-5-yl)pyridin-3-yl)imidazo[l,2- j]pyridazm-8-yl)morpholi ^" ne, 32ε and

4-(2-((Quinolm-2-ylthio)me†hyl)-3-(6-(2-CC2-(trimethylsily l)ethoxy)m 2H-tetrazol-5-yi)pyridin-3-yl)imidazo[l,2-0]pyridazin-8-yl)m orpholine, 32e~l

Using the procedure described in Example 22, Step A, the mixture of compounds 32e and 32e-l were prepared from the mixture of compounds 32d and 32d- 1. Mass Spectrum (LCMS, ESI pos.) Calcd. For C^fteN^SSi: 653.3 (M+H), Found: 653.2.

F. 4-(3-(6-(/H-Tetrazol-5-yl)pyridin-3-yl)-2-((qumolin-2- ylthio)niethyl)imidazo [ 1 ,2 -6]pyridazin- 8 -yl)morpholine trifluoroacetic acid salt,

Cpd 32

The mixture of compounds 32ε and 32e-l (84.5 mg, 0.129 mmol) was dissolved in DCM (5 mL) and then TFA (0.5 lnL) was added. The mixture was stirred at rt for 16 h and then additional TFA (0.5 mL) was added. The reaction was stirred for an additional 2 h, and then the solvent was removed under reduced pressure. The crude product was purified by RP FIPLC to afford the title compound 32. i s - WI R (400 MHz, DMSO-de) δ (ppm): 9.15 (s, I H), 8.42 (dd, J = 8.1 , 1 .7 Hz, I H), 8.32 (d, J = 8.1 Hz, IH), 8.1 1 ^■■ 8.20 (m, 2H), 7.86 (d, J - 8.1 Hz, IH), 7.50 - 7.60 (m, 2H), 7.37 ^■ 7.48 (m, 2H), 6.44 (d, J = 5.6 Hz, IH), 4.89 (s, 2H), 3.91 - 4.00 (m, 4H), 3.71 - 3.79 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C26H22N10OS: 523.2 (M+H), Found: 523.2. Example 33

-(3-(3-(iH-Tetrazoi-5-yl)phenyl)~2-(2-(quinolin-2~yl)vinyl)i midazo[l, ?]pyridazin-8~yl)morpboiit]e trifluoroacettc acid salt (Cpd US)

A. 3-(2-FoΓmyl-8-τnoφholmoimidazo[l,2-Z?] yΓidazin-3-y])berιzonkrile

Using the procedure described in Example 20, Step A, compound 33a was prepared from compound 5e (232 mg, 1.00 mmol), 3-bromobenzonitrile (273 mg, 1.50 mmol), Pd(OAc) ₂ (15.7 mg, 0.0700 mmol), PPh ₃ (18.4 mg, 0.0700 mmol), and KOAc (294 mg, 3.00 mmol) in DMA (4 ml,) at 110 °C for 16 h. ^: B-NMR (400 MHz, CDC1 ₃ ) δ (ppm): 10.14 (s, IH), 8.13 ^■ 8.17 (m, III).8.10 (d, J = 5.6 Hz, 1H), 8.03 (dt, J = 8.0, 1.3 Hz, IH), 7.76 (dt, J = 8.0, 1.3 Hz, ill).7.65 ft, J = 7.8 Hz, ill).6.18 id. J = 5.6 Hz, IH), 4.07 ^■■ 4.12 (m, 4H), 3.93 ^■■ 3.99 (m, 4H). Mass Spectrum {I. CMS. ESI pos.) Calcd. For C ₁₈ H ₁₆ N _S 02: 334.1 (M+H), Found: 334.3.

B. E/ ¹ -3-(8-Morpholino-2-(2-(quinolin-2-yl)vinyl)imida^

yl)benzonitrile, 33b

Compound 33a (232 nig, 0.696 mmol) was placed in an 8 mL vial equipped with a stir bar and then DMF (5 mL) and quinaldine (91 .0 μΕ, 0.696 mmol) were added, TMSCl (0.265 mL, 2.09 mraol) was added and then the reaction was heated to 90 °C and stirred for 18 h. The reaction was cooled to rt and poured into saturated NaHCOn solution (50 mL). A precipitate was isoiaied by filtration, and then the filtereake was washed with water (2 x 50 mL). The solid was chromatographed on a 12 g Si0 ₂ pre-packed column eluting with 0- 100 % EtO Ac/heptane to afford compound 33b. Ή-NMR (400 MHz, CDCi ₃ ) δ (ppm): 8.05 - 8.17 (m, 3H), 7.93 ^■ · 8.03 (m, 3H), 7.61 - 7.83 (m, 6H), 7.50 ft, J = 7.5 Hz, i l l ) . 6.14 (d, J = 5.6 Hz, 1H), 4.06 - 4.14 mi. 4H), 3.95 - 4.02 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C ₂ 8H ₂ 2 ₆ 0: 459.2 (M+H), Found: 459.4.

C. (jf^-4-(3-(3-(iH-tetrazol-5-yl)pheny^

Zj]pyridazin-8-y])morpholine triffuoroacetic acid salt, Cpd 105

Compound 33b (52.0 mg, 0, 1 13 mmol), NFLsCf (9.1 0 mg, 0.170 mmol), and aNn (1 1.1 mg, 0.170 mmol) were placed in an 8 mL vial equipped with a stir bar and then the vial was evacuated and backflushed with argon. Dry DMF (1 mL) was added and then the reaction was heated to 100 °C and stirred for 18 h. The reaction was cooled to rt, diluted with water (3 mL) and ACN (3 mL), and then the solution was purified by RP HPLC to afford the title compound 105. Ή-NMR (400 MHz, DMSO- d ₆ ) δ (ppm): 8.56 (d, J = 7.6 Hz, 1 H), 8.41 (s, 1 H), 8.1 7 - 8.26 (m, 2H), 8.09 - 8.17 (m, 1H), 7.91 - 8.08 (m, 5H), 7.80 - 7.91 (m, 3H), 7.67 (t, J = 7.3 Hz, 1H), 6.49 (d, J = 6.1 Hz, i 1 1 !. 4.04 - 4.19 (m, 4H), 3.83 - 3.95 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C2 ₈ H2 ₃ N ₉ O: 502.2 (M+H), Found: 502.4. Using the procedures described in Example 33, and reagents, starting materials and conditions known to those skilled in the art, the following compound representativ e of the present invention was prepared:

Example 34

4-(8-Mo hoIi o-2-((quinolin-2-yIthio)meth l)imidazo[l,2-ό]p^idazi - acid (Cpd 116)

A. tert-Butyl 4· ^■ (2 ^■ hydroxymeίhyί) ^■ 8 ^■■ nlOφhoίi oimidazΌ[l,2 ^■ ?] yrid zin ^■ 3 ^■ y!jbenzoate, 34a

Compound 5f (315 mg, 0.772 mmol) was placed in a 40 mL vial equipped with a stir bar and then dioxane (10 mL) and MeOH (10 mL) were added. N BHi (51.0 mg, 1.35 mmol) was added and then the reaction was stirred at rt for 18 h. The reaction was diluted with water (20 mL) and the mixture was extracted with DCM (3 x 25 mL). The organic extracts were combined, dried over a^SC , and filtered. The solvent was removed under reduced pressure to afford compound 34a. ¹ H-NMR. (400 MHz, CDCI ₃ ) δ (ppm): 8.09 - 8.17 (m, 2H), 8.06 (d, J = 5.6 Hz, Hi), 7.75 - 7.86 (m, 2H), 6.15 (d, J - 5.6 Hz, 1H), 4.86 (d, J - 5.6 Hz, 2H), 3.87 - 4.05 (m, 8H), 2.52 (t, J - 5.6 Hz, IH), 1.61 (s, 9H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C22H26 4O4: 41 1.2. (M+H), Found: 41 1.4.

13. iert- tyl 4-(8-morphoiino-2-((qumolin-2-yithio)methy3)imidazo[l,2- 6]pyridazm-3 -yl)benzoate, 34b

34b

Using the procedure described in Example 22, Step A, the title compound was prepared from compound 34a. ¹ H-NMR (400 MHz, CDC! ; ! δ (ppm): 8.09 (d, J = 8.1 Hz, 11 1 ). 7.96 (d, J - 5.6 Hz, I H), 7.80 - 7.89 (m, 3F1), 7.78 (d, J - 8.6 Hz, IH), 7.68 (d, J - 8.1 Hz, IH), 7.60 (t, J - 7.6 Hz, IH), 7.40 (t, j - 7.6 Hz, IH), 7.23 (d, J - 8.6 Hz, IH), 6.03 (d, J = 5.6 Hz, I H), 4.88 (s, 2H), 3.86 - 3.94 (m, 4H), 3.78 - 3.86 (m, 4H), 1.60 (s, 9H). Mass Spectrum (LCMS, ESI pos.) Calcd. For CSIHMNJOSS: 554.2 (M -H), Found: 554.5.

C. 4~(8-Moipboiino~2-({quinolin-2-y!thio)methy

yFibenzoic acid, Cpd 116

Compound 34b (347 mg, 0.627 mmol) was placed in an 8 mL vial equipped with a stir bar and then DCM (4 mL) was added and the solid dissolved, TFA (2. mL) was added dropwise and then the reaction was stirred at it for 4 h. The solvent was removed under reduced pressure and then the residue was dissolved in DCM (10 mL) and MeOH (3 mL) and the solvent was removed under reduced pressure. The residue was triturated with MeOH (10 ml.) to afford a white precipitate that was isolated by filtration. The residual solvent was removed under reduced pressure to afford the title compound 116. I i- N .VI R (400 MHz, DMSO-<fc) δ (ppm): 13.05 (br. s., IH), 8.12 ^■■ 8.20 (m, 2H), 8.06 (d, J = 8.6 Hz, 2H), 7.89 (d, J = 8.1 Hz, 3H), 7.59 - 7.71 (m, 2H), 7.47 ^■ · 7.53 (m, IH), 7.43 (d, J - 8.6 Hz, IH), 6.40 (d, J - 5.6 Hz, IH), 4.82 (s, 2H), 3.85 - 3.98 (m, 4H), 3.66 - 3.78 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C27H23 5O3S: 498.2 (M+H), Found: 498.4.

Example 35

A-(Methylsuifonyi)-4-(8-mo^holmo-2-((quinoiin-2-ylthio)Tn ethyl)

?]pyridazin-3-yl)benzamide (Cpd 120)

Compound 116 (140 mg, 0.228 mmol) was placed in an 8 mL vial equipped with a stir bar, dry DMF (1 mL) was added, followed by the addition DIEA (0.199 mL, 1.14 mmol). Metnanesuifonamide (21 7 mg, 2.28 mmol) and HATU (130 mg, 0.343 mmol) were added sequentially and then the reaction was stirred at rt for 18 h. The mixture was diluted with water (6 mL) and then the pH was adjusted to pH 4 using 10 % citric acid solution. The precipitaie was isolated by filtration, and then the filter cake was washed with water (2. x 5 mL). The solid was air-dried and then the residual solvent was removed under reduced pressure. The solid was triturated with MeOH (3 x 6 mL) and then the residual solvent was removed under reduced pressure to afford the title compound 120. Ή-NMR (400 MHz, DMSO-ifc) δ (ppm): 12.22 (br. s., M l ). 8.13 ~ 8.19 (m, 2H), 8.08 (d, J - 8.6 Hz, 2H), 7.89 (d, J = 8.1 Hz, 1H), 7.93 (d, J = 8.6 Hz, 2H), 7.60 - 7.70 (m, 2H), 7.50 (t, J = 7.3 Hz, 1H), 7.42 (d, J = 9.1 Hz, 1H), 6.41 (d, J = 5.6 Hz, IH), 4.82 (s, 2H), 3.89 - 3.98 (m, 4H), 3.69 - 3.77 (m, 4H), 3.41 (s, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C^e ^Sa: 575.2 (M+H), Found: 575.5.

Example 36

Sodium ¾-5-(8-morpholino-2-(2-(quinolm-2-yl)vmyl)imidazo[l ,2-0]pyridazin-3- yi)nicotinate (Cpd 123)

A. 5-(2-Formyl-8-mo^holmoimidazo[l ,2-0]pyridazm-3-yl)nicotinonitrile, 36a

Using the procedure described in Example 20, Step A, compound 36a was prepared from compound 5e (232 mg, 1.00 mmol), 3-bromobenzonitrile (273 mg, 1.50 mmol), Pd(OAc) ₂ ( 15.7 mg, 0.0700 mmol), PPh ₃ ( 8.4 mg, 0.0700 mmol), and KOAc (294 mg, 3.00 mmol) in DMA (4 mL) at 1 10 °C for 16 h. i i -N M (400 MHz, CDCL) 8 (ppm): 10.1 6 (s, IH), 9.26 (d, J - 2.0 Hz, 1H), 8.93 i d. J - 2.0 Hz, ! ! ! ;·. 8.46 - 8.56 (m, 1 H), 8.1 1 (d, J = 5.6 Hz, 1 H), 6.21 (d, J = 5.6 Hz, IH), 4.06 - 4.1 6 (m, 4H), 3.92 - 4.01 (m, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. For CnHwNeOa: 335.1 (M+H), Found: 335.2.

B. ^-5-(8-Morpholino-2-(2-(qiunolin-2-yl)vinyl)imidazo[l,2-& ;]pyridazm

yl)nicotmonitrile, 3

Using the procedure described in Example 33, Step B the title compound was prepared from compound 36a (207 mg, 0.619 mmol), quinaidine (81.0 μΕ, 0.619 mmol), and TMSCl (236 μΕ, 1.86 mmol) in DMF (5 mL) at 90 °C for 18 h. Mass Spectrum (LCMS, ESI pos.) Calcd. For C27H21N7O: 460.2 (M+H), Found: 460.5. C. Sodium ^-5-(8^οφΗο1ίηο-2-(2-( υΐηο1ΐη-2^3)νϊην1)ΐηιΐά3ζο[1 ,2- &]pyridazin-3-yl)nicotinaie (Cpd 123)

Compound 36b (95.0 mg, 0.207 ramol) was placed in an 8 mL vial equipped with a stir bar and then dioxane (1 0 mL) and 1 M NaOH (5 mL) were added. The reaction was heated to 100 °C and stirred for 18 h. The reaction was cooled to rt and then the volatile solvent was remo ved under a purge of N ₂ . The aqueous soluiion was diluted with water (2 mL) and then the precipitate was isolated by filtration. The filter cake was washed with water (2 x 5 mL) and then the solid was dried under reduced pressure to afford the tide compound 123. Ή- M (400 MHz, DMSO- ) δ (ppm): 9.03 (s, i l l ). 8.73 is, iPI), 8.41 (s, I I I ;. 8.32 (d, J = 8.6 Hz, Hi), 8.16 (d, J = 5.6 Hz, H b. 7.95 (t, J - 9.6 Hz, 2H), 7.85 (d, J = 8.6 Hz, IH), 7.67 - 7.81 (m, 3H), 7.54 (i, J = 7.1 Hz, IH), 6.46 (d, J = 5.6 Hz, IH), 4.04 - 4.16 (m, 4H), 3.81 - 3.92 (m, 4H). Mass Spectrum (LCMS, EST pos.) Cafcd. For ( ·■ l | . .N _ft O ;: 479.2 (M+H), Found: 479.4.

Example 37

( -3-(8~Μοφ1ι 1ϊ ο-2~(2-¾υϊηο1^

acid (Cpd 124)

Compound 33b (1 82 mg, 0.397 mmol) was placed in an 8 mL vial equipped with a stir bar and then dioxane (T O mL) and 1 M NaOH (5 mL) were added. The reaction was heated to 100 °C and stirred for 18 h before cooling to rt. The volatile solvent was removed under a purge of N ₂ and then the aqueous solution was diluted with water (2 mL) and the pH was adjusted to pH 2 using 6 M HC1. The resulting precipitate was isolated by filtration and then the filter cake was washed with water (2 x 10 ml.). The solid was dried under reduced pressure and then dissolved in DMSO (20 mL) and filtered. The solvent was removed under a stream of N? and then the residue was suspended in water (10 mi.) and filtered. The solid was dried under reduced pressure to afford the tide compound 124. Ή- M (400 MHz, DMSO-a'e) δ (ppm): 13.20 (br. s., ill).8.48 (br. s., \\\).8.29 (s, ill).8.18 (d, J = 5.4 Hz, Hi), 8.10 (d, J = 7.6 Hz, IH), 7.93 - 8.07 (m, 4H), 7.79 - 7.88 (m, 3H), 7.72 - 7.79 (m, 1H), 7.57 - 7.68 (m, IH), 6.47 (d, J - 5.6 Hz, 1H), 4.02 - 4.18 (m, 4H), 3.85 - 3.95 (m, 41! i. Mass Spectrum (LCMS, ESI pos.) Calcd. For ( NI1.;VO;: 478.2 i M Hi. Found: 478.5.

Example 38

-(5-(8-Mo^liolino-2-(2-(qi»nolin-2-yi)etliynyl)mi

2-ylamino) alt (Cpd 24)

tert-Butyl 5-(8- norpholino-2-(2-(quinolin-'2-yi)ethynyl)imidazO[l, pyridazin-3 -yl)pyri -2-yicarbamate, 38a

A solution of compound 18b (0.50 g, 1.2 mmol) and ferf-butyl 5-(4,4,S,5- tetramethyl-l,3,2~dioxaborola.n~2-yl)pyrid ^" in-2-ylcarbaniate (0.44 g, 1.4 mmol) in dioxane/water (4:1 v/v, 5 mL) was purged with ₂ .

Dichloro(diphenylphosphinoferrocene)palladium (42 mg, 0.06 mmol) was then added, followed by solid CS2CO ₃ (0.94 g, 2.9 mmol). The reaction mixture was stirred at 85 °C for 1 h under N ₂ , and allowed to cool to rt. EtOAc (100 mL) was then added. The organic layer was washed with water (2 x 50 mL), and brine (100 mL), dried over Na^SCu, filtered and concentrated to give a residue which was purified by flash column chromatography on silica gel (0-40% EtO Ac/heptanes) to give compound 38a as a yellow solid. Mass Spectrum (LCMS, EST pos.): Calcd, for C31H29N7O3: 548.2 (M+H); found: 548.1.

B. tert-Butyl 2-(tert-butoxycarbonyl(5-(8-morpholino-2-(quinolm-2-ylethyny l) imidazo[l,2-6]pyridazin-3-yr)pyrid n-2-y3)ammo)acetate, 38b

To a solution of compound 38a (1.0 g, 1.7 mmol) in DMF (20 mL), was added sodium hydride (60 %, 0.1 1 g, 2.7 mmol) in portions at 0 °C. The resulting mixture was stirred at rt for 30 min, and treated with terf-butyl 2-(tert-hutoxycarhonyl)acetate (0.53 g, 2.7 mmol). The resulting mixture was stirred at rt for 4 h, and treated with water (TOO mL). The solids formed were collected by filtration, washed with Et?0 (2 x 50 mL), and further purified by flash column chromatography on silica gel (ethyl acetate/petroleum ether (2: 1 )) to obtain compound 38b as a yellow solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C37H39N7O5: 662.3 (M+H); found: 662.2. 2-(5-(8-moφho3ino-2-(2-(qui olm-2-yl)ethyl yl)imidazo[l,2-έ]pyridazi - 3-yl)pyridin-2-ylamino)acetic acid trifluoroacetic acid salt, Cpd 24

Compound 38b (0.40 g, 0.57 mmol) was treated with TFA:DCM (1 :4 v/v, 15 mL) dropwise with stirring at 0 °C. The resulting mixture was stirred for 30 min at rt and concentrated under reduced pressure. The residue obtained was treated with 10 mL of Et ₂ 0. The solids formed were collected by filtration and washed with Et ₂ 0 (2 x 30 mL) to obtain the title compound 24 as an orange solid. Ή-NMR (300 MHz, DM80- d ₆ + D ₂ 0) δ (ppm): 8.64 (s, 1H), 8.42 (d, J = 8.4 Hz, 1 H), 8.35 (d, J= 9.3 Hz, 1H), 8.21 (d, J = 5.4 Hz, I H), 8.01 - 7.99 (m, 2H), 7.82 (t, J= 15.3 Hz, IH), 7.70 - 7.63 (m, 11 1 ). 7. 10 i d. ./ 9.3 Hz, IH), 6.43 (d. ./ 5.7 Hz, I H), 4.16 (s, 2H), 4.02 - 3.94 (m, 4H), 3.82 - 3.70 (m, 4H). Mass Spectrum (LCMS, ESI pos.): Calcd. for CasH^Os: 506.2 (M + H), Found: 506.1.

Example 39

4 ^■ (3 -(6-( lH-Tetrazol-5-yl)pyridin-3-yl)-2-(quino -2-ylethynyl)imidazo [1,2- 6] 21)

A. 5-(8-Moφholino-2-(2-(qumo{in-2-yl)eth nyl)imidazo[l,2-6] yrid zin-3- y])picolinoniirile ,

Compound 18b (0.15 g, 0.35 mmol) was subjected to Suzuki coupling conditions with 5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2~yl)picolinonitrile as described in Example 38, Step A to obtain compound 39a as a yellow solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C ₂ 7H, _{9 7} 0: 458.2 (M + H), Found: 458.2. B. 4-(3 -(6-( H-Tetrazol-5-yl)pyridin-3-yi)-2-(quinoiin-2-ylethynyl)iinida zo[l ,2- 6jpyridazin-8-yl)morpholine, Cpd 21

A solution of compound 39a (0.20 g, 0.44 mmol), sodium azide (50 mg, 0.77 mmol), and triethylamine hydrochloride (0.10 g, 0.73 mmol) in DMF (5 mL) was stirred at 100 °C for 1 h. After cooling to rt, the reaction was quenched with water (20 mL). The resulting mixture was extracted with DCM (2 x 30 mL). The combined organic layers were dried over Tsla ₂ S04, filtered, and concentrated under reduced pressure. The residue obtained was purified by flash column chromatography on silica gel (MeOiLCT ijCl?. (1 :50, v/v)) to obtain a residue, which was further purified by reverse phase Prep-HPLC. This resulied in the title compound 21 as a yeliow solid. Ή-NMR (300 MHz, DMSO - d ₆ ) δ (ppm): 8.85 - 8.91 (m, I H), 8.34 (d, J= 8.7 Hz, IH), 8.30 - 8.23 (m, 2H), 7.98 - 7.60 (m, 6H), 6.51 (d, J = 6.0 Hz, I H), 3.90 - 3.8 ! (m, 4H), 3.64 ^■■ 3.53 (m, 4H). Mass Spectrum (LCMS, ESI pos.): Calcd. for QT&ONJ OO: 501.2 (M + H), Found: 501.2.

Following the procedure described in Example 39 above, and substituting suitably selected and substituted reagents, starting materials and conditions as would be readily apparent to those skilled in the art, the following representative compound of the present invention was prepared.

Characterization

(£ -2-(2-(3-(6-(5H-Tetrazol-5-yl)pyridin-3-yl)-8-morpholinoimid azo[ l ,2- 6]pyridazin-2-yl)vinyl)quinoline

Ή-NMR (300 MHz, DMSO- ¾ δ (ppm): 9.06 (s, i l l ) 8.39 - 8.32 (m, 3H), 8.20 i d, .7 - 5.7 Hz, IH), 7.99 - 7.90 (m, M l ). 7.84 - 7.81 (m, 2H), 7.78 - 7.71 (m, IH ), 7.55(t, J = 6.9 Hz, IH), 6.49 (d, . 6.0 Hz, IH), 4.16 ^■■ 4.05 (m, 41 1 >. 3.90 - 3.82 (m, 4H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C27H22 1 O: 503.2 (M + H); Found: 503.1 .

Example 40 N-(Methylsulfonyl)-5-(8-mo^holino

-yl)picoiinamide (Cpd 28)

A. 5-(8-Moipholino- -(q ^" inoliii-2-ylethynyl)imidazo[l,2-6]pyridaziii-3-

yl)picolinic acid ,

A. solution of compound 3.9a (0.50 g, 1.1 mmol) in 50 % H ₂ S0 ₄ (20 mL) was stirred at 80 °C overnight. After cooling to rt, the reaction mixture was treated with water (20 mL). The solids formed were collected by filtration and washed with Et ₂ 0 (2 x 30 mL) to obtain compound 48a as a red solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C ₂₇ H ₂ oN ₆ 0 ₃ : 477.2 (M + H), Found: 477.1.

B. N-(Methylsulfonyl)~5-(8-moipholmo-2-(qumolm-2-ylethynyl)imid azo[l,2- Z)]pyridazm-3-yl)picolinamide, Cpd 28

A solution of compound 40a (0.20 g, 0.42 mmol), met anesulfonamide (60 mg, 0.63 mmol), dicyclohexylcarbodiimide (90.0 mg, 0.44 mmol) and NJV- diniet ylpyridin-4-amine (60.0 mg, 0.49 mmol) in DCM (5 mL) was stirred at rt overnight, then concentrated under reduced pressure. The residue obtained was purified by flash column chromatography on silica gel (MeOH/CH^Cl?, (1 :20)) to obtain a solid, which was washed with methanol (10 mL) to yield the title compound 28 as a yellow solid. I-NMR (400 MHz, DMSO-aV) δ (ppm): 9.50 - 9.41 (m, 1H), 8.62 (d, J = 8.8 Hz, 1H), 8.41 (d, J= 8.4 Hz, 1H), 8.30 · ^■ 8.27 (m, 2H), 8.03 - 7.99 (m, 2H), 7.82 (t, J= 7.6 Hz, 1H), 7.73 (t, J= 8.8 Hz, I H), 7.65 (t, J = 7.6 Hz, 1H), 6.51 (d, J= 5.6 Hz, IH), 4.08 - 3.97 (ra, 4H), 3.99 - 3.80 (m, 4H), 2.96 (s, 3H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C2 ₈ H2 _{3 7} O4S: 554.2 (M + H); Found: 554.0.

Following the procedure described in Example 40 above, and substituting suitably selected and substituted reagents, starting materials and conditions as would be readily apparent to those skilled in the art, the following representative compounds of the present invention were prepared.

(£)-N-(Methylsulfonyl)-3-(5-(8-morpholino-2-(2-(quinolm-2- yi)vmyl)imidazo[l ,2-0]p Tidazin-3-yl)pyridin-2-yl)propaiiamide trifluoroacetic acid salt

'H-NMR (300 MHz, DMSO-<¾ + D ₂ 0) δ (ppm): 8.86 (s, 1H), 8,76 (d, J = 8.7 Hz, I H), 8.29 (d, J= 8.7 Hz, 1H), 8.21 - 7.75 (m, 8H), 7.63 (d, J = 7.8 Hz, 1H), 6.48 (d, J = 5.7 Hz, 1H), 4.1 1 - 4.09 (m, 4H), 3.88 - 3.87 (m, 4H), 3.25 (s, 3H), 3.19 (t, ./= 6.6 Hz, 2H), 2.89 (i, J = 6.9 Hz, 2H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C ₃₀ H2 ₉ N ₇ O4S: 584.2 (M + H); Found: 584.1.

(£ -N-(Methylsulfonyl)-3-(4-(8-morpholino-2-(2-(quinolin-2- yl)vinyl)imidazo[l ,2-^]pyridazin-3-yl)phe ^" nyl)propanamide trifluoroacetic acid salt

Ή- MR (300 MHz, DMSO-ί/β) δ (ppm): 8.75 (d, J = 8.7 Hz, 1 H), 8.21 - 7.73

132

(m, 7H), 7.65 (d, J = 8.1 Hz, 2H), 7.47 (d, J = 7.8 Hz, 21 n. 6.4 ! (d, J = 5.7 Hz, 1H), 4.05 · ^■ 4.04 (m, 4H), 3.88 ^■ 3.87 (m, 4H), 3.23 (s, 3H), 2.98 (t, J = 7.2 Hz, 2H), 2.71 (t, J = 7.2 Hz, 2H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C ₃ iH ₃ oN ₆ 0 ₄ S: 583.2 (M + H); Found: 582.9.

Example 41

2-(4-(8-Morpholino-2-(quinolm-2-yleA^

yl)acetic acid trifluoroacetic acid salt (Cpd 25)

A. itTi-Butyl 4-(2-(hydiOxyniethyl)-8-morpholmoimidazo[l ,2-0]pyridazin-3-yl) -5,6-dihydropyridme- 1 (2H)-carboxylate, 41a

Compound 14a (2,5 g, 8.0 mmol) was subjected to Suzuki coupling conditions with N-Boc- 1 ,2,3 ,6-tetrahydropyridine-4-boronic acid pinacol ester as described in Example 38, Step A to obtain compound 41a as a white solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C21H29NSO4: 416.2 (M + H); found: 416.2.

B. feri-Butyl 4~(2-(hyd oxymethy{)-8~mo ho{i oimidazo[l,2- ?] y idazin-3- yl)piperidine- 1 -carboxyf ate, 41 b

4i

To a solution of compound 41a (3.5 g, 8,4 mmol) in methanol (30 niL) was added 10 % Pd/C (ca. 50% water, 3.5 g). The resulting mixture was hydrogenated at about 2 to 3 arm overnight, and filtered through a pad of diatomaceous earth. The filtrate was concentrated under reduced pressure to obtain compound 41b as a white solid. Mass Spectrum (LCMS, ESI pos.): Calcd, for C ₂₁ H ₃₁ N ₅ 0 ₄ : 418.2 (M + H): found: 418.2.

C. /eri-Butyl 4-(2-formyl-8-morpholinoimidazo[l ,2-6]pyridazin-3-yl)piperidine-l- carboxylate, 41c

To a solution of compound 41b (3.2 g, 7.7 mmol) in DMSO (22 mL) was added 2-iodoxybenzoic acid (3,4 g, 12 mmol) in portions. The reaction mixture was stirred overnight at rt and treated with IN NaOH (50 mL). The solids formed were collected by filtration and washed with Et ₂ 0 (2 x 50 mL) to obtain compound 41 c as an off-white solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C21H2. ₉ N ₅ O4: 416.2 (M-i-H); found: 416.2.

D. terl-But ] 4-(2-ethynyl-8-mo ho]moΐmΐdazo[l ,2- ] ridazin-3-yI i eridine- l - carboxylate, 41d

_; 41d

To a mixture of compound 41d (3.0 g, 7.2 mmol) and potassium carbonate (1.5 g, 10.9 mmol) in methanol (100 mL), dimethyl (I -diazo-2-oxopropyi)phosphonate (.1.7 g, 8.7 mmol) was added dropwise with stirring at rt. The reaction mixture was stirred overnight and treated with water (100 mL). The resulting mixture was extracted with DCM (3 x 1 00 mL). The combined DCM layers were dried over Na ₂ S0 ₄ and filtered. The filtrate was concentrated under reduced pressure to obtain compound 41 d as a white solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C Λ>Π >.;\ Η ) :4 ! 2.2 (M + H); found: 412.2.

E. teri-Butyl 4-(8^ο Ηο1ϊηο-2-( υϊηο1ί ^" η-2^1εί1ΐ 'ΐΐ5?1)™ϊά3ζο[1 ,2-ό] ΤΪά3ζίη-3- yl)piperidme- 1 -carboxylate, 41e

, 41e

A solution of compound 41 d ( 1.4 g, 3.4 rnmol) in DMF(5 mL) was treated with 2-bromoquinoline (2.0 g, 9.6 mol), Pd(PPli3) ₂ Cl ₂ (240 mg, 0.34 mmol), Cul (30 nig, 0.16 mmol) and DIPEA (4.4 g, 34.1 1 mmol) under N ₂ . The reaction mixture was stirred at rt overnight, and concentrated in vacuo. The residue obtained was purified by flash column chromatography on silica gel (EtOAc:peiroieum ether ( 1 :2)) to obtain compound 41e as a yellow solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C ₃ ]H34N60 ₃ : 539.3 (M + H); found: 539.4. 2-(2-(8-Morphoimo-3-(pipe

yl)ethynyl)quinoline T

411 ^"

A solution of compound 41 e (0.50 g, 0.93 mol) in TFA/DCM (1 : 3, 10 mL) was stin"ed at rt for 2 h. The resulting mixture was concentrated under reduced pressure to obtain compound 411 as a yellow solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C v.H v.X.-.O: 439.2 (M + H); found: 439.2. fcr/-Butyl 2-(4-(8-mo^holino-2-(2-(quinolin-2-yl)emynyl)-imidazo[l ,2- ?]pyridazm- 3-yi)piperidin~ 1 -yl)aceiate, 41g

To a solution of compound 41f (0, 15 g, 0.27 mmol) in DCM (3 ml . ) DIEA (54 mg, 0.42 mmol) was added. The resulting mixture was stirred for 15 min before the addition of teri-buiyl 2-bromoacetate (65 mg, 0.33 mmol). The reaction mixture was stirred at rt for 2 h, and concentrated under reduced pressure. The residue obtained was purified by flash column chromatography on silica gel (ethyl acetate:petroleum ether (1 :2)) to obtain compound 41g as a yellow solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C ^' .., I V.O .. 553.3 (M + H); found: 553.1. 2-(4-(8-Moipholino-2-(qumo]m-2-ylethynyl)imidazo[ { ,2-0]pw

yl)piperidm- l-yl)acetie acid triffuoroacetic acid salt, Cpd 25

A solution of compound 41 g (0.20 g, 0.36 mmol) in TFA/CH ₂ C1 ₂ (1 :3, 3 mL) was stin"ed at rt for 2 h, and concentrated under reduced pressure. The resulting mixture was diluted with 10 mL of water. The solids formed were collected by filtration and washed with Et ₂ 0 (2 x 30 mL), The crude solid product was then purified by re- crystallization from CH ₂ Cl ₂ :Et ₂ 0 (1 : 10) to obtain the title compound 25 as a yellow solid, I I - NMR (300 MHz, DMSO - d ₆ ) δ (ppm): 8.48 i d, J= 8.4 Hz, i l l !. 8.24 (d, J- ----- 5.7 Hz, 1 H), 8.06 - 8.03 (m, 2H), 7.87 - 7.80 (m, 2H), 7.70 - 7.65 (m, 1H), 6.41 (d, J

= 6.0 Hz, 1H), 4.19 (s, 2H), 4.08 ^■■ 3.95 (m, 4H), 3.82 ^■■ 3.64 (m, 7H), 3.42 ^■■ 3,29 (m, 2H), 2.70 - 2.57 (m, 2H), 2.23 - 2.19 (m, 2H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C ^' KJ N ) : : 497.2 (M + H) ; Found: 497.2. Example 42

3-(5-(8-Morpholmo-2-(quinolm-2-ylet ^

yl)- -oxadiazol-5-oi (Cpd 26)

A. Λ -Hydroxy-5-(8-moφhoίino-2-(quinolin-2- ίe1hJ^l l)imidazo[l ,2-ό] yridazm- 3 -yl)picolinimidami

A mixture of compound 39a (0.20 g, 0.44 mmol), liydroxyiamine hydrochloride (0.20 g, 2.9 mmol) and sodium carbonate (0.20 g, 1.9 mmol, ) in ethanol (4 ml.,) was stirred at 80 °C for 1 h. The reaction mixture was cooled to rt, and the solids formed were collected by filtration and washed with Et ₂ 0 (2 x 30 mi.) to obtain compound 42a as a yellow solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C27H22N8O2: 491.2 (M ^• l i s: Found: 491.2.

B. jV-((Ethoxycarbonyl)oxy)-5-(8-morphoIino-2-(quinolin-2- ylethynyI)imidazo[ l,2-0]pyridazin-3-yl)picoliniinidamide, 42b

A solution of compound 42a (0, 16 g, 0,33 mmol), DIEA (0.17 g, 1.3 mmol) and ethyl carbonochloridate (0.10 g, 0.93 mmol) in THF (10 mL), was stirred at rt for 2 h. The reaction was then quenched with water (50 mL). The solids formed were collected by filtration and washed with Et ₂ 0 (2 x 30 mL) to obtain compound 42b as a yellow solid. Mass Spectrum (LCMS, ESI pos.): Caicd. for C ₃ oH26 _s 0 : 563.2 (M + H); Found 563.2. 3-(5-(8-Moipholino-2-(qumolm^

2-yI)- l,2,4-oxadiazol-5-ol, Cpd 26

A solution of compound 42b (0.10 g, 0.18 mmol) and 2,3,4,6,7,8,9,10- octahydropyrimido[l,2-a]azepirie (0.10 g, 0.66 mmol) in -xyleiie (2 mL) was stirred at 130 °C in an oil bath for 2 h. The reaction mixture was allowed to cool to rt, and the solution was adjusted to pH 7 with 0.5 N HCl. The solids formed were collected by filtration and washed with CH ₂ Cl ₂ /MeOH (1 : 10) (3 x 10 mL) to obtain the title compound 26 as a brown solid. ^! H-NMR (300 MHz, DMSO-i ₆ ) δ (ppm): 13.25 (s, S i n. 9.48 (s, IH), 8.79 - 8.75 (m, I H), 8.47 i d. ./ 8.4 Hz, Hi), 8.33 (d../ 5.7 Hz, IH), 8.24 (d, ,/ 8.7 Hz, 1H), 8,06 ^■■ 8.01 (m, 2H), 7.87 ^■■ 7,66 (m, 3H), 7.56 (d, J = 6,0 Hz, IH), 4.10 - 3.98 (m, 4H), 3.91 - 3.78 (m, 4H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C ₂ 8i½ ₈ 0 ₃ : 517.2 (M + H), Found: 517.1.

Following the procedure described in Example 42 above, and substituting suitably selected and substituted reagents, starting materials and conditions as would be readily apparent to those skilled in the art, the following representative compounds of the present invention were prepared. Cpd Characterization

(£)-3-(5-(8-M φhojino-2-(2-(qui oj½-2-yΐ)vinyl)imidazo[l,2-έ] yridazm-3- yi)pyridin-2-yl)- 1 ,2 ₅ 4-oxadiazol-5(4H)-oie

i!-N R (400 MHz, DMSOaV) δ (ppm): 9.06 (s, IH), 8.41 - 8.32 (m, 2H),

34 8.20 - 8.18 (m, 2H), 7.98 ^■■ 7.93 (m, 3H), 7.82 (s, 2H), 7,76 ^■■ 7.72 (m, IH), 7.57 - 7.54 (m, IH), 6.50 (d, J =5.6 Hz, IH), 4.12 - 4.08 (m, 4H), 3.90 - 3.85 (m, 4H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C ₂ gi½ g03: 519.2 (M + H); Found: 519.2.

3-(5-(8-Mo^hoHno-2-(2-(qumo]m-2-yl)et y])imidazo[l,2-6]pyri.dazin-3- yi)pyridin-2-yl)- 1 ,2,4-oxadiazol-5(4/)-one

i!-N R (300 MHz, DMSOaV) δ (ppm): 9.00 (s, IH), 8.26 - 8.19 (m, 2H),

37 8.13 (d, J= 5.7 Hz, IH), 8.02 ^■ 7.99 (m, IH), 7.92 - 7.86 (m, 2H), 7.71 - 7.66 (m, IH), 7.55 - 7.50 (m, IH), 7.39 (d, J =8.4 Hz, IH), 6.41 (d, /= 5.7 Hz, IH), 3.94 - 3.91 (m, 4H), 3.75 - 3.72 (m, 4H), 3.42 - 3.35 (m, 4H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C _¾ H ₂ 4N ₈ 0 ₃ : 521.2 (M + H); Found: 521.1.

3-(5-(8-Mo^holino-2-((qumolin^

yi)pyridin-2-yl)- 1 ,2,4-oxadiazoI-5(4/)-one

i!-N R (400 MHz, DMSO-ik) δ (ppm): 9.00 fs, IH), 8.33 (d../ 8.4 Hz, IH),

35 8.26 · ^■ 8.20 (m, 2H), 8.02 id./ S i! Hz, IH), 7.88 id../ S i! Hz, IH), 7.64 (s,

2H), 7.44 - 7.43 (m, IH), 7.03 (d, J = 9.2 Hz, IH), 6.46 (d, J= 5.2 Hz, IH), 5.65 (s, 2H), 4.02 - 3.98 (m, 4l .3.81 - 3.77 (m, 4H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C27H22N8O4: 523.2 (M + H); Found: 523.2. Characterization

(£)-3-(4-(8-M φhojino-2-(2-(qui oj½-2-yΐ)vinyl)imidazo[l ,2-έ] yridazm-3- yi)pbenyl)- 1 ,2,4-oxadiazo]-5(4H)-oiie

i !- N R (400 MHz, DMSO-fifc) δ (ppm): 8.32 i d. ./ 8.4 Hz, ill), 8.16 i d. ./ 5.6 Hz, 1H), 8.03 (d, J = 8.0 Hz, 2H), 7.97 - 7.71 (m, 8H), 7.55 (t, J= 7.2 Hz, 1H), 6.46 (d, J = 5.6 Hz, 1 H), 4.1 1 - 4.10 (m, 4H), 3.88 - 3.87 (m, 4H). Mass Spectrum (LCMS, ESI pes.): Calcd. for C29H23N7O3: 518.2 (M + H); Found 518.1.

Example 43

(5)-3-Memyl-2-(4~(8-morpholffl^

yl)benzamido)butanoic acid trifluoroaceiic acid salt (Cpd 101)

A. (5 fef i-Butyl 3-methyl-2-(4-(4,4 _> 5,5-tetramethyl- 1 ,3,2-dioxaborolan-2- yl)benzamido)butanoa.te, 43a

, 43a

To a solution of 4-(teiramethyl- 1 ,3,2-dioxaborolan-2- l)benzoic acid (2.0 g, 8.1 mmoi) and {S)-tert-bxxty\ 2-amino-3-methylbutanoate (2.0 g, 9.5 mmoi) in DMF (10 mL) were added HATU (6.1 g, 16 mmol) and DIEA (4.2 g, 33 mmol). The reaction mixiure was stirred at rt overnight. The reaction was then quenched with water ( 100 mL). The resulting mixture was extracted with DCM (2 x 100 mL), and the organic layer was concentrated under reduced pressure. The residue obtained was purified by flash column chromatography on silica gel (EtOAc/petroieum ether (1 :50)) to obtain compound 43a as a white solid. Mass Spectrum (LCMS, ESI pos.): Calcd, for C22¾ ₄ B 0 ₅ : 404.3 (M + ! i ) Found 404.1 .

B. (S)-tert-Butyl 3-methyl-2-(4-(8-morpholino-2-(qui ^" nolin-2- ylethynyI)imidazo[l -0]pyridazin~3-yl)benzamido)butanoa.te, 43b

Compound 18b was subjected to Suzuki coupling conditions with compound 43a as described in Example 38, Step A to obtain compound 43b as a yellow solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for CJTHJSNGO : 631.3 (M + H): Found: 631.0. (S)-3-Methyl-2-(4-(8-morpholino-2-(quinolin-2-ylethynyl)imid azo[l ,2- )]pyridazin- 3-yi)benzamido)buianoic acid trifiuoroacetic acid salt

Compound 43b (0.20 g, 0.32 mmol) was treated with TFA as described in Example 41 , Step H to obtain the title compound 161 as an orange solid. Ή-NMR (400 MHz, !)MSO-(7, + !) ><)} δ (ppm): 8.42 i d. ./ 8.0 Hz, i l l ;. 8.23 - 8.18 (m, 3H), 8.07 · ^■ 7.99 (m, 4H), 7.84 - 7.78 (m, 1H), 7.69 ^■ 7.65 (m, 2H), 6.45 (d, J= 3.6 Hz, 1H), 4.30 (d, J= 6.0 Hz, 1H), 4.01 - 3.90 (m, 4H), 3.88 - 3.78 (m, 4H), 2.21 (d, J = 10.4 Hz, 1H), 0.98 (s, 6H). Mass Spectrum (LCMS, ESI pos.): Calcd. for ¾3Η ₃ οΝ ₆ 0 ₄ : 575.2 (M + H), Found: 575.3. Following the procedure described in Example 43 above, and substituting suitably selected and substituted reagents, starting materials and conditions as would be readily apparent to those skilled in the art, the following representative compounds of the present invention were prepared.

Cpd Characterization

yl)benzamido)acetic acid

U-\ViR (300 MHz, DMSO-Jt _f ) δ (ppm): 8,98 - 8.97 (m, IH), 8.32 (d, J= 8.4

66 Hz, IH), 8.16 lil../ 5.7 Fiz, IH), 8.10 id. J 8.1 Hz, 111).7.99 - 7.70 (m, 8F1), 7.55 i i. J 7.2 Hz, IH), 6.45 id. J= 5.7 Hz, IH), 4.11 - 410 (m, 4H), 4.00 - 3.98 (d, J - 4.5 Hz, 2H), 3.89 ^■ 3.87 (m, 4H). Mass Spectrum (LCMS, ESI pos.): Caicd. for C _¾ )H ₂ 6N ₆ 0 ₄ : 535.2. (M + H); Found: 535.3.

2-(4-(8-Mo^holinQ-2-(2-(qumolfe-2-y¾

yi)benzamido)acetic acid trifluoroacetic acid salt

il-W!R (300 MHz, DMSO-t¾) δ (ppm): 8.90 (t, ./ i 1.7 Hz, IH), 8.69 (d, ./

68 8.4 Hz, IH), 8.16-8.14 (m, 3H), 7.97-7.92 (m, 3H), 7.81-7.72 (m, 4H), 6.34 (d, ./ 5.7 Hz, IH), 3.98 (d, J= 5.7 Hz, 2H), 3.74-3.72 (m, 4H), 3.56-3.45 (m, 8FI). Mass Spectrum (LCMS, ESI pos.) Caicd. For C;.J UNr.O.: 537.2 (M + H), Found 537.1.

(S,i^-l-(4-(8-Mo holmo-2-(2-(qui olm-2-yl)vmyl)imidazo[l,2- J] yridazin-3- yI)benzoyI)pyrrol ^" idine-2-carboxyIic acid trifluoroacetic acid salt

il-W!R (300 MHz, DMSO-dg) δ (ppm): 8.73 (d, J= 8.7 Hz, IH), 8.44 - 7.59

71 (m, 12H), 6.42 (d, J = 5.7 Hz, IH), 4.48 - 4.45 (m, IH), 4.06 - 4.04 (m, 4F1), 3.86 - 3.84 (m, 4FI), 3.63 - 3.61 (m, 2H), 2.34 - 2.31 (m, IH), 1.93 - 1.90 (m, 3H). Mass Spectrum (LCMS, ESI pos.): Caicd. for C ₃ 3¾ ₆ 0 ₄ : 575.2 (M + H); Found: 575.1. (S)- l-(4-(8-Mo^holino-2-(2-(quinolin-2-yj e†hyl)imidazo[l ,2-0]pyrida2dn-3- yf)beiizoyf)pyrrolidme-2-carboxyfic acid trifluoroacetic acid salt

i ! - N R (300 MHz, DM80- -) δ (ppm): 8.67 (d, J 8.4 Hz, 1H), 8.15 - 7.92

72 (m, 4H), 7.76 ^■■ 7.45 (m, 6H), 6.29 (d, J = 5.7 Hz, 1H), 4.43 · ^■ 4.42 (m, 1H), 3.63 - 3.61 (til, 4H), 3.51 - 3.49 (m, 4H), 3.46 - 3.35 (m, 6H), 2.29 - 2.39 (m, 1H), 1.90 - 1.80 (m, M l ). Mass Spectrum (LCMS, EST os.): Calcd. for C33H32N6O4: 577.2 (M + H); Found: 577.1.

(5 ^, ,^)-3-Methyl-2-(4-(8-rao^holino-2-(2-(quino{in-2-yl)vi nyl)imidazo[^

6]pyridazm-3-yf)beiizamido)butar!oic acid trifluoroacetic acid salt

i ! - N R (300 MHz, DMSO-a¾ δ (ppm): 8.89 (d, ./ 8.4 Hz, IH), 8.50 fd, ./ 8.1 Hz, IH), 8.25 (d, J - 8.1 Hz, IH), 8.16 - 7.96 (m, 6H), 7.86 (t, J = 7.5 Hz,

73

IH), 7.72 (d, J = 8.4 Hz, 2H), 6.32 (d, / = 6.0 Hz, IH), 4.36 - 4.31 (m, IH), 3.65 - 3.57 (m, 6H), 3.50 - 3.48 (m, 4H), 2.26 - 2.19 (m, IH), 1.02 - 0.98 (m, 6H). Mass Spectrum (LCMS, ESI pos.): Calcd. for€¾¾4Ν ₆ 0 : 579.3 (M + H); Found: 579.1.

Example 44

(ii)-5-(8-Moiphoiii j-2-(2-(qidnolm-2-yl)vinyi)

Compound 14c (0.40 g, 0.92 mmol) was subjected to Suzuki coupling conditions with 5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)pyrid ^" in-2-amine (0.24 g, 1 .1 mmol) as described in Example 38, Step A, to obtain the title compound 18 as a yellow solid. i i -Vvl (300 MHz, DMSO-f¼) δ (ppm): 8.56 (d, . 8.7 Hz, 1H), 8.31 - 8.27 (m, IH), 8. 15 - 8.13 (m, 2H), 8.07 - 8.02 (m, 2H), 7.94 - 7.64 (m, 5H), 6.95 (d, J= 9.0 Hz, I H), 6.44 (d, J= 5.7 Hz, IH), 4.13 - 4.08 (m, 6H), 3.88 - 3.87 (m, 4H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C v,i L ;X (>: 450.2 (M + H); Found: 450.2.

Example 45

-(5-(8-Mo holmo-2-(2-(qui o]m-2-yl)vi yI)imidazo[l ,2-Z?] yΓidazin- yl)pyr d 17)

A. (is)-Ethyl 2-(5-(8-mo holino-2-(2-(qumolin-2-yl)vm l)imidazo[l ,2- 6]pyiidazin-3-yl)

A mixture of compound 18 (0.15 g, 0.33 mmol), oxalaldehyde (19 mg, 0.33 mmol), in periodic acid (2 mL) and EtOH (2 mL) was stirred at 80 °C for 2 h. The reaction was then quenched by the addition of ice/water (100 mL). The solids formed were collected by filtration, and washed with Et ₂ 0 (2 x 20 ml.) to obtain compound 45a as a yellow solid. Mass Spectmm (LCMS, ESI pos.): Calcd. for C30H29N7O3: 536.2 (M + H); Found: 536.2. B. (^)-2-(5-(8-mo^holino-2-(2-(quinolm-2-yl)vinyl)imidazo[l,2- j]pyridazin-3- yl)pyridin-2-ylamino)acetic acid, Cpd 17

To a solution of compound 45a (0.13 g, 0.24 mmol) in THF (3 mL) and water (2 ml.) was added LiOH (30 mg, 1.25 mmol). The resulting solution was stirred at rt for 4 h, and concentrated under reduced pressure to remove volatile solvent. The pH of the resulting soluiion was adjusted to -~4 with IN HCl solution. The solids formed were collected by filtration. The crude solid was further purified by flash column chromatography on silica gel (1 % -10 % MeOH/DCM) to obtain the title compound 17 as a red solid. 'H-NMR (300 MHz, DMSO-i¾ δ (ppm): 8.53 (d, ./ 8.7 Hz, 1H), 8.31 ■· 8.16 (m, 6H), 8,06■■ 8.03 (m, 2H), 7.94■■ 7.78 (m, 3H), 7.65 (t, J - 7.5 Hz, IH), 7.16 (d, J = 9.3 Hz, I H), 6.47 (d, J= 5.7 Hz, IH), 4.19 - 4.02 (m, 4H), 3.94 - 3.80 (m, 4H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C28H25 7O3: 508.2 (M + H); Found: 508.2.

Example 46

4-(3-(6-(lH-Tetrazol-5-yl)pyridin-3-yl)-2-(2-(qtunolin-2-yl) ethyl)imidazo[l,2- / ]pyridazin-8-y cid salt (Cpd 31)

A, 4-(3-Bromo-2-(2-(quinolin-2-yl)ethy{)imidazo[l,2-0]pyridazin -8- yljniorphoiine, 46a

A. mixtur of compound 14c (2.0 g, 4.6 mmol), 4- methylbenzenesuffonohydrazide (2.6 g, 14 mmol), and NaOAc (1.9 g, 23 mmol) in DME (30 mL) and water (6 niL) was stirred at SO °C overnight under a nitrogen atmosphere. The reaction mixture w ^r as allowed to cool to rt and treated with 50 mL water. The solids formed were collected by filtration to obtain compound 46a as a white solid. Mass Spectrum (LCMS, EST pos.): Calcd. for C2iH ₂ oBrN _S O: 438.1 (M H), Found: 438.2.

B. 5-(8-Mo^holino-2-(2-(qumolin-2-yl)ethyl)imidazo[ l,2-6]pyridazin-3- y pico!inomtrile, 46b

Compound 46a (0.5 g, 1 .1 mmol) was subjected to Suzuki coupling conditions with 5-(4,4,5,5-tetramethyl- l ,3,2-dioxaborolan-2-yl)picoli ^" nonitrile as described in Example 38, Step A, to obtain compound 46b as a yellow solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C27H23 7O: 462.2 (M + H), Found: 462.2.

C. 4-(3 -(6-( -Tetrazol-5-yl)pyridin-3-yI)-2-(2-(quinolin-2-yl)ethyl)imida z

Zj]pyridazin-8-y])morpholine trifluoroacetic acid salt, Cpd 31

A solution of compound 461) (0.40 g, 0.87 mmol) in DMF (3 mL) was treated with sodium azide (0, 17 g, 2.6 mmol) and irietlxyiamine hydrochloride (0.60 g, 4.3 mmol). The resulting mixture was stirred at 1 10 °C for 2 h, allowed to cool to rt, treated with water (50 mL) and extracted with DCM (2 x 50 mL). The combined organic layers were dried over NajSC , filtered and concentrated to obtain a residue, which was then purified by reverse phase Prep-FiPLC io yield the title compound 31 as a yellow solid. Ή-NMR (300 MHz, DMSG-i/ ₆ ) δ (ppm): 9.02 (s, 8.60 - 3.50 (m, 1H), 8.32 - 8.24 (m, 2H), 8.17 - 7.95 (m, 3H), 7.81 - 7.67 (m, 3H), 6.39 (d, J - 6.0 Hz, 1 H), 3.85 - 3.78 (m, 4H), 3.65 - 3.59 (m, 4H), 3.51 (s, 4H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C^HMNIOO: 505.2 (M + H): Found: 505.2. Example 47

(£)--5--(8-'Morphoiino--2--^

A mixture of compound 14c (0,2.0 g, 0,46 mmol), 5-(4,4,5,5-teiramethyl- 1,3,2- dioxaborolan-2-yi)pyridm-2-ol (0.30 g, 1.4 mmol), Pd(PPl¾)4 (27 mg, 0.02.0 mmol) and potassium carbonate (0.16 g, 1.1 mmol) in 1,4-dioxane: ater (1 :5 mL) was stirred at 80 °C for 2 h under a nitrogen atmosphere. The reaction mixture was cooled to rt and treated with water (50 mL). The resulting mixture was extracted with DCM (2 x 30 mL). The combined DCM layers were dried over a?S04, filtered and eonceniraied under reduced pressure. The residue obtained was purified by flash column chromatography on silica gel (1 -2% MeOH/DCM) to afford a semi-pure product, which was further purified by Prep-HPLC to give the title compound as an orange solid. Ή- NMR (300 MHz, DMSO-Λ.) δ (ppm): 8.66 - 8.63 (m, 1H), 8.29 - 8.26 (m, 1H), 8.18 - 7.86 (m, 5H), 7.80 - 7.68 (m, 4H), 6.55 (d, ./ 9.3 Hz, i l l ). 6.44 i d. J = 6.0 Hz, lH), 4.15 - 4.05 (m, 4H), 3.90 - 3.83 (m, 4H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C2 ₆ H22N ₆ O2: 451.2 (M + H): Found: 451.2.

Example 48

-(4~(8-Morpholino-2-(2-(quinolin-2-yl)vinyl)imidazo[l ,2-6]pyridazin-. yl)piperidin- 1 - d salt (Cpd 29)

A. (E)-terl-Batyl 4-(8-morpholino-2-(2-(quinolin-2-yi)vinyl)imidazo[ 1 ,2- i>]pyridazin-3-y{)pip

A solution of compound 41c (0.40 g, 0.96 rnmol), 2-methylquinoline (0.17 g, 1.2 ramol) and bromotrimethylsilane (0.32. g, 2.9 mraol) in DMF (4 niL) was stirred at 80 °C for 5 h and allowed to cool to rt. The solids formed were collected by filtration, and washed with methanol (50 mL) to obtain compound 48a as a brown solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for ( Y i L-.X.-.O ;: 541.3 (M + H), Found: 541.2.

B. teri-Butyl 2-[4-[8-(mo^holin-4-yl)-2-[(j¾-2-(quinolin-2- yl)ethenyi]imidazo[.l ,2-Z?]pyridazin-3-y]]piperidin- .l -yl]acetate, 48b

A solution of compound 48b (0.50 g, 0.92 mmol) in TFArDCM (1 :3, 4 mL) was stirred at rt for 2 h and then concentrated under reduced pressure. The residue obtained was dissolved in DMF (8 mL) and treated with DIEA (0,29 g, 2.3 mmol) and tert- butyl 2-bromoacetate (0.27 g, 1.4 mmol). The reaction mixture was stirred at rt for 5 h, and treated with water (10 mL). The solids formed were collected by filtration and washed with MeOH to obtain compound 48b as a yello solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C32H38N6O3: 555.3 (M + H), Found: 553.2.

C. (£)-2-(4-(8-mo hoίmo-2-(2-(qui oli -2-yl)vi l)imidazo[l ,2-/ ] yridazi ^■ -3- yl)piperidin- l -yl)acetic acid irifluoroacetic acid salt, Cpd 29

Compound 29 was obtained from compound 48b as described in Example 41 , Step H as a yellow solid. Ή-NMR (300 MHz, DMSO- ) 8 (ppm): 8.56 (d, J = 8.7 Hz, I i n. 8.18 - 8.04 (m, 5H), 7.86 (t, ,/ 7.2 Hz, III), 7.73 - 7.63 (m, 2H), 6.37 (d, ./ 5.7 Hz, 1H), 4.22 (s, 2H), 4.12 ^■■ 4.05 (m, 4H), 3.90 · ^■ 3.80 (m, 5H), 3.76 - 3.65 (m, 2H), 3.38 - 3.24 (m, 2H), 2.85 - 2.73 (m, 2H), 1.98 - 1.95 (m, 2H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C28H30N6O3: 499.2 (M + H); Found: 499.3.

Example 49

(^)-2-(2-(3-(6-(4H- 1 ,2,4-Triazol-3-ylthio)pyridin-3 -yl)-8-morpholinoimidazo[ 1 ,2- 6]pyri d 22)

A. (^)-4-(3-(6-Chloropyridm-3-y])-2-(2-(quinolin-2-yi)vmy3)imid azo[l ,2- 0]pyridazm-8-yl)mo

, 49a

Compound 14c (0.50 g, 1.2 mmol) was subjected to Suzuki coupling conditions with 2-chloro-5-(4,4,5,5 etramethyl- l ,3,2-dioxaborolan-2-yl)pyridme as described in Example 38, Step A to obtain compound 49a as a yellow solid. Mass Spectmm (LCMS, ESI pos.): Calcd. for i > C !V,0 : 469.1 (M + H); Found: 469.2.

B. (£ -2-(2-(3-(6-(4H- 1 ,2,4-Triazol-3-ylthio)pyridin-3-yl)-8- mo holmoimidazo[l ,2-ή]pyridazi -2-yl)vinyl) umol ^" ine, Cpd 22

A solution of compound 49a (0.50 g, 1.1 mmol) in DMA (3 mL) was treated with 4H- l ,2,4-triazole-3-th ol (0.16 g, 1.6 mmol) and potassium /er/-butoxide (0.24 g, 2.1 mmol). The resulting mixture was stirred at 140 °C for 3 h, allowed to cool to rt and treated with water (10 mL). The solids obtained were collected by filtration and purified by RP Prep-HPLC. The title compound 22 was obtained as a yellow solid. Ή-NMR (300 MHz, DM SO-/,) δ (ppm): 14.65 (s, 1H), 8.86 (s, I M ). 8.74 (s, 1H), 8.31 (d, J = 8.7 Hz, I H), 8.1 3 i d. ./ 5.7 Hz, 1H), 8.08 - 8.05 (m, i 1 1 i. 7.99 - 7.92 (m, M l ⁾ . 7.81 - 7.70 (m, 3H), 7.58 - 7.52 (m, 1H), 7.36 (d, J = 7.8 Hz, IH), 6.44 (d, J= 6.0 Hz, 1H), 4.15 ^■■ 4.05 (m, 4H), 3.85 ^■■ 3.75 (m, 4H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C28H23 9OS: 534.2 (M + H); Found: 534.2.

Following the procedure described in Example 49 above, and substituting suitably selected and substituied reagents, starting materials and conditions as would be readily apparent to those skilled in the art, the following representative compound of the present invention was prepared.

Example 50

5-(4-(8-Μοφηο1ϊηο-2-(2-( ώηοίίη-2^

yl)ph d 70)

A. Methyl 2-(4-bromophenyl)-2-hydroxyacetate, 50a

To a solution of 2-(4-bromophenyl)-2-hydroxyacetic acid (5.0 g, 22 mmol) in MeOH (10 niL) was added 2,2-dimethoxypropane (3,4 g, 33 mmol) and 4- methyibenzene- 1 -sulfonic acid (2.0 mg, 0,010 mmol). The resulting solution was stirred overnight at 55 °C and allowed to cool to rt. The resulting mixture was concentrated under reduced pressure and poured into water ( 100 ml,), The solids were collected by filtration and washed with hexanes (2 x 20 mL) to obtain compound 50a as a gray solid. 'PI-NMR. (300MHz, CDC1 ₃ ) δ (ppm): 7.54 -7.51 (m, 2H), 7.35-7.28 (m, 2H), 5.18-5.16 (m, 1H), 3.793 (s, 3H), 3.51-3.49 (m, 1H).

B. 2.-dioxaboroJan-2-yl)phenyl]acetate,

A solution of compound 50a (5,0 g, 20 mmol) and 4,4,4 ^, ,4',5,5,5',5'-octamethyi- 2,2'-bi( 1 ,3,2-dioxaborolane) (6.8 g, 27 mmol) in DMF (20 mL) was purged with N?. Pd(OAc)2 (0.46 g, 2.1 mmol) and PPh ₃ (1.1 g, 4, 1 mmol) were added, followed by KOAc (6,0 g, 61 mmol). The reaction mixture was stirred overnight at 80 °C under a nitrogen atmosphere, and allowed to cool to rt. The solids were removed by filtration. The filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtO Ac/petroleum ether (1 :50 v/v)) to obtain compound 50b as a white solid. Mass Spectrum (LCMS, ESI pos.): Caled. for C M - HO 293.1 (M + ! i i: found 293.2. 2-Hyclroxy-2-(4-(8-mo holino-2-(2-(quinolin-2-yl)eίhyl)imidazo[l ,2- Zjjpyridazin-3-y1)ph

Compound 46a was subjected to Suzuki coupling conditions with methyl 2- hydroxy-2-(4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)phenyl)acetate as described in Example 38, Step A to obtain compound SOc as a white solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for ¾οΗ ₂ 6Ν ₆ 0 ₄ : 524.2 (M + H); Found: 524.2.

D. 5-C4-(8-Morpholmo-2-(2-Cquinolm-2-yl)ethyl)imidazo[l ,2- ?]pyridazin-3- yl)phenyl)oxazolidine-2,4-dione, Cpd 70

A solution of compound SOc (0.15 g, 0.29 mmoi) and 2,2,2-trichloroacetyl isocyanate (81 mg, 0.43 mmoi) in dichloromethane ( 10 ml.) was stirred at rt for 30 m n and concentrated in vacuo. The residue obtained was dissolved in ethanol (1 0 mL), and TEA (87 mg, 0.86 mmoi) was added. The reaction mixture was heated at reflux for 2 h and allowed to cool to rt. Water (10 mL) was added. The solids formed were collected by filtration and washed with Et ₂ 0 (2 x 20 mL) to obtain the title compound 70 as a yellow solid. ! i- Wi k (300 MHz, DM80-i¾ + !) ·()} δ (ppm): 8.1 7 (d, J= 8.4 Hz, 1H), 8.00 i d. ./ 5.4 Hz, i l l ;. 7.88 (d. J 8.1 Hz, 2H), 7.70 i t. ./ 7.8 Hz, 1H), 7.54 - 7.48 (m, 3H), 7.37 - 7.31 (m, 3H), 6.27 (d, J = 5.7 Hz, I H), 5.27 (s, 1H), 3.90 - 3.73 (m, 4H), 3.68 - 3.56 (m, 4H), 3.34 - 3.28 (m, 4H). Mass Spectnim (LCMS, ESI pos.): Calcd. for C ₃ oH ₂ 6N ₆ 04: 535.2 (M + H); Found: 535.2.

Following the procedure described in Example 50 above, and substituting suitably selected and substituted reagents, starting materials and conditions as would be readily apparent to those skilled in the art, the following representative compound of the present invention was prepared. Cpd Characterization

(Z -5-(4-(8-Moφholmo-2-(2-(quinolin-2-yl)vinyl)imidazo[l ,2- ] yridazin-3- yl)phenyl)oxazolidine-2,4-dione trifluoroacetic acid salt

! ! - N R (300 MHz, DMSO-c¼) δ (ppm): 12.26 (s, 1H), 8.60 (d, J = 8.4 Hz,

65 1H), 8.16 (d, J = 5.7 Hz, 2H), 8.09 - 8.04 (m, 2H), 7.96 - 7.71 (m, 5H), 7.68 - 7.65 (ra, M l ). 6.47 (d, J = 5.7 Hz, 1 H), 6.20 (s, 1 H), 4.1 1 - 4.09 (m, 4H), 3.89 - 3.87 (m, 4H). Mass Specirum (LCMS, ESI pos.): Calcd.for CsoEbiNeCU: 533.2 (M + H); Found: 533.1.

Example 51

l ~Methyi -[4-[8-(morpholin-4-yl)-2~[2-(quiiiolin-2-yl)ethylJimidazo[ l ,2-6]pyridaz

3-yl]phenyl]-4,5-dihydro- 1H- 1 ,2,4-triazol-5-one (Cpd 78)

1 -[(£)-[(4-Bromophenyl)methylidene]amino]- 1 -methylurea, Sla

To a solution of 4-bromobenzaldehyde (4.3 g, 23 mmol) and 1 -amino- 1 - methylurea (2.5 g, 28 mmol) in EtOH (40 mL) was added AcOH (2.5 mL) and water (4.5 mL). The resulting solution was stirred overnight at 80 °C and allowed to cool to rt. A precipitate formed by the addition of Et ₂ 0 (50 mL), The solids were collected by filtration and compound 51 a was obtained as a white solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for (¼Η ₁₀ ΒΓΝ ₃ Ο: 256.0 (M + H), Found 256.1.

B. 3-(4-Bromophenyl)~ 1 -methyl-4,5-dihydro- 1H- 1 ,2,4-triazol-5-one, Sib

To a solution of compound 51a (5.8 g, 23 mmol) in AcOH (20 mL) was added Br _? (7.3 g, 46 mmol) dropwise at 95 °C. The reaction mixture was stirred for another 30 min at 95 °C and allowed to cool to rt. Et ₂ 0 (100 mL) was added. The solids formed were collected by filtration and washed with Et ₂ 0 (2 x 30 mL) to obtain compound Sib as a yellow solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C ₉ H ₈ BrN ₃ 0: 254.0 (M + H), Found 254.1.

C. 3-(4-Bromophenyl)- l -methyl-4-[[2-(tr^^

1 H- 1 ,2,4-triazol-5-one, Sic

To a solution of compound 51b (1 .0 g, 3.9 mmol) in DMF (5 mL) was added sodium hydride (0.2 g, 5.0 mmol) in portions at 0 °C. The mixture was stirred for 20 min, then 2-(trimethylsilyl)ethoxymethyl chloride (0.73 g, 4.4 mmol) was added dropwise. The reaction mixture was stirred at rt for 2. h. EtOAc (100 mL) was added. The organic layer was washed with water and brine, dried over N 2SO/|, filtered and concentrated to give a residue, which was purified by flash column chromatography on silica gel (EtO Ac/petroleum ether (1 :5 v/v)) to afford compound 51c as a yellow solid. Mass Spectrum (LCMS, EST pos.): Calcd. for 384.1 (M + H), Found 384.1.

D, 1 --Methyl- 3 - [4-(tetramethyl- 1 ,3,2-dioxaborolan-2-yl)phenylJ-4-[[2-

(trimethy]silyl)ethoxy]methyj.]-4,5-dihydro- lH- l ,2,4-triazol-5-one, Sid

Compound Sid was prepared from compound Sic (0.50 g, 1.3 mmoi) as described in Example 50, Step B, as a white solid. Mass Spectrum (LCMS, ESI pos,): Calcd. for C21H34BN3O4S1: 432.2 (M + H), Found 432.4.

E. l-Methyl-3 4-[8-(morpholm-4-yI)-2-[2-(qu

Z)]pyridazin-3-yl]plienyl]-4~[[2.-(trimethylsiiy1)ethoxy]met hy

i,2,4-triazol-5-one, 51e

Compound 46a was subjected to Suzuki coupling conditions with compound Sid as described in Example 38, Step A to obtain compound 51e as a light yellow solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C36H ₄₂ N ₈ i¾Si: 663.3 (M + H); Found: 663.4.

F. 1-Με 1-3-[4-[8-^οφΗο1ϊη-4^1)-2-[2-( υώο1ίη-2^1)6ί1ινΙ]ϊηιΐά ζο[1,2- i>]pyridazin-3-y1]phenyl]-4,5-dihydro- 1H- 1 ,2,4-triazol-5-one, Cpd 78

A solution of compound 51 e (0.20 g, 0.29 mmol) in TFA/DCM(1 :3 v/v, 5 mL) was stirred overnight at rt. The mixtitre was concentrated under reduced pressure, and the residue obtained was treaied with Et?0 (10 mL). The solids formed were collected by filtration, washed with Et ₂ 0 (2 x 20 mL), and treated with ΜεΟΗ (5 ml.) and DJEA (0.5 mL). The resulting solution was stirred at 70 ^C C for 30 min and allowed to cool to rt. The solids formed were collected by filtration and washed with Et ₂ 0 (2 x 20 mL) to obtain the title compound 78 as a white solid. Ή-NM (300 MHz, DMSO-d ₆ ) δ (ppm): 12.30 (s, IH), 8.21 (d, J = 8.7 Hz, I H), 8.08 (d, J= 5.4 Hz, IH), 7.85-7.92 (m, 4H), 7.76 - 7.67 (m, 3H), 7.55 - 7.50 (m, IH), 7.41 (d, J = 8.4 Hz, I H), 6.34 (d, J = 5.7 Hz, IH), 3.92 - 3.85 (m, 4H), 3.78 - 3.70 (m, 4H), 3.39 ^■ · 3.34 (m, 7H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C ₃ oH2s s0 ₂ : 533.2 (M + H); Found: 533.3.

Following the procedure described in Example 51 above, and substituting suitably selected and subsiituted reagents, starting materials and conditions as would be readily apparent to those skilled in the art, the following representative compounds of the present invention were prepared.

Example 52

1 -(4-(8-Μοφηο1ώο-2-(2-(ςαίηοΠη-2^1^

1 ,2-dihydro- 1 ,2,4-triazol-3-one trifluoroacetic acid salt (Cpd 59)

A. 1 -(4-Bromophenyl)semicarbazide, 52a

A solution of 1 -(4 -bromophenyl) hydrazine hydrochloride (25 g, 1 10 nimol) and KOCN (0.73 g, 9.0 ramoi) in water (500 mL) was stirred overnight at 40 °C, and allowed to cool to rt. The solids formed were collected by filtration to obtain compound 52a as a grey solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C ₇ HsBrN ₃ 0: 230.0 (M + H), Found 230.2.

B. 1 -(4-Bromopheny])- 1 ,2-dihydro- 1 ,2,4-triazoi-3-one, 52b

A solution of compound 52a (10 g, 43 mmol) and triethoxymethane (300 mL) was stirred at 120 °C for 2 h and allowed to cool to rt. The solids were collected by filtration and washed with Et ₂ 0 (2 x 50 mL) to obtain compound 52b as a grey solid. Mass Spectrum (LCMS, EST pos.): Calcd. for C _s H ₆ BrN _? 0: 240.0 (M + H), Found

240.2. C. ί -(4-Bromopheiiyl)-2-((2-(trimethylsiiyl)ethoxy)methy])- 1 ,2-dihydro- 1 ,2,4- triazoi-3-οηε. 52c

Compound 52b (30.0 g, 125 rnmol) was treated with SEMC1 as described in Example 51 , Step C to obtain compound 52c as a white solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C . _: ! Hr\ _; 0 >S: 370.1 (M + H), Found 370.2.

D. l-(4-(4,4 _! 5,5-Teffamethyl-l _! 3,2-dioxaborolaii-2-y1)phenyl)-2-((2- (trimethylsilyl)ethoxy)meth 1 ,2,4-triazol-3-oiie, 52d

Compound 52d was prepared from compound 52c (30.0 g, 81 ,3 mmoi) using the procedures described in Example 50, Step B, as a a grey solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C ₂₀ H3 ₂ BN ₃ O ₄ Si: 418.2 (M + H), Found 418.4. l-(4-(8-Mo^holmo-2-(2-(qumolin-2-yl)ethyl)rmidazo[l,2-6]pyri dazm-3- yl)phenyl)-2-((2-(trimethy 3silyl)ethoxy)methy 1)- 1 ,2-dihydro- 1 ,2,4-triazol-

52ε

Compound 46a was subjected to Suzuki coupling conditions with compound 52d using the procedures described in Example 38, step A, to obtain compound S2e as a white solid. Mass Spectrum (LCMS, EST pos.) Calcd. For CM¾9lsl9(¾Si: 649.3(M + H), Found 649.2.

F. l-(4-(8-Morpholmo-2-(2-(quiiiolm-2-yl)ethyl)imidazo[l,2-6]py iidazin-3- yl)phenyl)- 1 ,2-dihydro- 1 ,2,4-triazol-3-one trifluoroacetic acid salt, Cpd 59 A solution of compound 52e (45 mg, 0.070 mmol) in TFA:DCM( 1 :3 v/v, 5 mL) was stirred overnight at rt. The resulting mixture was concentrated under reduced pressure and the residue obtained was treated with F¾0 (10 mL). The solids formed were collected by filtration and washed with Et ₂ 0 (2 x 20 mL). The title compound 59 was obtained as a yellow solid. 'PI-NMR (300 MHz, DM80-d ₆ ) δ (ppm): 8.92 i d. ./ 8.4 Hz, 1H), 8.87 (s, 1H), 8.25 (d, .1 8.4 Hz, 1H), 8.06■· 8.03 (m, 3H), 7.94■■ 7.85 (m, 2H), 7.72 (d, J= 8.4 Hz, 2H), 7.64 (d, J= 8.4 Hz, 2H), 6.30 (d, J = 5.7 Hz, IH), 3.56 - 3.43 (m, 12H). Mass Spectrum (LCMS, ESI pos.): Calcd. for 519.2 (M + H): Found: 519.1.

Following the procedure described in Example 52 above, and substituting suitably selected and substituted reagents, starting materials and conditions as would be readily apparent to those skilled in the art, the following representative compounds of the present invention were prepared. Cpd Characterization

(^-1-(4-(8-Μ φ ^η οΗ ^η ο-2-(^^

yi)pheiyl)-lH-l,2,4-triazoi-3-ol trifluoroacetic acid salt

¹ H-NMR (300 MHz, DMSO-ik) δ (ppm): 9.02 fs, IH), 8.66 (d../ 9.0 Hz, IH),

54

8.21 - 7.70 (m, 12H), 6.46 (d, J= 6.0 Hz, IH), 4.10 - 4.08 (m, 4H), 3.89 ^■ 3.87 (m, 4H). Mass Spectram (LCMS, ESI pos.): Calcd. for C29H24N8O2: 517.2 (M + H); Found: 517.2.

yI)pyridin-2-yl)- 1 ,2-dihydro- 1 ,2,4-triazoI-3-one trifluoroacetic acid salt 1 H-NMR (300 MHz, DMSO- ) δ (ppm): 9.13 (s, IH), 8.82 - 8.75 (m, 2H),

56 8.44 - 8.39 (m, 2H), 8.21-8.10 (m, 4H), 8.07 - 7.85 (m, 3H), 7.77 (t, J= 7.5 Hz, IH), 6.50 (d, J= 5.7 Hz, IH), 4.13 ^■■ 4.11 (m, 4H), 3.91 ^■■ 3.89 (m, 4H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C28H23N9O2: 518.2 (M + H); Found: 518.1.

(£)-1-(2-Ρ1υοΓο-4-(8^οφΗο1ίηο-2-(2-( ηίηο1ίη-2^1)νη 1)ίηιίά3ζο[1,2- 6]pyridazm-3-yi)pbenyl)- 1 ,2-dihydro- 1 ,2.,4-triazoi-3-one

1 H-NMR (300 MHz, DMSO- ) δ (ppm): 11.64 (br, IH), 8.73 (d, J= 2.1 Hz,

158 ill).8.33 id../ 8.7 Hz, Hi), 8.18 (d, ,/ 5.4 Hz, ill).7.99 - 7.87 (m, 5H), 7.81 (d, J = 4.2 Hz, 2H), 7.76 - 7.71 (m, 2H), 7.55 (t, J= 7.5 Hz, IH), 6.47 (d, J = 6.0 Hz, IH), 4.11 - 4.10 (m, 4H), 3.88 - 3.87 (m, 4H). Mass Spectram

(LCMS, ESI pos.): Calcd. for Ca^F gO _? .: 535.2 (M + H); Found: 535.1.

Example 53

l-(4-(8-Mo holmo-2-(2-(qumolin-2-yI)ethyl)imidazo[l ₅ 2-6] yridazi - lH-tetrazol-5(4H)-one (Cpd 62)

A. 1 -(4-Bromophenyl)- lH-tetrazoi-5(4H)-one, S3a

To a solution of 1 -bromo-4-isocyanatobenzene (5.0 g, 25 nimol) and sodium azide (5.0 g, 77 mmol) in TFIF (30 mL) was added a solution of AICF (4.0 g, 30 mmol) in TFIF (18 mL) dropwise. The reaction mixture was heated to reflux overnight. The organic solvent was removed under reduced pressure, then water (50 mL) was added. The solids formed were collected by filtration to obtain compound 53a as a white solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C ₇ Fi ₅ BrN ₄ 0: 241.0 (M + H), Found 241 .1.

B. l -(4-Bromophenyl)-4-((2-(trimethylsilyl)ethoxy)methyl)- lH-tetrazol

one, 53b

S3b Compound 53a was treated with SEMC1 as described in Example 51, Step C to obtain compound S3b as a white solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C .11 lirViO.-Si: 371.0 (M + KQ, Found 371.1.

C. l-(4-(4,4,5,5-Tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)-4- ((2- (trimethy3silyl)ethoxy)methyl)-lH-tetrazol-5(4H)-one, 53c

,53c

Compound 53c was prepared from compound 53b using the procedures described in Example 50, Step B. Mass Spectrum (LCMS, ESI pos.): Calcd. for ( !L BX-O-Si: 419.2 (M + 111 Found 419.2.

D. l-(4-(8-Morpholmo-2-(2-(qumolm-2-yl)ethyl)miidazo[l,2-6]pyri dazin-3- y])phenyl)-4-((2- lH-tetrazol-5(4H)-one, S3d

Compound 46a (0.30 g, 0.68 mmol) was subjected to Suzuki coupling conditions with compound 53c using the procedures described in Example 38, Step A to obtain compound 53d as a white solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for i uLA Ch i: 650.3 (M + IT); Found: 650.2. E. i -(4-(8-M φhoiino-2-(2-(qumoiin-2- l)ethyi)imidazo[.l ,2- J] yridazin-3- yl)phenyl)- lH-teirazol-5(4H)-one, Cpd 62.

The title compound 62 was prepared from compound 53d using the procedures described in Example 51, Step F. ¹ H-NMR. (300 MHz, DMSO-c¾ 8 (ppm): 8.1 8 d, J ----- 8.7 Hz, 1H), 8.04 (d, J = 5.7 Hz, I H), 7.89 - 7.85 (m, 4H), 7.69 - 7.66 (m, 2H), 7.54 - 7.51 (m, 1H), 7.34 (d, J = 8.4 Hz, 1H), 6.31 (d, J = 6.0 Hz, M b . 3.81 - 3.79 (m, 4H), 3.68 - 3.66 (m, 4H), 3.36 - 3.35 (m, 2H), 3.17 - 3.16 (m, 2H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C ₂₈ H ₂₅ N ₉ 0 ₂ : 520.2 (M + H); Found 520.1 .

Following ihe procedure described in Example 53 above, and substituting suitably selected and substituted reagents, starting materials and conditions as would be readily apparent to those skilled in the art, the following representative compound of the present invention was prepared.

Example 54

(£)-l -(4~(8-Morpholino-2-(2-(quinolin-2-yl)vinyl)imidazo[l,2-6]p^

yl)phenyl)piperidine-4-carboxylic acid trifluoroacetic acid salt (Cpd 100)

Ethyl l-(4-nitrophenyl)piperidine-4-carboxyla.t

To a solution of 1 -fluoro-4-nitrobenzene (3.0 g, 21 mmol) in DMSO (30 mL) was added ethyl piperidine-4-carboxylate (5.0 g, 32 mmol) and K2CO ₃ (5.9 g, 43 mmol). The resuliing mixture was stirred at 100 °C for 8 h, and allowed to cool to rt. EtOAc (300 mL) was added. The organic layer was washed with water (3 x 100 mL) and brine, dried over Na^SC! _* , filtered and concentrated to give a residue, which was purified by flash column chromatography on silica gel ( EtOAc /petroleum ether (1 :2 v/ ^' v)). Compound 54a was obtained as a yellow solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C _]4 L¼N ₂ 04: 279.1 (M + H), Found 279.1.

Ethyl l -(4-aminophenyl)piperidine-4-carboxyla.t

To a solution of compound 54a (15 g, 51 mmol) in MeOH (100 mL) was added saturated NH ₄ CI solution (100 mL) followed by Fe< _S) (9.1 g, 160 mmol). The resulting mixture was stirred for 5 h at 80 °C and then 200 mL of EtOAc was added. The organic layer was washed with brine, dried over Na?804, filtered, and concentrated under reduced pressure. The residue obtained was purified by flash column chromatography on silica gel (EtO Ac/petroleum ether (1 :5 v/v)) to obtain compound 54b as a black solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C14H20N2O2: 249.2 (M + H), Found 249.0.

C. Ethyl 1 -[4-(tetramethyl- 1 ,3,2-dioxaborolan-2-yl)phenyl]piperidme-4- carboxylate, 54c

To a solution of 4,4,5, 5-tetramethyl -2-(tetrameth l-l,3,2-dioxaborolan-2-yl)- 1,3,2-dioxaborolane (6.1 g, 24 mmol) in MeCN (50 mL) was added BPO (98 mg, 0.38 mmol). The resulting mixture was stirred at rt for 10 min before compound S4b (5.0 g, 19 mmol) and i-BuONO (3.1 g, 30 mmol) were added. The reaction mixture was stirred at rt for 4 h, and EtOAe (200 mL) was added. The organic layer was washed with water and brine, dried over filtered and concentrated under reduced pressure. The residue obtained was purified by flash column chromatography on silica gel (EtO Ac/petroleum ether (1 :30 v/v)) to obtain compound 54c as a yellow solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C2 ₀ H ₃₀ BNO ₄ : 360.2 (M + H), Found 360.2.

D. (£)-Ethyl i-(4-(8-morpholino-2-(2-(quinolin-2-yl)vinyl)imidazo[l,2- Z?]pyridazm-3- yi)ph te, 54d

54d

Compound 14c (0.35 g, 0.76 mmol) was subjected to Suzuki coupling conditions with compound 54d using the procedures described in Example 38, Step A to obtain compound 54d as yellow oil. Mass Spectrum (LCMS, ESI pos.): Calcd. for C ₃₅ H ₃ 6 ₆ 0 ₃ : 589.3 (M + H), Found: 589.2.

E. (^-l -(4~(8-Moφholi o-2-(2-(quinolin-2-yl)villyl)imidazo[l,2-6] yridazin-3- yi)phenyl)piperidme-4-earboxylic acid trifluoroacetic acid salt, Cpd 100 To a solution of compound 54d (0.20 g, 0.34 mmoi) in THF ( 5 mL) was added a solution of LiOH (0.13 g, 3.4 mmoi) in water ( 1 mL). The resulting solution was stirred at rt overnight. The solution was concentrated under reduced pressure and diluted with water (10 mL). The pH of the solution was adjusted to ca. 3-4 with 2 N HQ solution. The solids were collected by filtration and washed with Et ₂ 0 (2 x 20 mL) to obtain 1 0 mg of a crude product, which was further purified by RP Prep- HPLC. The title compound 100 was obtained as a brown solid. ^J H-NM_R. (300 MHz, DM SO-;/, } δ (ppm): 8.55 - 8.56 (m, 1H), 8.14 - 8.06 (m, 4H), 7.96 - 7.79 (m, 3H), 7.69 - 7.64 (m, 1H), 7.58■■± .! 8.7 Hz, 2H), 7.17 l ./ 8.4 Hz, 2H), 6.41 ul ./ 5.7 Hz, 1H), 4.09 ^■■ 4.08 (m, 4H), 3.87 ^■■ 3.73 (m, 7H), 2.98 · ^■ 2.90 (m, 2H), 1.97 - 1.94 (m, 2H), 1.75 - 1.64 (m, 2H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C33H32 6O3: 561.3 (M + H); Found: 561.0.

Example 55

(5',/ j-3-Methyl-2-(4-(8-moipliolino-2-(2-(qumolin-2-y

3-yl)phenylamino acid salt (Cpd 99)

A. (S)-iert- utyl 3-methyf-2-(4-n trophenylamino)butanoate, SSa

To a solution of l -fluoro-4- nitrobenzene (3.0 g, 2.1 mmol) and fe/ -butyl (2S)-2- amino-3- methyfhutanoate hydrochloride (5.4 g, 26 mmol) in DMSO (20 mL) was added K2CO3 (8.8 g, 64 mmol). The reaction mixture was stirred at 100 °C for 8 h. EtOAc (200 mL) was added. The organic layer was washed with water and brine, dried over NaaSO.}, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (EtOAc/petroleum ether (1 : 10 v/v)) to obtain compound 55a as a yellow solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for Q 5H22N2O4: 295.2 (M + H), Found 295.2.

B. (S)-iert- utyl 2-(4-ammophenylamino)-3-methylbuianoate, 55b

Compound 55b was prepared from compound 55a (4.7 g, 16 mmol) using the procedures described in Example 54, Step B. Compound 55b was obtained as a red solid. Mass Spectmm (LCMS, EST pos.): Calcd. for C15H24N2O2: 265.2 (M + H), Found 265.1.

(S)-tert-Bu yl 3-methyi-2-(4-(4,4,5,5-tetramethyl- l ,3,2-dioxaborolan- phenylammo)butanoate, 55c

Compound SSc was prepared from compound 55b ( 1.8 g, 6.8 mmol) using the procedure described in Example 55, Step C. Compound 55c was obtained as a white solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C21H ₃ 4BNO4: 376.3 (M + H), Found 376.3. {S,E)~tert-&xxty\ 3-ηιεΐ1ψ1-2-((4-(8-ηιοφίιοΗηο-2-(2-( Ηίηο{ίη-2- y3)vmyl)imidazo[l,2-6]pyridazii -3-yr)phenyl)arnino)butanoate, SSd

Compound 14c (0.50 g, 1.2 ramol) was subjected to Suzuki coupling conditions with compound 55c using the procedure described in Example 38, Step A to obtain compound SSd as a yellow solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C ₃ 2H ₃ 2iM ₆ 03: 605.3 (M + H), Found: 605.1.

E. (S,is)-3-Memyl-2-(4-(8-morpholmo-2-(2-(qum^

jjpyridazin~3-yl)phenylamino)butanoic acid trifluoroacetic acid salt, Cpd 9.9

The title compound 99 was prepared from compound 54d using the procedure described in Example 41, Step H. Ή-NMR (300 MHz, DMSO-ife) δ (ppm): 8.68 ^■ · 8.66 (ffl, 1H), 8.21 - 8.06 (m, 4H), 8.00 - 7.90 (m, 2H), 7.80 - 7.70 (m, 2H), 7.47 (d, J= 8.1 Hz, 2H), 6.86 (d, J= 8.4 Hz, 2H), 6.42 (d, J= 5.4 Hz, Hi), 6.28 (br, IH), 4.10 - 4.09 (m, 4H), 3.89 - 3.88 fm, 4H), 3.79 (d, ./ 6.9 Hz, i l l ). 2.18 - 2.12 (m, IH), 1.09 - 1.03 (in, 6H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C ^f^C 549.3 (M + H); Found: 549.1. Example 56

(£)-3 -(4~(8-Morpholino-2-(2-(quinolin-2-yl)vinyl)imidazo[l ,2-6]pyridazin-3 yl)pheny!ammo)propanoic acid trifluoroacetic acid salt (Cpd 93)

ieri-Butyl 2- [(4-iodophenyl)amino] acetat

A solution of l ,4~diiodobenzene (33 g, 100 mmol) and ieri-butyi 2- aminoacetate hydrochloride (25 g, 150 mmol) in DMF (100 mL) was purged with ?. Cul (1 9 g, 100 mmol) was added, followed by K :( ^' () . (35 g, 250 mmol). The reaction mixture was stirred overnight at 90 °C and allowed to cool to rt. The mixture was filtered through a pad of diatomaceous earth, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by flash column chromatography on silica gel (EtOAc/petroleum ether (1 :25 v/v)) to obtain compound 56a as a red oil. Mass Spectrum (LCMS, ESI pos.): Calcd. for C - >Η ·,. Ι\Ό >: 334.2 (M + H), Found 334.0.

ieri-Butyl 2-[[4-(tetramethyl- l ,3,2-dioxaborolan-2-yl)phenyl]amino]a.cetate,

Compound 56b was prepared from /eri-butyl 2-[(4-iodophenyl)amino]acetate ( 1 1 g, 32 mmol) using the procedure described in Example 50, Step B. Compound 56b was obtained as a red oil. Mass Spectrum (LCMS, ESI pos.): Calcd. for CigtLgBNQ/i : 334.2 (M + IT), Found 334.0.

C. (E)-tert-B tyl 3 -(4~(8-morpholino-2~(2-(quinolin-2-yl)vinyl)-irnidazo[ 1 ,2- i')]pyridazin-3-yl)p

Compound 14c (0.35 g, 0.76 mmol) was subjected to Suzuki coupling conditions with compound 56b using the procedure described in Example 38, step A to obtain compound S6d as a red oil. Mass Spectrum (LCMS, ESI pos.): Calcd. for

C34H36N6O3: 577.3 (M + IT), Found: 577.2.

D. (£)-3-(4-(8-Moφholi o-2-(2-(qumolm-2-yl)vinyl)i ^■ midazo[l ,2- J] yridazin-3- yl)phenylamino)propanoic acid trifluoroacetic acid salt, Cpd 93

The title compound 63 was prepared from compound S6d (0.20 g, 0.35 mmol) using the procedure described in Example 41 , Step H to obtain the title compound 93 as a brown solid. Ή- MR (400 MHz, DMSO-a' _e + D ₂ 0) δ (ppm): 8.84 (d, ,/ 8.8 Hz, 1H), 8.32 (d, J - 8.8 Hz, l i b. 8.19 ^■ 8.00 (m, 6H), 7.82 - 7.63 (m, 2H), 7.47 i d. ./ 8.8 Hz, 2H), 6.80 (d, J= 8.8 Hz, 2H), 6.38 (d, J = 6.0 Hz, IH), 4.03 - 4.02 (m, 4H), 3.85 - 3.84 (m, 4H), 3.36 (t, J= 10.4 Hz, 2Fi), 2.56 (t, J= 10.4 Hz, 2H). Mass Spectrum (LCMS, ESI pos.): Calcd. for 521.2 (M + H): Found: 521.3.

Example 57

(^-3-(5-(8-Mo holmo-2-(2-(quinolm-2-yl)vm l)imidazo[i ,2-ή] yridazm-3- yl)pyridin-2-yl)propanoic acid (Cpd 12S)

A. Ethyl 3-iodopropanoate, 57a , 57aTo a solution of ethyl 3-bromopropanoate (120 g, 663 mmoi) in acetone (500 mL) was added Nal (150 g, 1.00 mol). The resulting solution was heated at reflux for 5 h and allowed to cool to rt. Et ₂ 0 (500 mL) was added. The solids formed were removed by filtration. The filtrate was concentrated in vacuo. The resulting residue was treated with Et ₂ 0 (150 mL) and filtered. The filtrate was washed with saturated NaHCCh solution (2 x 50 mL). The organic layer was dried over lS!a ₂ S04, filtered and concentrated under reduced pressure to obtain compound 57a as a yellow oil. Mass Spectrum (GCMS, ESI pos.): Calcd. for C5H9IO2: 228.0 (M); Found: 228.0.

B. Ethyl 3-(5-bromopyridm-2-yl)propanoate, 57b

A solution of Zn metal(l 8 g, 0.27 mol) in DMF (5 mL) was purged with N ₂ . BrCH ₂ CH ₂ Br (2.0 g, 10 mmol) was added, followed by TMSC1 (0.92 g, 8.5 mmoi). The resulting mixture was stirred at 90 °C for 30 min, and allowed to cool to rt. A solution of compound S7a (50 g, 0.22 mol) in DMF (150 mL) was added, and the resulting mixture was stirred overnight at rt. Pd(PPli ₃ ) ₂ Cl ₂ (7.4 g, 10 mmoi) was added, followed by 2,5-dibromopyridine (50 g, 0.21 mol). The resulting mixture was stirred at 68 °C for 2 h. The reaction was quenched by the addition of saturated Is!aHCOs solution (300 mL). The resulting solution was extracted with EtOAc (2 x 100 mL), and the combined organic layers were dried over Na?S04, filtered and concentrated under reduced pressure. The residue obtained was purified by flash column chromatography on silica gel (EtO Ac/petroleum, ether (1 :2 v/v)) to obtain compound 57b as a yellow oil . Mass Spectrum (LCMS, EST pos.): Calcd. tor Ci ₀ Hi ₂ Br O ₂ : 258.0 (M + H); Found: 258.2.

C. ( _J fi)-4-(2-(2-(Quinol -2-yl)vinyl)imidazo[ 1 ,2-6]pyridazi.n-8-yl)morpholine, 57c

To a solution of compound 5e (10 g, 43 mmol) and 2-methylquinoiine (4.6 g, 32 mmoi) in DMF (10 mL) was added TMSBr (2.9 g, 19 mmol) dropwise. The reaction mixture was stirred at 80 °C for 2 h. MeOH ( 10 mL) was added. The soiids formed were collected by filtration and washed with Et ₂ 0 (2 x 50 mL) to obtain compound 57c as a yellow solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C21H19N5O: 358.2 (M ^• l i s: Found: 358.3.

D. (is)-Eihyi 3-(5-(8-morpholino-2-(2-(quinoiin-2-yl)vinyl)imidazo[l,2- b jpyridazin-3 -yl)py

A solution of compound 57c (0.90 g, 2.5 mmol) and compound 57b (0,96 g, 3.7 mmol) in DMF (5 mL) was purged with ls . Pd(OAc) ₂ (67 mg, 0.30 mmol) was added, followed by KOAc (1.1 g, 11 mmol) and PPhj (73 mg, 0.28 mmol). The resulting mixture was stirred at 105 °Cfor 1.5 h, and allowed to cool to rt. water (100 mL) was added. The resulting mixture was extracted with DCM (3 x 50 mL), The combined organic layers were dried over N 3.280 , filtered and concentrated under reduced pressure. The residue obtained was purified by flash column chromatography on silica gel (EtO Ac/petroleum ether (1 :2-2: l v/v)) to obtain compound 57d as a yellow solid. Mass Spectrum (LCMS, ESI pos.): Calcd. tor C ₃ iH ₃ o ₆ 0 ₃ : 535.2 (M + H); Found: 535.2.

E. £ 3-(5-(8-MQ^holino-2-(2-(qum^

y])pyridm-2-yi)propanoic acid, Cpd 125

Compoimd 57d (0.58 g, 1.1 mmol) was hydrolvzed with LiOH using the procedure described in Example 54, Step E. The title compound 125 was obtained as a yellow solid. I i-X.YiR (300 MHz, CD ₃ OD) δ (ppm): 8.81 (d, J= 1.5 Ηζ,ΙΗ), 8.30 (d, J 8.4 Hz, I H), 8.16 (dd, ./ 8.1, 2.1 Hz, ill), 8.09 (d, J 5.7 Hz, IH), 8.00 (t, J= 8.4 Hz, IH), 7.92 ^■ 7.87 (m, 3H), 7.80 - 7.73 (m, 2H), 7.63 ^■ · 7.54 (m, 2H), 6.40 (d, J - 5.7 Hz, IH), 4.13 - 4.10 (m, 4H), 4.00 - 3.97 (m, 4H), 3.23 (i, J= 7.5 Hz, 2H), 2.71 (t, J = 7.5 Hz, 2H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C^eNeOs: 507.2 (M + S i s; Found: 507.1 .

Following the procedure described in Example 57 above, and substituting suitably selected and substituted reagents, starting materials and conditions as would be readily apparent to those skilled in the art, the following representative compound of the present invention was prepared.

Characterization

(£)-3-(4-(8-M φhoj.mo-2-(2-(qui oj.m-2-yl)vinyl)imidazo[l ,2- 6]pyridazin-3-yi)pbenyl)propanoic acid

¹ H-NMR (400 MHz, DMSO- ) δ (ppm): 12.19 (br, IH), 8.31 (d, J

= 8.8 Hz, IH), 8.1 1 (d, J= 5.6 Hz, IH), 7.94 (t, J = 8.4 Hz, 2H),

7.82 (d, J = 8.4 Hz, IH), 7.76 - 7.71 (m, 3H), 7.64 (d, J = 8.0 Hz,

2H), 7.55 (t, J= 7.6 Hz, I H), 7.47 (d, J= 8.0 Hz, 2H), 6.41 (d, J=

6.0 Hz, IH), 4.09 - 4.07 (m, 4H), 3.88 - 3.85 (in, 4H), 2.96 (t, ./

7.6 Hz, 2H), 2.66 (t, ,1= 7.6 Hz, 2H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C30H27N5O3: 506.2 (M + H); Found: 506.5.

Example 58

(ii)-4-(8-Morpholino-2-(2--(5,6,7,8-ietraliydroquinol^

-3-yl)benzoic acid (Cpd 76)

To a solution of diisopropylamine (15 g, 150 mmoi) in THF (250 mL) was added n-BuLi (2.5 M in hexane, 59 mL, 150 mmol ) at -78 °C under a nitrogen atmosphere. The resulting solution was stirred at -45 °C for 0.5 h, then cooled to -78 °C, and 2-metliylquinoline (10 g, 70 mmol) was added. The resulting solution was stirred at -78 °C for 0.5 h and then diethyl chlorophosphonate (14 g, 80 mmol) was added. The reaction mixture was stirred at -78 °C for 1 h and then at rt for 1 h. The reaction mixture was treated with saturated NH4CI (300 mL) and extracted with EtOAc (3 x 350 mL). The organic layers were combined, dried over N ^SC , filtered and concentrated under reduced pressure. The residue obtained was purified by flash column chromatography on silica gel (EtO Ac/petroleum ether (1 :2 v/ ^' v)) to obtain compound 58a as a yellow oil Mass Spectrum (LCMS, ESI pos.) Calcd. For C ₁₄ H ₁₈ N0 ₃ P: 280.1 (M + H), Found 280.2.

B. Diethyl (5,6,7,8-tetrahydroquinolin-2-yl-methyl)phosphonate, 58b

A solution of compound 58a (6,0 g, 17 mmol) in trifiuoroacetic acid (20 mL) was hydrogenated at about 2. to 3 aim over PtO? (0.4 g, 1.8 mmol) at 30 °C for 20 h. The resulting mixture was filtered through a pad of diatomaceous earth and the filtrate was concentrated under reduced pressure. The residue obtained was purified by flash column chromatography on silica gel (EtO Ac/petroleum ether (1 :2 v/v)) to obtain compound 58b as a colorless oil. Mass Spectrum (LCMS, ESI pos.): Calcd. for C2SH27 5O3: 284.1 (M + H); Found: 284.2.

C. Methyl 4-(2-fomyl-8-morpholinoiinidazo[l,2-i>]pyridazin-3-yl)ben zoate, 58c

Compound 14b (3.0 g, 1 1 mmol) was subjected to Suzuki coupling conditions with [4-(methoxycarbonyl)phenyl]boronic acid using the procedure described in Example 38, Step A to obtain compound 58c as a gray solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for Ci ₉ HisN ₄ 0 ₄ : 367.1 (M + H); Found: 367.2. (£)-Methyl 4-(8-morpho]mo-2-(2-(5,6,7,8-tetrahydroqumoiin- yljviny i)imidazo [ 1 ,2 -6]pyridazin- 3 -yl)benzoate, S8d

A solution of compound 58b (0.70 g, 2.5 mmol) in THF ( 15 mL) was purged with N2. n-BuLi (2.5 M in hexane, 1.1 mL, 2.8 mmol) was added dropwise with stirring at ri and allowed to stir for 1 h. To the mixture was added compound 58c (0.70 g, 1.9 mmol). The resulting mixture was stirred overnight at rt, and quenched with saturated NH4CI solution (1 00 mL). The resulting solution was extracted with DCM (3 x 100 mL), The combined organic layers were dried over Na ₂ S0 , filtered and concentrated under reduced pressure. The residue obtained was purified by Hash column chromatography on silica gel (EiOAc/petroleum ether (1 :2 v/v)) to obtain compound 58d as a white solid. Mass Spectrum (LCMS, ESI pos,): Calcd. for

C29H29N5O3: 496.2 (M + H); Found: 496.2.

E. (^-4-(8-Moφholmo-2-(2- 5,6,7,8-tetrahydroqumo]m-2-yl)vi yl)imidazo[l ,2- &]pyridazm-3-yl)benzoic acid, Cpd 76

Compound S8d (0.30 g, 0.74 mmol) was hydroiyzed with LiOFI using the procedure described in Example 54, Step E to obtain the title compound 76 as a yellow solid. i l-\ \l R (300 MHz, DMSO-d ₆ ) δ (ppm): 13.00 (br, 1H), 8.14 - 8.1 1 (m, M i ). 7.81 (d, J= 8.1 FTz, 2H), 7.60 - 7.49 (m, 2H), 7.43 (d, J = 8.1 Hz, 1 FT), 7.33 (d, J = 8.1 Hz, 1FI), 6.43 (d, ./ 5.7 Hz, IH), 4.07 - 4.02 (m, 4H), 3.85 - 3.83 (m, 4H), 2.78 - 2.73 (m, 41 ! ) . 1.80 - 1 .75 (m, 4H). Mass Spectrum (LCMS, EST pos.): Calcd. for

C28H27N5O3: 482.2 (M + FT); Found: 482.1 .

Following the procedure described in Example 58 above, and substituting suitably selected and substituted reagents, starting materials and conditions as would be readily apparent to those skilled in the art, the following representat ve compound of the present invention was prepared.

Example 59

(ii)--5- 2-Fluoix 4-(8--m

y1)phenyl)- - 1 ,2,4-triazol-3(4H)-one (Cpd 162)

A. (Zi)-2-(4-Bromo-2-fluorobenzy3idene)hydrazinecarboxamide, S9a

To a mixture of ammourea hydrochloride (2.8 g, 25 mmol) and aOAc (4.1 g, 49 mmol) in water (50 mL) was added dropwise a solution of 4-bromo-2- fluorobenzaldehyde (5.0 g, 25 mmol) in methanol (50 mL). The resulting solution was stirred at rt for 3 h. The solids formed were collected by filtration to obtain compound 59a as a white solid. Mass Spectmm (LCMS, ESI pos.): Calcd. for CgH ₇ BrFN ₃ 0: 260.0 (M + H); Found: 260.1.

5-(4-Bromo-2-fluorophenyl)- - 1 ,2,4-triazol-3(4H)-oiie, 59b

A solution of compound 59a (7,2 g, 28 mmol) in AcOFl (30 mL) was treated with Br ₂ (8.8 g, 55 mmol). The resulting solution was stirred at 95 °C for 2 h. The resulting solution was allowed to cool to rt and treated with Et?0 (50 mL). The solids formed were collected by filtration to obtain compound 59b as a yellow solid. Mass Spectrum (LCMS, ESI pos,): Calcd. for C ₈ H ₅ BrFN ₃ 0: 258,0 (M + H); Found: 258,0.

C. 5-(4-Bromo-2-fluorophenyl)-2,4-bis((2-(trimethy3silyl)ethoxy )methyl)-2H- 1 ,2,4-triazol-3(4H)-one, 59c

Compound S9b (0.26 g, 1.0 mmol) was treated with SEMC1 using the procedure described in Example 51, Step C to obtain compound 59c as a yellow oil Mass Spectrum (LCMS, ESI pos,): Calcd. for (\>„i f ; :Brl ^; \ _: ⁽ ) :Si/ 518.1 (M + H); Found: 518.1.

D, 5-(2-Fiuoro-4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)phenyl)-2,4-bis((2- (trimethy]silyl)ethoxy)me -3(4H)-one , 59d

Compound 59d was prepared from compound S9d (0,30 g, 0.57 mmol) as described in Example 50, Step B. Compound 59d was obtained as a yellow oil. Mass Spectrum (LCMS, ESI pos.): Calcd. for C26H45BFN3O5S-2: 566.3 (M + FI); Found: 566, 1.

E. (£)-5-(2-Fluoro-4-(8-morpholino-2-(2-(qumolin-2-yl)vinyl)im idazo[l,2- 0]pyridazm-3-yl)phenyl)-2,4-bis((2-(trim^

triazol-3(4H)-one, 59e

Compound 14c (0.30 g, 0,68 mmol) was subjected to Suzuki coupling conditions with compound 59d using the procedure described in Example 38, Step A to obtain compound 59e as a yellow solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for 795.4 (M + H); Found: 795.2.

F. (£)-5-(2-Fluoro-4-(8-mo holino-2-(2-(q molm-2-yl)vin l)rmidazo[l ,2- 6]pyridazin-3-yl)phenyl)-2H- 1 ,2,4-triazol-3(4H)-one, Cpd 162

The title compound 162 was prepared from compound 59e using the procedure described in Example 51, Step F. The title compound 162 was obtained as a yellow solid. ! ! - \ R (400 MHz, DM8G--d ₆ ) δ (ppm): 1 1.96 (s, 1H), 1 1.92 (s, 1H), 8.34 i d. J = 8.8 Hz, I H), 8.1 8 (d, J= 6.0 Hz, 1H), 7.99 - 7.91 (m, 4H), 7.86 - 7.68 (m, 5H), 7.56 (t, ./ 7.6 Hz, IH), 6.48 (d, J = 5.6 Hz, I I I ). 4.1 1 - 4.09 (m, 4H), 3.89 - 3.86 (m, 4H). Mass Spectrum (LCMS, ESI pos.): Calcd. for 535.2 (M + H); Found: 535.3.

Example 60

4--(8 -Morpho!ino-2--(2- ^' 5,6,7,8 eto

3-yl acid salt(Cpd 79)

CF ₃ CO2H

A. (E)-tert-Butyl 4-(8-nlOφhoiino-2-(2-(5,6,7,8-tetrahydroquinolin-2- y])vinyl)imidazo[l, - ?]pyridazin-3-yl)benzoate, 0a

To a solution of compound 58a (125 mg, 0.441 mmol) in 2.5 mL of THF at RT was added n-BuLi (275 uL, 0.441 mmol, 1.6M in hexane) dropwise. After stirring at rt for 15 min, the mixture was added slowly to a suspension of compound 5f (150 mg, 0.367 mmol) in 2.5 mL of THF. The resulting mixture was stirred at rt for 30 mm, then 2 mL of saturated NH4CI was added. The mixture was diluted with 10 mL of water, then extracted with EtOAc (2x20 mL). The combined organic layers were washed with brine (15 mL) and dried with a^SC , filtered and concentrated. The solvent was removed in vacuo and the residue was purified by flash column chromatography on silica gel (0: 1-1 :4 EtOAc/ ^' DCM) to afford compound 60a as a pale yellow solid. ^] H~ NMR (CDCI3; 400 MHz) 8 8.16 (d, J = 8.1 Hz, 2H), 7.98 id, J = 5.6 Hz, ill), 7.79 (d, J

- 8.6 Hz, 2H), 7.73 (d, J - 15.7 Hz, lH), 7.50 - 7.58 (m, 1H), 7.29 - 7.35 (m, I I I ). 7.21

- 7.26 (m, l l . 6.1 1 (d, J = 5.6 Hz, 1H), 4.02 - 4.09 (m, 4H), 3.93 - 4.02 (m, 4H), 2.93 (t, J = 6.3 Hz, 2H), 2.77 (t, J = 6.1 Hz, 2H), 1.86 - 1.95 (m, 2H), 1.77 - 1.86 (m, 2H), 1.63 (s, 9H). Mass spectrum (ESI, m/z): Calcd. for C32H35N5O3, 538.1 (M+H), found 538.0.

B. tert-Butyl 4-(8-morpho]mo-2-(2-(5,6,7,8-tetrahydroqu noiin-2- yl)ethyl)imidazo[l ,2- j]pyridazin-3-yl)benzoate, 60b

A mixtur of compound 60a (60.0 mg, 0.1 12 mmol), 4- methylbenzenesulfonohydrazide (104 mg, 0.558 mmol) and sodium acetate (46.2 mg, 0.558 mmol) in 3.3 mL of 10: 1 DME/water was refluxed for 4 h. After cooling to rt, the mixture was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (0: 1 -3 :2 EtOAc/DCM) to afford compound 60b as a colorless oil Ή-NMR (CDCi ₃ ; 400 MHz) δ 8.05 (d, J - 8.6 Hz, 2H), 7.96 (d, J = 5.6 Hz, l l . 7.57 (d, J = 8.6 Hz, 11 1 ). 7. 15 (d, J = 7.6 Hz, i l l ). 6.76 id, J = 7.6 Hz, 1H), 6.07 (d, J - 5.6 Hz, 1H), 3.96 - 4.03 (m, 4H), 3.89 ^■ 3.96 (m, 4H), 3.15 - 3.30 (m, 4H), 2.83 ( J = 6.3 Hz, 2H), 2.69 ( J = 6.3 Hz, 2H), 1.82 - 1.91 (m, 2H), 1.73 - 1.82 (m, 2H), 1.61 (s, 9H). Mass spectrum (EST, m/z): Calcd. for C32H37N5O3, 540.3 (M+H), found 540.5.

C. 4-(8-Morpholino-2-(2-(5,6 ,7,8-tetrahydroquinolin-2-yl)ethyl)imidazo[l ,2- 0]pyridazm-3-yl)benzoic acid trifluoroacetate, Cpd 79

To a solution of compound 60b (55.0 mg, 0.102 mmol) in DCM (2 mL) at RT was added TFA (500 μΕ, 6.53 mmol). After stirring at rt for 0.5 h, the mixture was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (0: 1 - 1 :9 MeOH-DCM) to afford the title compound 79 (with 1.1 eq TFA) as a white solid. Ή-NMR (CDCI3: 400 MHz) δ: 8.03 (d, J = 8.6 Hz, 2H), 8.00 (d, J = 5.6 Hz, 1H), 7.64 (d, J - 8.1 Hz, 1H), 7.56 ^■■ 7.62 (m, 2H), 7.15 (d, J = 8.1 Hz, 1H), 6.1 1 (d, J = 5.6 Hz, 1H), 3.87 - 4.05 (m, 8H), 3.57 (t, J = 7.1 Hz, 2H), 3.34 - 3.43 (m, 2H), 3.07 - 3.1 8 (m, 2H), 2.71 - 2.83 (m, 2H), 1 .77 - 1 .95 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C ^' > d ! >.;\ H ) . 484.2 (M+H), found 484.5. Example 61

(£)-5-(8-morpholino-2-(2-(5,6,7,8-tetrahydroquinolin-2-yl)v inyi)imidazo[ l ,2- ?]pyrida -3-yl)picolinic acid trifluoroacetic acid salt (Cpd 107)

A. tert-Butyl 5-(2-foimyl-8-morpholinoimidazo[l ,2-i>]pyrida2in-3-yl)picolinate _> 61a

Compound was prepared using an adaptation of the procedure described in Example 5, Step F. Ή NMR (DMSO-d ₆ ,400MHz): δ 10.15 (s, IH), 9.16 (d, J = 2.0 Hz, IH), 8.25 ^■ 8.32 (m, I I I ) . 8.17 - 8.24 (m, H I ). 8.08 (d, J = 5.6 Hz, 1H), 6.17 (d, J - 5.6 Hz, I H), 4.03 - 4.17 (m, 4H), 3.88 - 4.00 (m, 4H), 1.67 (s, 9H).Mass spectrum (ES , m/z): Caicd. for C21H23N5O , 410.2 (M+H), found 410.4.

(ls)-ieri -Butyl 5-(8-morpholino-2-(2-(5,6,7,8-tetrahydroquinolin- yl)vinyl)imidazo [ 1 ,2- ?]pyridazin-3 -y])picolinate, 1b

To a solution of compound 58a (218 mg, 0.771 mmol) in 3 mL of THF at rt was added n-BuLi (482 uL, 0.771 mmol, 1.6M in bexane) dropwise. After stirring at rt for 15 min, the mixture was added sl owly to a suspension of compound 61a (263 mg, 0.642 mmol) in 5 mL of THF. The resulting mixture was stirred at rt for 1 li then 2 mL of saturated NH ₄ C1 was added. The mixture was diluted with 10 mL of water, and the mixture was extracted with EtOAc (2x20 mL). The combined organic layers were washed with brine (15 mL) and dried with Na ₂ S0 ₄ , filtered and concentrated. The residue was purified by flash column chromatography on silica gel (0: 1-1 :4 EtOAc- DCM) to afford compound 61b as a pale yellow solid. Ή-NMR (CDCI ₃ : 400 MHz) 5 9.07 (d, J = 2.0 Hz, IH), 8.25 - 8.31 (m, 1H), 8.17 - 8.25 (m, IFF), 7.98 (d, J = 5.6 Hz, I H), 7.77 (d, J = 15.6 Hz, IH), 7.53 (d, J = 15.7 Hz, lH), 7.29 - 7.37 (m, IH), 7.23 - 7.29 (m, I H), 6.13 (d, J - 5.9 Hz, I H), 4.02 - 4.1 1 (m, 4F1), 3.91 - 4.02 (m, 4FQ, 2.88 - 2.98 (m, 2H), 2.69 - 2.83 (m, 2H), 1.86 - 1.96 (m, 2FI), 1.77 - 1.86 (m, 2H), 1.68 (s, 9H). Mass spectrum (ESI, m/z): Calcd. for C ₃ i¾ _{4 6} 0 ₃ , 539.3 (M-f-H), found 539.5.

C. (E)-5-(8-Mo^holino-2-(2-(5,6,7,8-tetrahydroquinolin-2-yl)vin yl)iniidazo[l,2-

5jpyridazin-3-yl)picolinic acid trifluoroacetate, Cpd 107

To a solution of compound 61b (200 mg, 0.371 mmol) in 5 mL of DCM at rt was added TFA. (2.00 mL, 2.6.1 mmol). After stirring at rt for 6 h, the mixture was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (0: 1-1 :9 MeOH-DCM) to afford the title compound 107 (with 1 eq of TFA) as a bright yellow solid. I l-NM R (CDCL; 400 MHz) δ 8.97 (br. s., I H), 8.35 (br. s., 2H), 7.88 - 8.05 (m, 2H), 7.65 - 7.79 (m, 2H), 7.51 - 7.65 (m, IH), 6.16 (d, J = 5.6 Hz, I H), 4.09 (br. s., 4H), 3.90 - 4.03 (m, 4H), 3.19 (br. s., 2F1), 2.84 (br. s., 2H), 1.93 (br. s., 2FI), 1.78 - 1.89 (m, 2H). Mass spectrum (ESI, m z): Calcd. for C27H26 6O3, 483.5 (M+H), found 483.4. Example 62

-N-(Meth.ylsulfonyl)-5-(8-morpholino-2-(2-(5,6,7,8-tetrah.yd roqumol

yl)vinyl)imidazo[l ,2- ]pyridazin-3-yi)picolinamide (Cpd 112)

To a solution of compound 1Θ7 (50.0 mg, 0.0838 mmol), methanesultonamide (24.7 mg, 0.251 mmol) and DMAP (24.7 mg, 0.251 mmol) in 3 mL of DCM at rt was added EDCI (48.2 mg, 0.251 mmol). After stirring at rt for 2.0 h, the mixture was diluted with 20 mL of water and extracted with EtOAc (3x 15 mL). The combined organic layers were washed with brine ( 15 mL) and dried with Na ₂ S04, filtered and concentrated. The residue was purified by flash column chromatography on silica gel (0: 1-6:94 MeOH-DCM) to afford the title compound 112 as a bright yellow solid. ^J H- NMR (CDCL; 400 MHz) 8 8.99 (s, 1H), 8.37 is, 2H), 8.01 (d, J = 5.6 Hz, 1H), 7.77 (d, J = 15.7 Hz, 1 H), 7.56 (d, J = 15.7 Hz, 1H), 7.35 fd, J = 7.6 Hz, 1H), 7.24 (d, J = 7.6 Hz, 1H), 6.17 (d, J - 5.6 Hz, 1H), 4.04■■ 4.1 1 (m, 4H), 3.94 · 4.02 (m, 4H), 3.44 (s, 3H), 2.94 (t, j = 6.3 Hz, 2H), 2.78 (t, J = 6.3 Hz, 2H), 1.87 - 1.97 (m, 2H), 1.77 - 1.87 (m, 2H). Mass spectrum (ESI, m/z): Calcd. for C ₂₈ H ₂₉ N ₇ 0 ₄ S, 560.2 (M+H), found 560.5. Example 63

(E) -(2-(2-(3-Meihoxyquin^

yljbenzoie acid (Cpd 11 )

A. (E)-tert-Buty] 4-(2-(2-(3-methoxyqumolin-2-yl)viny3)-8- morphol inoimi dazo [ 1 ,2-b y ridazin- 3 -yl)benzoate, 63a

To a mixture of compound Sf (100 mg, 0.245 mmol) and 3-methoxy-2- met ylqumoline (212 mg, 1.22. mmol) in 4 mL of DMF was added TMSC1 (312 μΕ, 2.45 mmol) dropwise. The resulting mixture was stirred at 90 °Cfor 24 h. After cooling to ri, the mixture was treaied with 60 mL of EtOAc and washed wiih water (3 x 20 mL), brine (15 mL) and then dried with Na2SC>4, filtered and concentrated. The residue was purified by flash column chromatography on silica gel (0: 1-1 :9

EtOAc/DCM) to afford compound 63a as a yellow solid. Ή-NMR (CDC¾; 400 MHz) δ 8.10 - 8.25 (m, 4H), 7.99 (d, J = 5.9 Hz, 2H), 7.86 (d, J = 8.3 Hz, 2H), 7.68 (d, J = 8.1 Hz, 1H), 7.49 - 7.55 (m, 1H), 7.39 - 7.47 (m, 1 H), 7.37 (s, IH), 6.11 (d, J = 5.6 Hz, 1H), 4.04 - 4.12 (ra, 4H), 3.96 - 4.04 (m, 4H), 4.01 (s, M l ). 1.64 (s, 9H). Mass spectrum (ESI, m/z): Caled. for C33H33N5O4, 564.3 (M+H), found 564.5.

B. (E)-4-(2-(2-(3-Methoxyqumolm-2-yl)vinyl)-8-morpholmoimidazo[ l ,2- 6]pyridazm-3 -yl)benzoic acid, Cpd 119

To a solution of compound 63a (212 mg, 1.22 mmol) in 3 niL of DCM at rt was added TFA (1.00 mL, 13.1 mmol). After stirring at rt for 0.5 h, the mixture was concentrated in vacuo and the residue was triturated with DCM to give a red solid. Recrysiaiiization of the soiid in 1 : 1 MeOH/DCM afforded the title compound 119 as a red solid. Π NMR (DMSO- ,400MHz): δ - 8.09 - 8.22 (m, 2 H), 8.00 (s, 1 H), 7.77 - 7.93 (m, 3 H), 7.44 - 7.59 (m, 2 H), 6.43 (d, ./ : .< ^■ ■ Hz, 1 H), 5.99 (d, ./ 6. ! Hz, 2 H), 5.81 (s, 1 H), 5.71 (s, I ! i :·. 4.06 (br. s., 4 H), 3.99 (s, 3 H), 3.86 ppm (br. s., 4 H). Mass spectrum (ESI, m/z): Caled. for C29H25N5O4, 508.2 (M+H), found 508.5.

Example 64

(£)-4-(2-(2-(4-hydroxyquinolm-2- l)vmyί)-8-mo holmoimidazo[l ,2-ό] yridazi ^■ n-3- yl)benzoic acid (Cpd 136)

A. (£)-tert-Butyl 4-(2-(2-(4-hydroxyqu nofin-2-yl)vinyl)-8- morpholinoimidazo[i ,2-/i]pyridazin-3-yl)benzoate, 64a

To a mixture of compound 5f (150 mg, 0.367 mmol) and 2-methylquinolin-4-ol (292 mg, 1.84 mmol) in 4 mL of DMF was added TMSCi (469 uL, 3.67 mmol) drop wise. The resulting mixture was stirred at 90 °C for 16 h. After cooling to rt, the mixture was treated with 60 mL of EtOAc and washed with water (3 x 20 mL) and brine ( 15 mL). The solvent was removed in vacuo and the residue was treated with DCM (5 mL). To this mixture was added imidazole (50.0 mg, 0.734 mmol), and the resulting mixture toned clear and was purified by flash column chromatography on silica gel (0: 1 - 1 : 19 MeOH/DCM) to afford compound 64a as a yellow solid. Ή- MR (CDCL; 400 MHz) 8 1 1.97 (br. s., IH), 8.26 (d, J = 7.8 Hz, IH), 7.88 - 8.03 (m, 3H), 7.43 - 7.83 (m, 6H), 7.22 (t, J - 7.5 Hz, 1H), 6.49 (s, IH), 6.03 (d, J = 5.6 Hz, I H), 3.94 (br. s., 4H), 3.82 (br. s., 4H), 1.55 (s, 9H). Mass spectrum (ESI, mlz) Calcd. for ί¾Η _3ί Ν ₅ 0 ₄ , 550.2 (M+H), found 550.5.

B. (E)-4-(2-(2-(4-h droxyquinolin-2-yl)vinyl)-8-mo holΐnoimida2:o[l,2- j]pyridazin-3-yl)benzoic acid, Cpd 136

The title compound 136 was prepared from compound 64a using the procedure described in Example 63, Step B. Ή NMR (DMSO-i¼ ,400MHz): δ 8.05 - 8.20 (m, 4H), 7.81 - 7.90 (m, 21 1 ). 7.63 - 7.76 (m, 3H), 7.45 - 7.56 (m, I H), 7.40 (br. s., 1H), 6.59 (s, IH), 6.45 fd, J = 5.9 Hz, IH), 4.06 (br. s., 4H), 3.84 (br. s., 4H). Mass spectrum (ESI, m/z): Calcd. for C28H23M5O4, 494.2 (M+H), found 494.4. Example 65

l -(4~(8-Moφholi o-2-(quinolill-2- leth nyl)imidazo[l,2- ?J yridazin-3- yl)phenyl)etlianone (Cpd

N-Methoxy-N-methyl-4-(8-morpholino-2-(quinolin-2-ylethyny l)imidazo[l b jpyridazin-3 -yl)benzamide, 65a

A mixture of compound 40a (200 mg, 0.421 mmoi), N,0- dimetliylhydi'oxylamine hydrochloride (46.1 mg, 0.463 mmoi), EDC1 (88.7 mg, 0.463 mmoi) arsd DIEA (87.0 μΐ,, 0.505 mmoi) in 12 mL of 2: 1 DCM DMF was stirred at rt for 16 h. The mixture was treated with 100 ml, of EtOAc and washed with water (2x30 mL), brine (30 mL) and then dried over Na ₂ SC>4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (0: 1-1 : 1

EtOAc/DCM) to afford compound 65a as a pale yellow solid. Ή-NM (CDC1 ₃ ; 400 MHz) 8 8.33 (d, J = 8.6 Hz, 2H), 8.07 - 8.21 (m, 5H), 7.83 id, J = 8.1 Hz, ill), 7.75 (t, J - 7.6 Hz, l H), 7.53 - 7.65 (m, 2H), 6.16 (d, J - 5.6 Hz, lH), 4.05 (br. s., 4H), 3.89 - 4.00 (m, 4H), 2.66 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C29H23NSO2, 474.5 (MtH), found 474.2. B. l-(4-(8-M ^holino-2-(quinolin-2-yiethynyl)imidazo[l ,2-Z?]pyridazin-3- yl)phenyl)ethanone, Cpd 159

To a suspension of compound 65a ( 140 mg, 0.270 mmol) in 10 mL of THF at 0 °C was added methyimagnesium bromide (0.270 mL, 0.810 mmol, 3.0 M in Et ₂ 0) dropwise under an Argon atmosphere. After stirring at 0 °C for 1 h, the reaction was quenched with 2 mL of saturaied NH ₄ CI. The mixture was treated with 50 mL of EtOAc and washed with water (25 mL), brine (25 mL) and then dried over Na ₂ S0 ₄ . filtered, and concentrated. The residue was purified by flash column chromatography on silica gel (0:1-1 :4 EtOAc DCM) to afford the title compound 159 as a white solid. 'H NMR (DMSO-de ,400MHz): δ = 8.09 - 8.22 (m, 2 H), 8.00 (s, 1 H), 7.77 - 7.93 (m, 3 H), 7.44 ^■■ 7.59 (m, 2 H), 6.43 (d, J= 5.6 Hz, 1 H), 5.99 (d, J= 6.1 Hz, 2 H), 5.81 (s, 1 H), 5.71 (s, 1 H), 4.06 (br. s., 4 H), 3.99 (s, 3 H), 3.86 ppm (br. s., 4 H). Mass spectrum (ESI, m/z): Calcd. for C29H25N5O4, 508.2 (M H), found 508.5.

Example 66

)-2-(4-(8-Mυφholino-2- lR,3S)-3-(qumolΐ -2-yl)cyclobutyl)imidazo[l 6]pyridazin-3-yl)phenyl)cyciopropanecarboxylic acid (Cpd 170)

A. 1 -Methyl- 1 -nitrourea, 66a

0 ₂ N , 66a To a stirred solution of 1-methylurea (20 g, 0,27 mol) in water (160 ml.) and Et ₂ 0 ( 160 inL) at 0°C, a solution of NaN0 ₂ (20 g, 0.29 mol) in water (20 niL) was added drop wise. The resulting solution as stirred for 1 h. at 0 °C and then treated with a solution of sulfuric acid (130 ml., 1.5N). The solids formed were collected by filtration to obtain compound 66a as white solid.

B. Diazomethane, 66b

66b

To a solution of compound 66a (20 g, 0.17 mol), in i¾>Q (250 mL) was added a solution of sodium hydroxide (72 g, 1.8 mol) in water (150 mL) over 30 min at room temperature. The Et ₂ 0 layer was separated, dried over potassium hydroxide, and filtered. The ethereal filtrate containing diazomethane was used without further purification in Step D.

C. Methyl (E)-3-(4-brom 66c 66c

To a stirred solution of (2£)-3-(4-bromophenyl)prop-2-enoie acid (4.5 g, 0.020 mol) in MeOH (20 mL), suifuryl dichioride (2.7 g, 0.023 mol) was added dropwise at 0 °C. The resulting solution was heated to reflux for 1 h. The reaction mixture was allowed to cool to rt and concentrated to dryness under reduced pressure to yield a residue, which was subjected to flash column chromatography on silica gel (5- 10 % EtO Ac/petroleum ether) to afford compound 66c as a colorless oil. Mass Spectrum (GCMS, ESI pos.): Calcd. for C ₁₀ H BrO ₂ : 241.1 (M); found: 241.0.

D, (1 S, 2. S) -Methyl 2-(4-b carboxylate, 66d d

To a mixture of compound 66c ( 1.50 g, 6.22 mmoi) and Pd(OAc) ₂ (90 mg, 0.40 mmol) in DCM (20 mL) was added an ethereal solution of compound 66to (200 mL). After stirring for 10 min at 0 °C, the reaction mixture was concentrated under reduced pressure to yield a residue, which was subjected to flash column chromatography on silica gel (10% EtO Ac/petroleum ether) to afford compound 66d as colorless oil. Mass Spectrum (GCMS, ESI pos.): Caled. for ( U Br() >: 254.0 (M); found: 254.0.

E. (1 S,2S)-Methyf 2-(4-(4,4,5,5-tetramet!iyi- 1 ,3,2-dioxaborolan-2-yl)phenyl) cyclopropanecarbo

A mixture of (lS,2S)-methyl 2-(4-bromophenyl)cyclopropanecarboxylate (1.4 g, 5.5 mmol), bis(pinacolato)diboron (2.1 g, 8.3 mmol), Pd(dppf)Ci2 (270 mg, 0.37 mmol), dppf (200 mg, 0.36 mmol) and KOAc (1.6 g, 16 mmol) in dioxane (20 mL) was stin"ed overnight at 80 0 °C under a nitrogen atmosphere. The reaction mixture was allowed to cool to rt and extracted with EtOAc (2x50 mL). The combined organic layers were concentrated under reduced pressure to yield a residue which was subjected to flash column chromatography on silica gel (10 %, EtO Ac/petroleum ether) to afford compound 66e as a off-white solid. Ή NMR i C ^' iX ^' h. 400 MHz) 8 (ppm): 7.73 - 7.75 i d. ./ 7.6 Hz, 21 h. 7.10 - 7.12 (d, ./ 8.0 Hz, 21 1 ). 3.74 is, 31 1 ). 2.53 - 2.57 (m, 1 1 1 ). 1.93 - 1 .97 (m, 1H), 1.66 - 1.62 (m, 1H), 1.39 - 1.34 (m, 13H). Mass Spectrum (LCMS, ESI pos.): Calcd. for CnH BC^: 303.2 (M + H); found: 303.2.

F. (lR,2S)-Meth l 2- 4-(8-mo holino-2-((lR,3S)-3-(quinolin-2- yl)cyclobutyl)imidazo[l ,2-6]pyridazm-3-yl)phenyl)cyclopropanecarboxylate,

66f

A mixture of compound 2d (0.0500 g, 0.108 mmol), compound 66e (0.0651 g, 0.215 mmol), [l , i'~bis(diphenylphospbino)ferrocene]dichloropaUadium ( U s (0.0079 g, 0.01 1 mmol), and potassium carbonate (0.0571 g, 0.538 mmol) in dioxane (5 mL) and water (2 mL) was heated at 100 °C for 10 h under an Argon atmosphere. The reaction mixture was allowed to cool to rt and concentrated to a residue which purified by flash column chromatography on silica gel (0-50 % EtO Ac/heptanes) to afford compound 66f as a yellow oil Mass Spectrum (LCMS, ESI pos.): Calcd. for C34H33N5O3: 560.7 (M + H); Found 560.2.

G. (lR,2S)-2-(4-(8-Morpholino-2-((lR,3S)-3-(quinolin-2- yl)cyclobutyl)imidazo[l,2-0]pyridazin-3-yl)phenyl)cyclopropa necarbox lic acid, Cpd 178

To a solution of compound 66f (0.036 g, 0.0643 mmol) in THF (2 mL) and MeOH (2 mL) was added 3M aOH (0.129 mL, 0.386 mmol). The resulting mixture was stirred for 6 h, cooled to 0 °C and treated with 2M HC1 ( _aq ) (0.193 mL, 0.386 mmol). The reaction mixture was then concentrated to a residue, which was purified by flash column chromatography on silica gel (0-25 % MeOH/DCM) to afford the title compound 178 as light brown oil. Ή NMR (400 MHz, CD ₃ OD) δ (ppm): 8.25 (d, J=8.6 Hz, 1 H), 8.01 (d, J=8. i Hz, 1 H), 7.98 (d, J=5.6 Hz, 1 H), 7.86 (d, J-8.1 Hz, 1 H), 7.71 (m, 1 H), 7.46 - 7.57 (m, 4 H), 7.22 (d, J=8.1 Hz, 2 H), 6.26 (d, J=5.6 Hz, 1 H), 4.13 - 4.24 (m, 1 H), 4.00 - 4.08 (m, 4 IT), 3.85 - 3.98 (m, 4 H), 3.91 - 3.86 (m, I H), 2,93 (m, 2 H), 2.75 - 2.86 (m, 2 H), 2.47 - 2.58 (m, 1 H), 1.84 - 1.95 (m, 1 H), 1.59 ^■ · 1.55 (m, 1 H), 1.33 - 1.45 (m, 1 H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C33H31N5O3: 545.6 (M + H); Found 546.3.

Example 67

-(3-(4-(8-Moφhoiino-2-((lR,3 )-3-(qυinolin-2- l)cyclobutyl)imid zo

6]pyridazin-3-yl)phenyl)oxetan-3-yl)acetic acid (C-pd 174)

A. Ethyl 2-(3-(4-(triflu ian-3-yl)aceta.te, 67a

67a

To a solution of ethyl 2-[3-(4-hydroxypheny3)oxetan-3-yi]acetate (500 mg, 2.12 mmoi), TEA (321 mg, 3.17 mmol), and DCM (40 mL) was added dropwise a solution of Tf ₂ Q (658 nig, 2.33 mmol) in DCM (20 mL) in 15 min at -5 °C (ice/salt bath). After stirring for an hour, the reaction was quenched by the addition of water (50 mL). The crude mixture was extracted with DCM (2x40 mL). The organic layers were combined and concentrated to a residue which purified byflash column chromatography on silica gel (1 -5 % EtO Ac/petroleum ether) to afford compound 67a as white oil. Mass Spectrum (LCMS, ESI pos.): Cafcd. for C1 H15F3O6S: 369.3 (M + H); found: 369.1.

B. Ethyl2-(3-(4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)phenyl)oxetan-3- yi)aeetate, 67b

A mixture of compound 67a (600 mg, 1 .63 mmol), 4,4,5,5-tetramethyl-2- (tetramethyl- l ,3,2-dioxaborolan~2-yl)~ l ,3,2-dioxaborolane (456 mg, 1 ,80 mmol), KG Ac (480 mg, 4.89 mmol), Pd(dppf)Cl ₂ (84 mg, 0.1 1 mmol), dppf (60 mg, 0.1 1 mmol), and dioxane (12 mL) was stirred at 80 °C under an argon atmosphere. The reaction mixture was allowed to cool to rt, treated with water (20 mL) and extracted with EtOAc (3x30 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to yield a residue, which purified byf!ash column chromatography on silica gel ( 10 % EtOAc/petrofeum ether) to afford compound 67b as off-white solid. Ή NMR (CDCL, 400 MHz) δ (ρρτη): 7.82 - 7.80 (d, J=8.0 Hz, 2H), 7.21 - 7.19 (d, ./ 8.0 Hz, 2H), 5.05 - 5.03 (d, J=6.0 Hz, 2H), 4.89 - 4.88 (d, =6A Hz, 2H), 4.04 ^■■ 3.99 (m, 2H), 3.14 (s, 1H), 1.36 (s, 12H), 1.16 - 1 .13 (t, J=7.2 Hz, 3H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C _!9 H27B0 ₅ : 347.2 (M + H); found: 347.2.

C. Ethyl 2-(3-(4-(8-morpholino-2-(( lR,3R)-3-(quinolin-2- y])cyclobuty3)imidazo[ l,2-0]pyridazin-3-yl)phenyl)oxetan-3-yl)acetate, 67e

A mixture of compound 2d (0.0500 g, 0.108 mmol), compound 67b (0.0746 g, 0.215 mmol), [l, -bis(diphenylphosphino)ferrocene]dichloropalladium. (Π) (0.0079 g, 0.0108 mmol), and potassium carbonate (0.0571 g, 0.538 mmol) in dioxane (5 mL) and water (2 mL) was heated at 80 °C for 10 h under an argon atmosphere. The reaction mixture was allowed to cool to rt and concentrated to a residue, which was purified byflash column chromatography on silica gel (0-50 % EtO Ac/heptanes) to afford compound 67c as yellow oil. Mass Spectrum (LCMS, EST pos.): Calcd. For

C36H37N5O4: 604.7 (M + H); Found: 604.3.

D. 2-(3-(4-(8-Mo^holino-2-((lR,3R)-3-(quinolin-2-yl)cyclobutyl) imidazo[l ,2- 6]pyridazin-3-yl)phenyl)oxetan-3-yl)acetic acid, 67d

To a solution of compound 67c (0.046 g, 0.0762 mmol) in THF (2 mL) and MeOH (2 mL) was added 3M NaOH (0.152 mL, 0.457 mmol). The resulting mixture was stirred for 6 h, cooled to 0 °C and treated with 2M HCl ( _aq ) (0.229 mL, 0.457 mmol). The reaciion mixture was concentrated to a residue which was subjected io flash column chromatography on silica gel (0-25 % MeOH/DCM) to afford compound 67d as light brown oil. Ή NMR (400 MHz, CD3OD) δ (ppm): 8.25 (d, J-8.6 Hz, 1 H), 7.97 - 8.08 (m, 2 H), 7.86 (m, 1 H), 7.72 (m, 1 i n. 7.48 - 7.64 (m, 4 H), 7.41 (d, ./ 7. i Hz, 2 H), 6.29 (d, J=5.6 Hz, 1 H), 5.04 (d, J=5.6 Hz, 2 H), 4.95 (d, ./ 5 6 Hz, 2 H), 4.16 - 4.28 (m, 1 H), 4.07 (br. s., 4 i f ). 3.96 (br. s., 5 H), 3.18 (s, 2 I I I 2.99 - 2.91 (m, 2 H), 2.89 - 2.80 (d, 2 H). Mass Spectrum (LCMS, ESI pos.): Calcd. For C34H33N5O4: 575.7 (M + H); Found: 576.2.

Example 68

2-Methyl-2-(4-(8-mo holmo-2-((l ,3R)-3-(qumoli ^■ n-2- l)cyclobut l)imidazo[l ,2- 0]pyridazin-3-yl)phenyl)propanoic acid (Cpd 171)

A. Methyl 2~(4-bromo To a stirred solution of 2-(4-bromopbenyl) acetic acid (10 g, 0046 mol) in MeOH (100 mL) was added sulfuryi dichloride (8.3 g, 0,069 mol) dropwise. The reaction mixture was stirred overnight at 80 °C , allowed to cool to rt and concentrated under reduced pressure to afford compound 68a as a colorless oil . Mass Spectrum (GCMS, ESI pos.): Caicd. for (¾Η ₉ ΒΓ0 ₂ : 228.0 (M); found: 228.0.

B. Methyl 2-(4-bromoph

To a stirred solution of compound 68a (7.5 g, 0,032 mol) in THF (100 mL), 1 M THF solution of NaHMDS (36 mL, 0.036 mol) was added dropwise at 0 C. The resulting solution was allowed to warm to room temperature and stirred for 1 h before cooling back down to 0 ^c C, The cooled reaction mixture was treated dropwise with iodomethane (5.1 g, 0.035 mol). The ice-water bath was removed and stirring was continued for an additional hour at room temperature. The reaction was then quenched by the addition of water (50 mL). The reaction mixture was extracted with EtOAc (3x100 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford compound 68b as a yellow oil. Mass Spectrum (GCMS, ESI pos.): Caicd. for C ₁₀ HnBri¾: 242,0 (M); found: 242.0.

C. Methy 1 2-(4-bromoph 8c

To a stirred solution of compound 68b (5 g, 0.02 mol) in THF (100 mL) was added a ί M THF solution of NaHMDS (2.2.6 mL, 22.6 mmoi) at 0 °C under a nitrogen atmosphere. The resulting solution was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was then cooled to 0 °C and iodomethane (3.19 g, 22.5 mmoi) was added dropwise. The ice-water bath was removed and stirring was continued for an additional hour at room temperature. The reaction mixture was then treated with water (50 mL) and extracted with EtOAc (3x100 mL). The combined organic layers were dried o ver anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford compound 68c as brown oil. Mass Spectrum (GCMS, ESI pos.): Caled. for ( U .Br() >: 256.0 (M); found: 256.0.

D. Methyl 2-methyl-2-(4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2- yl)phenyl)propanoa

A mixture of compound 68c (1.0 g, 3.9 mmo!), 4,4,5,5-tetramethyl-2- (tetramethyl- 1 ,3,2-dioxaborolan-2-yi)- l,3,2-dioxaboroiane (1.2 g, 4.7 mmol), Pd(dppf)CT ₂ (95 mg, 0.12 mmol), KOAc ( 1.1 g, 12 mmol), and DMSO (10 mL) was stirred for 3 h at 80 °C under a nitrogen atmosphere. The reaction mixture w ^r as then treated with water (50 ml.) and extracted with EtOAc (2x2.0 ml.). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to yield a residue, which was subjected to flash column chromatography on silica gel (10 % EtO Ac/petroleum ether) to afford compound 68d as a off-white solid. ^! H NMR (CDC , 400 MHz) δ (ppm): 7.79 - 7.81 (d, .7-8.0 Hz, 2H), 7.37 - 7.34 (d, .7-8.4 Hz, 2H), 3.66 (s, 3H), 1.60 (s, 6H), 1.35 (s, 12Ii). Mass Spectrum (LCMS, ESI pos.): Calcd. for C17H25BO4: 305.2 (M+H); found: 305.0.

E. Methyl 2^6 1-2-(4-(8^οφΗο1ίηο-2-((1Κ,3Κ)-3-(ςαϊηο1ϊη-2- yl)cyclobutyl)imidazo[l,2-b]pyridazin-3-yi)phenyl)propanoate , 68e

A mixture of compound 2d (0.0500 g, 0.108 mmol), compound 68d (0.0655 g, 0.215 mmol), [l, -bis(diphenylphosphmo)ferrocene]dichloropalladium (II) (0.0079 g, 0.0108 mmol), and potassium carbonate (0.0571 g, 0.538 mmol) in dioxane (5 mL) and water (2 mL) was heated at 80 °C for 10 h. The reaction mixture was allowed to cool to rt and concentrated to obtain a residue, which was purified by flash column chromatography on silica gel (0-50 % EtO Ac/heptanes) to afford compound 68e as a yellow- oil. Mass Spectrum (LCMS, ESI pos.): Calcd. For C34H35N5O3: 562.7 (M + H); Found: 562.3.

F. 2-Methyl-2-(4 8-morpholino-2-((lR,3R)-3-(quinolm-2- yl)cyclobutyl)imidazo [ 1 ,2- ?]pyridazin- 3 -y l)phenyl)propanoic acid, Cpd 171 To a solution of compound 68e (0.032 g, 0.057 mmol) in THF (2 mL) and MeOH (2 mL) was added 3M NaOH (0.1 14 mL, 0.342 mmol). The resulting mixture was stirred for 6 h, cooled to 0 °C and treated with 2M HCl (0.171 mL, 0.342 mmol). The reaction mixture was then concentrated to a residue which was purified by flash column chromatography on silica gel (0-25 % MeOH/DCM) to afford the title compound 171 as fight brown oil. ^J H NMR (400 MHz, CD ₃ OD) δ (ppm): 8.26 (d, 8.0 Hz, 1 H), 7.99 - 8.05 (m, 2 H), 7.84 - 7.90 (m, I H), 7.69 - 7.75 (m, 1 H), 7.50 - 7.61 (m, 6 H), 6.29 (d, ./ 5 6 Hz, 1 H), 4.18 ^■■ 4.28 (m, 1 H), 4.05 ^■ · 4.12 (m, 4 H), 3.89 · ^■ 4.00 (m, 5 H), 2.93 - 3.04 (m, 2 H), 2.81 - 2.90 (m, 2 H), 1.61 (s, 6 H). Mass Spectrum (LCMS, ESI pos.): Calcd. For C33H33N5O3: 547.7 (M + H); Found: 548.2.

Unless otherwise specified, the resin-bound materials were synthesized in a fritted glass vial equipped with a stopcock. Agitation was accomplished using a rotator apparatus ai low speed.

Example 69

(S)-N-(5,6-dΐarr)mo-6-o ohexyl)-4-(8-rr)Oφholmo-2-(quinolΐn-2- ylethynyl)imidazo[i,2-0]pyridazm-3-yl)benzamide (Cpd 188)

A. FMOC-Lys(Mtt)-CONH-Resin

Rink ChemMatrix resin (0.5 nieq/g; 200 mg, 0.1 nieq) was allowed to swell in DMF (5 mL) for 5 min, then drained and washed with DMF (3 x 5 mL). A solution of FMOC-Lys(Mtt)-OH (288 mg, 0.45 mmol) and 2-(li -benztriazol- l-yl)- l,L3,3- tetramethylaminiuni hexafiuorophosphate (HBTU) (164 mg, 0.43 mmol) in DMF (3.5 mL) was treated with 2M DIEA NMP (0.5 mL, 1 mmol). After 1 min, the solution was added to the swollen resin and the mixture was slowly agitated over the weekend. The reagents were drained, and the resin was washed extensi vely with DMF (5 x 5 mL), then DC-M (5 5 mL). The resin was used directly in the subsequent step.

B. -Lys(Cpd 77)-CONH-Resin,

FMOC-Lys(Mtt)-CONH-Resin was agitated with a solution of DCM/TTS/TFA (95:5:2; 4 mL) for 15 min, then drained. This deprotectioii step was repeated 4 times, and the resin was then washed with DCM (4 x 5 mL) followed by DMF (4 x 5 mL). A solution of compound 77 (95 mg, 0.2 mmol) and l-[( l -(cyano-2-ethoxy-2- oxoethy3idineaniinooxy)-diTnethylaniino-morpholino)] uronium hexatluorophosphate (COMU) (75mg, 0.18 minol) was treated with 2M DIEA/NMP (0.2mL, 0.4 mmoi). After 1 mill, the solut on was added to the swollen resin and the mixture was slowly agitated for 4 h. After draining the reagents, the resin was washed with DMF (4 x 5 mL) then treated with 20% Ac _? 0/DMF for 1 h. The resin was then washed with DMF (4 5 mL), then DCM (4 5 mL). The resin was used directly in the subsequent step.

C. -Lys(Cpd 77)-CONH-Resin, 69c

Cpd 69b (as prepared in Step B) was treated with a solution of 20% piperidine in DMF (7 mL) and reacted in a CEM microwave reactor using a modified 3 -stage deprotectton protocol (open vessel, 52 W, 60 °C, 0.5 min; 70W, 60 °C, 3 min; 70W, 60 °C, 3 min). The reaction was drained and the resin was washed extensively with DMF (5 x 7 mL) and DCM (5 x 7 mL). The resin was used directly in the subsequent step.

D. (S)-N-(5,6-diammo-6-oxohexyl)-4-(8-morpholino-2-(quinoIin-2- ylethynyi)imidazo[l,2-ft]pyridazin-3-yl)benzamide, Cpd 180

Cpd 69c (as prepared in Step C) was treated with a solution of TFA/TlS/water (95:2,5:2.5; 7 mL) and reacted under microwave conditions (38 °C; 30 min) in a CEM Accent reactor system. The resin was filtered and washed with TFA (7 mL). The combined filtrate was concentrated to a volume of about 1 mL, cooled and then treated with cold ether (~ 35 mL) to precipitate the crude product. The mixture was centrifuged (5 min; 5000 rpm) and decanted. The product pellet was washed by re- suspending it in cold ether, and centrifuging/decanting as above (2x) to afford 12 mg of crude product as a yellow-orange powder. Product purification by preparative HPLC was carried out on an Atlantis T3 C18 column (250 X 19 mm) at 35 °C using a gradient of 30 - 40% AcCN (0.1 % TFA; 17 mL min) with a reduced flow (8.5 mL/min) during 10:05 - 28 min (34.5-40% AcCN). Pure fractions were combined, concentrated to remove AcCN, and lyophillized to afford compound 180 (7 mg) as an orange fluffy electrostatic solid. Mass Spectrum (LCMS, ESI pes.): Cafcd. for C34H3 N8O3: 603.3 (M + H); found: 603.3.

Example 70

(S)-]^!-(6-ammo-5-(2- minoacetamido)-6-oxohexyl)-4-(8-mo holmo-2-(quinolin-2- ylethyny l Cpd 181)

A. -Gly-Lys(Cpd 77)-CONH-resin, 70a

A mixture of compound 69c (0.35 meq/g; 31 1 mg, 0.11 mmol), FMOC-Gly-OH (0.2.M in DMF; 2.5 niL, 0.5 mmol), HBTLi (0.45M in DMF; 1 mL, 0.45 mmol) and DIEA (2M in NMP; 0.5 mL, 1 mmol) was reacted in a CEM Liberty microwave reactor using a double-coupling proiocoi [(20W, 75 °C, 10 min) x 2]. (After the first coupling, reagents were drained, the resin was washed with DMF (7 mL) and fresh reagents were added for the second coupling.) FMOC deprotection was carried out with 20% (v/ ^' v) piperidine in DMF (7 mL) using a two-stage protocol (40W, 75 °C, 0.5 min; 40W, 75 °C, 3 min). The deprotected (FMOC) resin was washed extensively with DMF (5 x 7 mL) and DCM (5 x 7 mL). The resin was used directly in the subsequent step.

B. (S)-N-(6-amino-5-(2-ammoacetamido)-6-oxohexyl)-4-(8-morpholi no-2- (quinolin-2~ylethynyi)imidazo[ 1 ,2- >]pyridazin-3-yl)benzamide, Cpd 181 Compound 70a was treated with a solution of TF A/TlS/water (95:2.5:2.5; 7 mL) and reacted under microwave conditions (38 C; 30 min) in a CEM Accent reactor system. The resin was filtered and washed with TFA (7 mL). The combined filtrate was concentrated to a volume of about 1 mL, cooled and then treated with cold ether (approximately 35 mL) to precipitate the crude product. The mixture was eentrifuged (5 min; 5000 rpm) and decanted. The product pellet was washed by re-suspending it in cold ether, and centrifuging/decanting as above (2x) to afford 45 mg of crude product as a yellow-orange powder. Product purification by preparative HPLC was carried out on an Atlantis T3 CI 8 column (250 x 19 mm) at 35 °C using a gradient of 30 - 40% AcCN (0.1% TFA; 17 ml/min) with a reduced flow (8.5 mL/min) during 10:05 - 28 min (34.5-40% AcCN). Pure fractions were combined, concentrated to remove AcCN, and lyophillized to afford compound 181 as a yellow-orange fluffy electrostatic solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C ^' -.l h Ν,,ϋ..: 660.3 (M + H); found: 660.3.

Example 71

-((S)-6-amino-5-((S)-2-amino ro anamido)-6-oxohexyl)-4-(8-mo holino-2- (quinolin-2-yleihynyl)imidazo[l,2-/ ]pyridazin-3-yl)benzamide (Cpd 179)

A. -Ala-Lys(Cpd 77)-CONH-Resin, 71a

Compound 71a was prepared according to the general solid phase synthetic method described in Example 70, Step A , using FMOC-Ala-OH in place of FMOC- Gly-OH. The resin thus prepared was used directly in (he subsequent step.

B. N-((S)-6-ammo-5-((S)-2-ammopropanamido)-6-oxohexyl)-4-(8-mor pholino-2- (quinol ^" in-2-ylethynyl)imidazo[l,2-6]pyridazin-3-yl)benzamide, Cpd 179 Compound 179 was prepared from compound 71a according to the general cleavage method described in Example 70, Step B. The crude product (48 mg, yellow- orange powder) was purified by preparative HPLC on an Atlantis T3 CI S column (250 X 19 mm) at 35 °C using a gradient of 30 - 40% AcCN (0.1% TFA; 17 mL/rnin) with a reduced flow (8.5 mL/rnin) during 10:05 - 28 min (34.5-40% AcCN). Pure fractions were combined, concentrated to remove AcCN, and lyophillized to afford the title compound 179 (26.5 mg) as a yellow-orange fluffy electrostatic solid. Mass Spectrum (LCMS, ES pes.): Calcd. for C ₃₇ H ₃₉ N ₉ O4 674.3 (M + H); found: 674.3.

Example 72

>!-((S)-6-ammo-5-((S)-2-((S)-2-((S)-2-aminopropanamido)-4 - methylpentanamido)propanamido)-6-oxohexyj.)-4-( ^' 8-morpholmo-2-(quinolin-2- yfethynyl)imidazo[l ,2-0jpyridazin-3-y])benzamide (Cpd 178)

Using the general solid phase synthetic method described in Example 70, Step A, compound 72a was synthesized on a CEM Liberty Peptide Synthesizer using standard FMOC amino acids (0.2M in DMF) in about 4.5-fold excess, HBTL/DIEA activation and a double-coupling microwave protocol [(20W,

75 °C, 10 min) x 2]. FMOC deprotections were carried out with 20% (v/v) piperidine in DMF (7 mL) using a two-stage protocol (40W, 75 °C, 0.5 min; 40W, 75 °C, 3 min). Thus, compound 69c (0.35 meq/g; 31 1 mg, 0.1 1 mmoi), was coupled sequentially with FMOC-Aia-OH, FMOC-Leu-OFi and FMOC-Ala-OH. The final deprotected resin- bound conjugated teirapeptide thus obtained was washed extensively with DMF (5 x 7 mL) and DCM (5 x 7 mL).

B. N-((S)-6-amino-5-((S)-2-((S)-2-((S)-2-aminopropanamido)-4- methylpentanamido)propanamido)-6-oxohexyl)-4-(8-moipholino-2 -(quinolin-2- ylethynyl)imidazo[ 1 ,2-6]pyridazm-3-yl)benzamide, Cpd 178

Compound 178 was prepared from compound 72a according to the general cleavage method described in Example 70, Step B. The crude product (57 mg, reddish- orange powder) was purified by preparative HPLC on an Atlantis T3 C I 8 column (250 x 19 mm) at 35 °C using a gradient of 31 ^■■ 40% AcCN (0.1 % TFA; 18 mL/ mm) with a reduced flow (9 mL/ mm) during 13:05 - 27 rain (36-40% AcCN). Pure fractions were combined, concentrated to remove AcCN, and lyophiilized to afford the title compound 178 (15 mg) as a yellow iluffy electrostatic solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C^ssNuOe: 858.4 (M + H); found: 858.5.

Example 73

fii)-2-f2-(6-Chloro-8-morphoiino-3-(pyridin-3-y1)imi

yl)vinyl)qumoline-5--carboxyiic acid, sodium sa (Cpd 140)

A. mixtur of 3-ammobenzoic acid (9.0 g, 65 mmol), ferrous sulfate heptahydrate (5.2 g, 18 mmol) and 3-nitrobenzenesulfonic acid sodium salt (8.1 g, 35 mmol) in 9 M HCi (140 mL) was heated to 90 °C. Crotonaldehyde (9.00 mL, 108 mmol), was then added over a 1.5 h period and the resultant mixture was allowed to stir overnight. The reaction mixture was allowed to cool for 10 min and the solid obtained was collected by filtration while warm. The solids formed from the filtrate upon further cooling were collected by filtration. The filtrate was again stirred for 30 min and a third crop of solids was collected by filtration. The combined solids were washed with water and dried under reduced pressure to afford compound 73a. Mass spectrum (LCMS, ESI pos.) Calcd. For C ₁₃ H ₉ N0 ₂ : 188.1 (M+H); found 188.2. B. Ethyl 2-methylquinolitie-5-carboxylate, 73b

To a slurry of compound 73a (3.1 g, 16 mmol) in EtOH (50 mL) was added concentrated H2SO4 (1.0 mL) and the resultant slum' was reflux ed overnight. The homogeneous solution was cooled, diluted with DCM (300 mL), washed with IN NaOH (1 x 100 mL), dried (NauSCV), and concentrated in vacuo to give compound 73b as an off-white solid. Mass spectrum (LCMS, ESI pos.) Calcd. For C13H13NO2: 216.2 (M+H); found 216.2.

C. Ethyl 2~(bi momethyl)quinoline-5-carboxylate, 73c

Compound 73b (2.24 g, 10.4 mmol) and benzoyl peroxide (252 mg, 1.04 mmol) were heated to reflux in CCU (1 0 mL) overnight. The reaction was cooled, washed with saturated sodium bicarbonate (75 mL), dried over Na ₂ S04, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (0 - 30% EtO Ac/heptane) to give compound 73c. Mass spectrum (LCMS, ESI pos.) Calcd. For C _!3 H ₁₂ BrN0 ₂ : 294.0 (M+H); found 294.1.

D. Ethy]-2-[(diethoxyphosphoryl]methy])qumoline-5-carboxyj.ate, 73d

Compound 73e (2.40 mg, 0.816 mmol) was treated with triethyl phosphite (2.12 mL, 12.2 mmol) and the resuitant slurry was heated to 110 °C for 4 h. The reaction was concentrated in vacuo, diluted with DCM (50 mL), washed with sodium bicarbonate, dried over N ?S04, filtered, and concentrated in vacuo. The residue was purified by preparative TLC (10% MeOH/DCM) to afford compound 73d as an oil. Mass spectrum (LCMS, EST pos.) Calcd. For Ci ₇ H ₂₂ N0 ₅ P: 352.1 (M+H); found 352.2.

E. 6-Chloro-8-morpholinoimidazo[ 1 ,2-6] ridazme-2-carbaldehyde, 73e

Compound 73e (222 mg, 0.832 mmol) was prepared from compound Sb 'ding to the procedures described in Example 5, Steps D and F.

6-Chloro-8-morpholino- 3 -(pyridin- 3 -y Fjimkiazo [ 1 ,2-b jpyridazine-2 ^■ carbaldehyde, 73f

Compound 73 e was a coupled with 3-bromopyridine (0.100 mL, 1 ,25 mmol) according to the procedures described in Example 20, Step A to afford compound 73 f. Mass Spectrum (LCMS, ESI pos.): Calcd. for Ci6H, ₄ ClN ₅ 0 ₂ : 344.0 (M+H); found: 344.0.

G. (£)-2-(2-(6-Chloro-8-mo^holmo-3-(pyriaUn-3-yl)imidazo[l ,2- j]pyridazin-2- yl)vinyi)quinoline-5-carboxylic acid, 73g

To a solution of compound 73d (90 mg, 0.26 mmol) in DMF (3 mL) was added NaH (29 mg, 0.72 mmol) in one portion. Compound 73f (88 mg, 0.26 mmol) was then added as a slurry in DMF (1 mL). The reaction mixture was stirred for 10 min, quenched with water (1 mL) and acidified to pH 5 with 10% citric acid. The solid formed was collected by fiiiTation, washed with water (2 mL), diethyl ether (5 mL), and dried under reduced pressure to afford compound 73g (107 mg). Mass spectrum (LCMS, ESI pos.) Calcd. For C27H ₂ ]ClN ₆ i¾: 513.1 (M+H); found 512.8;

H. (is)-2-(2-(6-Chloro-8-morpholino-3-(pyr^

yl)vinyl)quinoline-5-carboxylic acid sodium salt, Cpd 14(5

To compound 73g (31.3 mg, 0.061 mmol) in MeGH (0.6 mL) was added NaOMe (0.12 mL, 0.061 mmol). The resulting mixture was stirred for 30 min and the solvent was removed in vacuo to obtain a solid which was then dried at 70 °C under high vacuum to afford the title compound 140 as a white solid. ^] H NMR (400 MHz, DM SO-;/, } 8 (ppm): 9.47 (d, J - 8.8 Hz, 1H), 8.89 (s, 1H), 8.74 (d, J - 3.9 Hz, 1H), 8.15 (d, J = 7.6 Hz, 1H), 7.53 - 7.87 (m, 7H), 6.57 (s, I H), 4.22 (br. s., 4H), 3.86 (br. s., 4H). Mass spectrum (LCMS, ESI pos.) Calcd. For C ₂₇ H _2J C1N ₆ 0 ₃ : 513.1 (M+H); Found 512.8;

Example 74

(J^-2-(2-(8-Morpholino-3-phenylimidazo[l ,2- >]pyridaz n-2-yl)vi^

carboxylic acid, sodium salt (Cpd 121)

A. 8-Morpholino-3-phenylimidazo[l ,2-6]pyridazme-2-carbaldehyde, 74a

Compound 5e (300 mg, 1 .3 mmol) was coupled with iodobenzene (0.21 mL, 1.9 mmol) according to the procedures described in Example 20, Step A to afford compound 74a. Ή NMR (400 MHz, CDC1 ₃ ) δ (ppm): 10. 1 i (s, M l ). 8.09 (d, J = 5.6 Hz, 1H), 7.73 (d, J - 8.1 Hz, 2H), 7.44 ^■■ 7.63 (m, 3H), 6.13 (d, J = 5.6 Hz, 1H), 4.04 - 4.16 (m, 4H), 3.80 - 4.02 (m, 4H).

B. ((£)-2-(2-(8-Morpholino-3-phenylimidazo[ l,2-i>]pyr ^" idazin-2- yl)vinyl)quinolin -5-carboxylic acid, 74b

A solution of compound 73d (1 19 mg, 0.339 mmol) in THF (6 mL) was treated with aH (36.9 mg, 0,924 mmol) at 0 °C and the resulting mixture was allowed to warm to room temperature over 10 min. Compound 74a (95.0 mg, 0.308 mmol) was then added in one portion and the resultant mixture was heated to 55 °C for 1 h. The reaction was allowed to cool to rt, quenched with saturated sodium bicarbonate (2 mL) and extracted with DCM (10 mL). The DCM layer was separated, dried over N ₂ S0 ₄ , filtered, and concentrated, and the resultant residue was purified by flash column chromatography over silica gel (0- 100% EtOAc / DCM) to afford compound 74b. Mass spectrum (LCMS, ESI pos.) Calcd. For C ₂₈ H ₂₃ Ns0 ₃ 478.2 (M+H); found 478.1.

5-carboxylic acid, sodium salt, Cpd 121 To a solution of compound 74b (99 mg, 0.20 mmol) in 3.4 mL of 1 : 1

MeOH/THF was added 3N NaOH (0, 1 1 mL, 0.35 mmol) and the resulting mixture was heated at 70 °C for 2. h. The reaction mixture was allowed to cool to rt, concentrated to about 50% of its volume and then filtered. The filtrate was dried under reduced pressure to give the title compound 121 as a white solid. Ή- NMR. (400 MHz,

CD ₃ OD) δ (ppm): 8.99 (d, J = 9.1 Hz, IH), 7.95 - 8.05 (m, 2H), 7.81 ^■ · 7.90 (m, 2 \ l ). 7.67 - 7.80 (m, 5H), 7.61 ft, J = 7.6 Hz, 2H), 7.48 - 7.56 (m, IH), 6.33 id, I H), 4.03 - 4.14 (m, 4H), 3.93 ^■■ 4.03 (m, 4H). Mass spectrum (LCMS, ESI pos.) Calcd. For C28H23N5O3 478.2 ( M · ! ! :·: found 478.5.

Following the procedure described in Example 74 and selecting and substituting reagents, starting materials, and conditions as would be known to those skilled in the art, the following compounds of formula (Γ) of the present invention were prepared.

Cpd

No. Characterization

(Iij-2-(2-(6-Cliloro-8-moipholmo-3-(pyridin-3-yl)imidazo[ L2- /, ^, ]pyridazin-2-yi)vinyl)qunioline-4-carboxylic acid sodium salt

Ή NMR (400 MHz, CD3OD) δ (ppm): 9.35 (br. s., I H), 8.66 -

142

9.1 1 (m, 4H), 7.99 ^■ 8.38 (m, 5H), 7.83 - 7.99 (m, IH), 6.47 (br.

s., I H), 4.12 - 4.26 (m, 4H), 3.83 - 4.01 (m, 4H). Mass Spectrum

(LCMS, ESI pos.) Calcd. For C27H21CIN6O3 513.1 (Μ+ϊί),

Found 512.8.

Cpd

No, Characterization

(B)-2-(2-(8-MΌφhoj½o-3-(pyri.dm-3-yl)imidazo[l ,2- 6]pyridazin-2-yl)vmy3)quinoline-5- carboxylic acid sodium salt

i i NMR (400 MHz, CD ₃ OD) δ (ppm): 9.01 (d, J = 8.6 Hz, 1H),

8.94 (s, i l l ). 8.64 i d. J = 3.5 Hz, l i s }. 8.22 - 8.27 (m, ill), 8.04 -

137 8.07 (m, 1H), 8.05 (d, J - 5.6 Hz, 1H), 7.93 ^■■ 7.99 (m, 1H), 7.90

(s, I H), 7.77 - 7.85 (m, 2H), 7.67 - 7.75 (m, 2H), 6.37 (d, 1H),

6.36 - 6.39 (m, IH), 4.08 - 4.12 (m, -H I ). 3.96 ( m, 4H). Mass

Spectrum (LCMS, ESI pos.) Caicd. For C ₂ 9H ₂ 6 ₆ 0 ₄ S 479.2

(M+H), Found 479.4.

Example 75

To a solution of compound 121 (75 mg, 0, 15 mmol) in DMF (3 mL) was added D1EA (0.77 mL, 0.45 mmol) and HATU (170 mg, 0.45 mmol). The reaction was stirred for 5 min and treated with methanesulfonamide (57 mg, 0.60 mmol) and then stirred for 24 h. The reaction mixture was diluted with DCM (50 mL), and washed with brine (50 mL). The organic layer was separated, dried over Na ₂ S04, filtered, and concentrated in vacuo. The resultant residue was purified by preparative TLC (10% MeOH/DCM) to afford the title compound 122. i i NMR (400 MHz, DMSO-de) δ (ppm): 9.27 (d, J - 9.1 Hz, IH), 8.13 (d, J - 5.6 Hz, IH), 7.85 - 7.95 (m, 2H), 7.68 ^■ 7.83 (m, 5H), 7.58 - 7.68 (m, 3H), 7.49 - 7.57 (m, IH), 6.43 (d, IH), 4.09 (d, J - 5.1 Hz, 4H), 3.83 - 3.91 (m, 4H), 2.95 (s, Ml). Mass spectrum (LCMS, ESI pos.) Calcd. For i\;iiv,:y,0:S: 555.2 (νΙ-ΙΠ: found 555.3.

Following the procedure described in Example 75 and selecting and substituting reagents, starting materials, and conditions as would be known to those skilled in the ari, the following compounds of formula (I) of the present invention were prepared.

Example 76

-2-(2-(3-(4-cyanophenyl)~8-morpholinoimidazo[l ,2-0]pyridazin~2- yl)vmyl)qui (Cpd 148)

A. 4-(2-Fomyl-8-rao^holinoimidazo[l,2-i>]pyridazin-3-yl)beii zonitrUe _! 76a

Compound Se (162 mg, 0.698 mmol) was coupled with 4-bromobenzonitrile (190 mg, 1.04 mmol) using the procedures described in Example 20, Step A to afford compound 76a. Mass spectrum (LCMS, ESI pos.) Calcd. For C18H15 5O2: 334.1 (MtH); found 334.1.

B. (E)-2-(2-(3-(4-cyanophenyl)-8-moipholmoimidazo[l,2-j]pyridaz in-2- yl)vmyl)quinolme-5-carboxylic acid, 761)

Compound 73d (55.0 mg, 0.165 mmol) was reacted under Horner-Emmons coupling conditions with compound 76a (58.0 mg, 0.165 mmol) using the procedures described in Example 74, Step B to afford compound 76b. Mass spectmm (LCMS, EST pos.) Calcd. For C ₂₉ H22N ₆ 0 ₃ : 503.2 (M+H); found 503.2.

C. (j¾-2-(2-(3-(4-cyanophenyl)-8-mo^holinoiniidazo[l _! 2-6]pyridazm-2- y])vinyl)quinoline-5-carboxylic acid sadium salt, Cpd 148

Compound 76b (28.2 mg, 0.056 mmol) was treated with NaOMe (0.11 mL, 0.056 mmol) using the procedures described in Example 73, Step H to obtain the title compound 148. ^] H NMR (400 MHz, CD ₃ OD): δ (ppm) 9.02 (d, J - 9.1 Hz, Hi), 8.07 (d, J = 5.6 Hz, 1H), 7.89 - 8.02 (m, 6H), 7.79 - 7.88 (m, 3H), 7.65 - 7.74 (m, IH), 6.39 (d, J - 6.0 Hz, Hi), 4.08 - 4.13 (m, 4H), 3.92 - 4.00 (m, 4H). Mass spectrum (LCMS, ESI pos.) Calcd. For C2 ₉ H22 ₀ O ₃ : 503.2 (M+H); found 503.2.

Example 77

(£)-2-(2-(3-(3-methox henyl)-8-mo holinoir idazo[i,2-ή] yridazm-2- yi)vinyl)quinoiine-5-carboxylie acid sodium salt (Cpd 149)

A, 3~(3-Methoxyphenyl)-8-moipholmoiim

77a

Compound Se ( 162 mg, 0.698 mmol) was coupled with 3-bromoanisole (0.13 mL, 1 ,04 mmol) according to the procedures described in Example 20, Step A to obtain compound 77a. Mass spectrum (LCMS, ESI pos.) Calcd. For 339.1 (M+H); found 339.2.

B. (^-2-(2~(3-(3 -methoxyphenyl)-8-moipholinoiinidazo[l ,2-/ ]pyridazin-2- yl)vinyi)quinolin -5-carboxylic acid, 77b

Compound 73d (53 mg, 0.15 mmol) was reacted under Horner-Emmons coupling conditions with compound 77a (51 mg, 0.1 5 mmol) using the procedures described in Example 20, Step A to afford compound 77b. Mass spectrum (LCMS, ESI pos.) Calcd. For C29H25N5O ₄ 508.2 (M+H); found 508.2.

C. ^)-2- 2-(3-(3-metho y henyl)-8-mo holmoimidazo[l ,2-ό]p 'ridazi -2- yl)vinyl)quinolme-5-earboxylic acid sodium salt, Cpd 149

Compound 77b (28 mg, 0.055 mmol) was treated with ^' NaOMe (0.1 1 mL, 0.055 mmol) using the procedures described in Example 73, Step H to afford the title compound 149. ^] H NMR (400 MHz, CD ₃ OD) δ (pprn)i 8.99 (d, J = 9.1 Hz, 1H), 7.92 ^■■ 8.04 (m, M l ). 7.87 i d. J = 7.6 Hz, i l l ). 7.59 - 7.79 (m, 3H), 7.49 (t, J = 8.1 Ηζ, ΙΗ), 7.22 ^■ · 7.35 (m, 2H), 7.08 (dd, J = 7.8, 2.3 Hz, 1H), 6.23 (d, 1H), 4.07 ^■ · 4.12 (m, 4H), 3.93 ^■■ 3.99 (m, 41 ! !. 3.88 (s, M l ). Mass spectrum (LCMS, ESI pos.) Calcd. For (\,M.,<\ ^' «().: 508.2. (M+H); found 508.3.

Example 78

(^-2-(2-(3-(3-Methox henyl)-8-mo holinoimidazo[l,2-ό] ridazm-2-yl)vi ^" nyl)- -

(m d ISO)

Compound 77b (32.3 mg, 0.0636 mmol) was coupled with methanesulfonamide (60.5 mg, 0.636 mmol) using the procedures described in Example 75 to give the title compound 158. ^] H NMR (400 MHz, CD ₃ OD): δ (ppm) 8.82 (br. s., H i ). 7.92 ^■■ 8.04 (m, 3FI), 7.87 (d, J = 7.6 Hz, 1H), 7.66 - 7.78 (m, 3H), 7.62 (d, J = 7.1 Hz, l H), 7.49 (t, J - 8.1 Hz, 1H), 7.24 - 7.32 (m, 1H), 7.08 (dd, J = 7.8, 2.3 Hz, I I I ) . 6.23 (d, J = 5.6 Hz, i 1 1 !. 3.96 - 4.06 (m, 4H), 3.95 (s, 3H), 3.34 (s, 3FI). Mass spectrum (LCMS, EST pos.) Calcd. For CjoH ₂ gN ₆ O _s S 585.2 (M+H); found 585.3.

Example 79

terl-Butyl 4-(6-chloro-8-morpholmo-2-((lR,2S)-2-(qumolm-2- yl)cyclopropyl)imidazo[l,2-6]pyridazin-3-yl)benzoate (C d 146)

A. (£)-Methyl 3-(qmnolin-2-yl)acrylate, 79a

To a solution of methyl 2-(dieihoxyphosphoryl)acetate (4.41 g, 20,9 mmol) in THF (8 mL) was added NaH (0.91 g, 22 mmol) and the resultant solution was stirred for 20 min. The reaction mixture was cooled to 0 °C and quinolme-2-earbaldehyde (3.0 g, 19 mmol) in THF (4 mL) was added via syringe. The reaction was allowed to warm to room temperature and stirred for 3 h. The reaction was quenched with saturated sodium bicarbonaie (10 mL) and the resulting mixture was extracted wiih DCM (100 mL). The DCM layer was dried over Na ₂ S0 ₄ , filtered, and concentrated in vacuo. The residue obtained was purified by flash column chromatography on silica gel (0-30% EtOAc-heptane) to afford compound 79a. Mass spectrum (LCMS, ESI pos.) Ca!cd. For & ₃ ΗιιΝ0 ₂ 214.1 ( +H); found 214, l .

B. trans -Methyl 2-(quinol -2-yl)cyclopropanecarboxylate, 79b

To a solution of tri-methylsulfoxonium iodide (495 mg, 2,25 mmol) in DMSO (4 mL) was added NaH (90 mg, 2.2 mmol) and the resulting mixture was stirred for 30 min. At this time compound 79a (400 mg, 1.87 mmol) was added in one portion and the resulting mixture was stirred overnight. The reaction mixture was then diluted with EtOAc (100 mL), washed with saturated sodium bicarbonate (100 mL) and concentrated in vacuo to obtain a residue which was purified by flash column chromatography on silica gel(0-50% EtOAc-heptane) to afford compound 79b as a white solid. Mass spectrum (LCMS, ESI pos.) Calcd. For C1 H13NO2 228,0 (M+H); found 228.2,

C. 2-Bromo-l-((lR,2S)-2-(quinolin~2-yl)cyclopropyl)ethanone, 79c

To a solution of compound 79b (65 mg, 0.286 mmol) in 50% THF-MeOH (2.4 mL) was added 3N NaOH (95.3 }iL, 0.286 mmol). The reaction was stirred overnight and concentrated in vacuo. The residue obtained was azeotroped with toluene (2 x 5 mL), dried under reduced pressure and slurried in DCM (4 mL). DMF (2.5 pL) was then added, followed by oxalyl chloride (87 iiL, 1.00 mmol). The reaction mixtitre was stirred for 1.5 h and concentrated in vacuo. The resultant solid was dried in vacuo for 30 min and slurried in 4 mL of ACN. The slurry was then treated with

trimethylsilyldiazomethane (0.28 mL, 0.57 mmol, 2M hexanes) and allowed to stir for 1 h. The reaction mixture was cooled to 0 °C and HBr ⁽ 0.1 lmL, 0.57 mmol, 5 M acetic acid) was added via syringe. After 30 min of stirring, the reaction mixture was diluted with DCM (50 mL), washed with cold saturated sodium bicarbonate (50 mL), dried over Na?S0 ₄ , filtered, and concentrated in vacuo to give compound 79c which was used without further purification. Mass spectrum (LCMS, ESI pos.) Calcd. For C :i l >Br ) 290.0 (M+H); found 290.2.

D. 4-(6-Chloro-2-((l R,2S)-2-(quino]in-2-yl)cyclopropyl)imidazo[l,2-b]pyridazin-

Compound 79c (67 mg, 0.23 mmol) was dissolved in DMF (2. mL) and compound 19a (50 mg, 0.23 mmol) was added in one portion. The reaction was allowed to stir for 48 h under an argon atmosphere, at which time it was diluted with DCM (SO mL) and washed with saturated sodium bicarbonate (50 mL). The organic layer was concentrated under reduced pressure and then purified by preparative TLC (5% MeOH/DCM) to afford compound 79d. Mass spectrum (LCMS, ESI pos.) Calcd. For C22H20CIN5O 406.1 (M+H); found 406.2. E. ten-Butyl 4-(6-chloro-8-morpholino-2-((lR,2S)-2-(quinolin-2- yl)cyclopropyl)imidazo[l ,2-&]pyridazin-3-yl)benzoate, Cpd 146

Compound 7 d (33 mg, 0.081 mmol) was coupled with tert-buty] 4- bromobenzoate (29 μΕ, 0.12 mmol) using the procedure described in Example 20, Step A to afford title compound 146. ¾ NMR (400 MHz, CD ₃ OD) δ (ppm): 7.93 - 8.08 (m, 4H), 7.72 - 7.85 (m, 3H), 7.66 (t, J - 7.6 Hz, I I I ). 7.41 - 7.50 (m, H), 7.24 - 7.31 (m, I i n. 6.12 (s, I H), 4.05 ( In . s., 4H), 3.95 i d. J = 3.9 Hz, 4H), 2.80 - 2.93 (m, 2H), 1.87 - 2.00 (m, 2H), 1.58 (s, 9H) Mass Spectrum (LCMS, ESI pos.): Calcd. for

C33H32CIN5O3: 582.2 i \f · ! ! :·: found: 582.2.

Example 80

4~(6-ChlolΌ-8-nlOφholino-2-((lR,2S)-2~(quinoIin-2-yl)cycIo propyl)imidazo

b]pyridazin-3-y1)benzoic acid trifluoroacetic acid salt (Cpd 147)

To compound 146 (38 mg, .065 mmol, Example 79) in DCM ( 1 mL) was added TFA (0.1 mL). After 1.5 h the reaction was concentrated in vacuo to obtain a residue which was dried under reduced pressure at 50 °C for 0.5 h, then at rt over the weekend to afford title compound 147. ^J H NMR (400 MHz, CD ₃ OD) δ (ppm) 8.90 (d, J - 9.1 Hz, 2H), 8.22 (d, J - 8.6 Hz, I H), 7.98 - 8.16 (m, 4H), 7.86 (t, J - 7.3 Hz, I H), 7.79 (d, J = 8.6 Hz, 2H), 7.70 (d, J = 8.6 Hz, I H), 6.42 (s, I H), 4.04 - 4.15 (m, 4H), 3.83 - 3.96 (m, 4H), 3.20 ^■■ 3.28 (m, IH), 3.04 · ^■ 3.20 (m, IH), 2.22 ^■ 2.35 (m, IH), 2.10 - 2.22 (m, IH). Mass Spectrum (LCMS, ESI pos.): Calcd. for C29H23CIFN5O3: 544.1 (M+H); found: 544.1 . Example 81

4~(6-Chloro-8-moφholino-2-((lR,2S)-2~(quinoiin-2-yl)cyciopr o yl)imidazo[l,2- b]pyridazin-3-yl)-2-fluorobenzoic acid tnfiuoroacetic acid salt (Cpd 165)

teri- butyl 4-(6-ο1ι1οΓο-8-ηιοφ1ιο1ϊηο-2-((1Κ,28)-2~(ςα ίηο1ϊη-2- yl)cyc]opropyl)irnidaz -b]pyridazm-3-yi)-2-fluorobenzoate, 81

Compound 79d (100 mg, 0.246 mmol) was coupled with fer/-butyl 4-bromo-2- fluorobenzoate ( 102 mg, 0.370 mmol) using the procedures described in Example 20, Step A to afford compound 81a. Mass Spectrum (LCMS, ESI pos.): Calcd. for C33H3 ₁ CIFN5O3: 600.2 (M+H); found: 600.2.

B. 4-(6-Chloro-8-rao^holino-2-((lR,2S)-2-(quinolin-2-yl)cyclopr opyl)

imidazo[{,2-6]pyridazm-3-yl)-2-fluorobeiizoic acid tnfiuoroacetic acid salt, Cpd 165

Compound 81a (30 mg, 0,05 mmol) was treated with TFA using the procedures previously described in Example 80 to afford the title compound 165. ^J H NMR (400 MHz, CD ₃ OD) δ (ppm): 8.87 (d, J = 8.6 Hz, I I I ;. 8.20 i d. J - 8.6 Hz, Hi), 8.02 - 8.12 (m, 21 1 ). 7.99 (t, J - 8.1 Hz, I I I ). 7.84 (t, i 7. ! Hz, 1H), 7.71 (d, J - 9.1 Hz, I f i s. 7.58 - 7.66 (m, 2H), 6.46 (s, 1H), 4.05 - 4.14 (m, 4H), 3.85 - 3.95 (m, 4H), 3.18 - 3.25 (m, 1H), 3.08 - 3.16 (m, IH), 2.22 - 2.30 (m, 1H), 2.16 (m, IH); Mass Spectrum (LCMS, ESI pos.): Calcd. for C29H24CIN5O3: 526.1 (M+H); found: 526.3.

Example 82

2-(4-(6-Chloro-8-mo holmo-2-((lR,2S)-2-(qumolm-2-yl)c clo ro yl)i ^" midazo[l,2

6]pyridazin-3- salt (Cpd 173)

Methyl 2-(4-(6-ch3oro-8-morpholino-2-((l ,2S)-2-(quinolin-2- yl)cyclopropy i)imidaz -b]pyridazin-3 -ylipheny l)acetate, 82a

Compound 7 d (60 mg, 0.14 mmol) was coupled with methyl 2-(4- bromophenyl)acetate (46 0.22 mmol) using the procedures described in Example 20, Step A to afford compound 82a. Mass Spectrum (LCMS, ESI pos.): Calcd. for C31H28CIN5O3: 554.2 (M+H); found: 544.2.

B. 2-(4-(6-Chloro-8-moφho]mo-2-((l R,2S)-2-(qumo]m-2- yl)cyclopropyl)irnidazo[l,2-0]pyridazin-3-yl)phenyl)acetate sodium salt, Cpd

Compound 82a (30 mg, 0.054 mmol) was treated with NaOMe (36 μΕ, 0.10 mmol) using the procedures described in Example 73, Step H to afford title compound 173. ! i NMR (400 MHz, CD ₃ OD) δ (ppm): 8.18 i d. J === 8.6 Hz, IH), 7.92 (d, J === 8.1 Hz, IH), 7.84 (d, J - 8.1 Hz, IH), 7.68 (t, J - 7.6 Hz, IH), 7.56 (d, J - 8.1 Hz, 2H), 7.49 (t, J === 6.8 Hz, IH), 7.36 i d. J === 8.6 Hz, 2H), 7.32 (d, J === 8.6 Hz, IH), 6.34 (s, IH), 4.02 - 4.11 (m, 4H), 3.85 - 3.95 (m, 4H), 3.49 (s, 2H), 2.79 - 2.89 (m, 1 H), 2.68 - 2.79 (in, 1H), 1.84 ^■■ 1.94 (m, 2H). Mass Spectrum (LCMS, ESI pos.): Calcd. for

C\,,i Ci\\0 ;: 540.1 (M+H); found: 539.8.

Example 83

2-((3 -(6-( lH- ietrazol-5-y¾

yj)methoxy)qumolme (Cpd 33)

A. 3-ΒΓθΓηο-8-Γηο ΗοΗ -γ1)ηΐ6ΐίΐ3ηο], 83a

A solution of compound 5d (40.0 g, 171 mmol) in CFLCN (400 mL) was treated dropwise with a solution of NBS (30.2 g, 170 mmol) in CH ₃ CN (906 mL) at -20 °C. After addition, the reaction mixture was stirred for 2 h at room temperature. The reaction was quenched by the addition of 50 mL of saturated Na ₂ S ₂ 0 ₃ solution. The solids formed were collected by filtration and washed with diethyl ether to afford compound 83a as a white solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C I i ;BrN,i) >: 313.0 (M+H); found: 313.0.

B. 2-((3-Bromo-8-mo^hoIinoimidazo[l,2-0]pyridazii -2-yl)methoxy)qumolme, 83b

To a solution of compound 83a (1 g, 3 mmol) and 2-chloroquinoline (780 mg, 4.76 mmol) in N,N-dimethylformamide (20 mL), 60% sodium hydride (200 mg, 5.00 mmol) was added in portions. The reaction mixture was stirred overnight at 80 °C and quenched by the addition of 20 mL of water. The solids were collected by filtration to afford compound 83b as a white solid. Mass Spectrum (LCMS, ESI pos.) Caicd. For C ^' v.i i ,Br\ ·(} .: 440.1 (M + H), Found 440.2.

C. 5-( ^' 8-morpholino-2-( ^' ( ^' quinolm-2-yloxy)methyl)imidazo[l ,2- ?]

pyridazin-3-yl)pico

, 83c

Compound 83b was reacted under Suzuki coupling conditions with 5~(4,4,5,5- tetramethyl- 1 ,3,2-dioxaborolan-2-yl)picolinonitrile using the procedures described in Example 1, Step E to afford compound 83c as a white solid. Mass Spectrum (LCMS, ESI pos.) Caicd. For C26H21N7O2: 464.2 (M + H), Found 464.2.

D. 2-((3-(6-(lH-terxazol-5-yl)pyridm-3-yl) ^■ 8-moφholinoilmdazo

[l ,2-Zj]pyridazin-2-y])methoxy)qumoline, Cpd 33

A solution of compound 83c (200 mg, 0.430 mmol), sodium azide (85 mg, 1.31 mmol) and triethyiamine hydrochloride (300 mg, 2.17 mmol) in NN- dimethylformamide (3 mL) was stirred for 2 li at 1 10 °C. The reaction was quenched by the addition of 10 mL of water. The solids were collected by filtration. The crude product was purified by flash column chromatography on silica gel (methanol/DCM, 1 :200-l : 10) to afford title compound 33 as a yellow solid. Ή-NMR (400 MHz, DMSO-ifc) δ (ppm): 9.1 3 (s, IH), 8.52 - 8.50 (ra, 1H), 8.38 - 8.36 (m, 1H), 8.26 - 8.22 (in, 2H), 7.88 (d, J= 7.6 Hz, 1H), 7.64 - 7.59 (m, 2H), 7.43 · ^■ 7.39 (m, IH), 7.04 (d, J= 8.8 Hz, 1 H), 6.49 - 6.48 (m, H), 5.68 (s, 2H), 4.05 - 3.98 (m, 4H), 3.85 - 3.75 (m, 4H). Mass Spectrum (LCMS, EST pos.): Calcd. for C26H22 10O2: 507.2 (M + H); Found: 507.1.

Following the procedure described in Example 83, Steps A-C, and selecting and substituting reagents, starting materials, and conditions as would be known to those skilled in the art, the following compounds of formula (I) of the present invention were prepared.

Cpd Characterization

N,N-dimethyl-5-(8-mo holmo-2-((qumolm-2- y3oxy)methyi)imidazo

[l ,2-/ ]pyridazin-3-yl)pyridin-2-amine methane sulfonic acid Ή NMR (400 MHz, CDC1 ₃ ) δ (ppm): 8.84 (d, J = 2.0 Hz, 1H), 8.28 (dd, J - 9.5, 2.2 Hz, 1H), 8.13 (d, J = 8.8 Hz, IH), 8.00 -

5

8.07 (ffl, IH), 7.92 (d, J = 8.6 Hz, IH), 7.77 (d, J = 7.3 Hz, I H), 7.68 (td, J - 7.7, 1.2 Hz, I H), 7.41 - 7.48 (m, I H), 7.1 6 (d, J - 8.3 Hz, IH), 6.94 (d, J = 9.5 Hz, IH), 6.13 (d, J - 5.9 Hz, IH), 5.73 (s, 2H), 3.99 - 4.04 (m, 4H), 3.88 - 3.95 (m, 4H), 3.37 (s, 6H), 2.78 (s, 3H); Mass Spectrum (LCMS, EST pos.) Calcd. For C27H27N7O2 504.2 (M+Na), Found 504.2.

N,N-diethyl-5-(8-morpholi ^" no-2-((quinolin-2- yloxy)memyi)imidazo[ l ,2-&]pyridazm-3-yl)pyrid ^" in-2-amine methane sulfonic acid

^! H NMR (400 MHz, CDClj) 8 (ppm): 8.84 (br. s., I H), 8.21 (d, J - 9.3 Hz, I H), 8.01 - 8.14 (m, 2ϊί), 7.88 i d. J - 7.8 Hz, IH), 7.75 (d, J === ^: 7.8 Hz, IH), 7.66 (t, J === 7.6 Hz, IH), 7.37 - 7.48 (m, IH), 7.14 (d, J = 7.3 Hz, IH), 6.87 (d, J = 9.3 Hz, IH), 6.13 (d, J = 5.6 Hz, IH), 5.72 (s, 2H), 4.02 (br. s., 4H), 3.92 (br. s., 4H), 3.70 (d, J === 6.8 Hz, 41 n. 2.79 is, 3H), 1.34 (t, J === 6.8 Hz, 6H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C29H31N7O2 510.2

(M+H), Found 510.2.

Cr Characterization

4-(3-(1 '-methyl- r,2 ^, ,3',6'-tetrahydro-[2,4 ^, -bipyridin]-5-yl)-2-

((qumo]iii-2-yloxy)methy])imidazo[i ,2- ?]pyiidazm-8- yl)morpholine

Ή NMR (CDCI ₃ ) δ (ppm): 8,97 (d, J = 1.8 Hz, 1H), 8.1 1 (dd, J = 8.3, 2.3 Hz, 1H), 7.96 ^■■ 8.05 (in, 2H), 7.78 (d, J = 8.3 Hz, 1H),

7.72 (d, J = 7.8 Hz, 1H), 7.57 - 7.64 (m, 1H), 7.49 (d, J = 8.3 Hz, 1 H), 7.35 - 7.42 (m, I H), 6.96 (d, J - 8.8 Hz, IH), 6.68 (br. s.,

1H), 6.1 1 (d, J = 5.8 Hz, I H), 5.68 (s, 2H), 3.98 - 4.08 (m, 4H), 3.85 - 3.95 (m, 4H), 3.18 (d, J = 2.3 Hz, 2H), 2.62 - 2.77 (m, 4H), 2.42 (s, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For Cj ₁ Hj ₁ N ₇ 0 ₂ 534.2 (M+H), Found 534.2.

Biological Examples

In Vitro Assays

Example 1

In vitro assay PDElOa

Rat recombinant PDE Oa (rPDElOa) was expressed in Sf ceils using a recombinant rPDEl Oa bacuiovirus construct. Cells were harvested after 48 h of infection and the rPDE l Oa protein was purifsed by metal chelate chromatography on Ni-sepharose 6FF. Tested compounds were dissolved and diluted in 100% DMSO to a concentration 100 fold of the final concentration in the assay. Compound dilutions (0.4 μΕ) were added in 384 well plates to 20 iL of incubation buffer (50 mM Tris pH 7.8, 8.3 mM MgCl ₂ , 1.7 mM EGTA). Ι ΟμΓ. of rPDEl 0a enzyme in incubation buffer was added and the reaction was started by addition of 10 iiL substrate to a final concentration of 60 nM cAMP and 0,008 uCi Ή-cAMP. The reaction was incubated for 60 mm at rt. After incubation, the reaction was stopped with 20 μΕ of 17.8 mg/mL PDE SPA beads. After sedimentation of the beads during 30 min the radioactivity was measured in a Perkin Elmer Topcount scintillation counter and results were expressed as cpm. For blank values the enzyme was omitted from the reaction and replaced by incubation buffer. Control values were obtained by addition of a final concentration of 1% DMSO instead of compound. A best fit curve was fitted by a minimum sum of squares method to the plot of % of control value subtracted with blank value versus compound concentration and the half maximal inhibi tory concentration (IC ₅₀ ) value was derived from this curve. Resultant data is shown in Table 3.

Example 2

In vitro hPDElOa

Human recombinant PDE10A2 was expressed in Sf9 cells, using a recombinant bacuiovirus construct containing the full length sequence containing a 6xHis sequence following the start Met to allow metal affinity purification of the recombinant protein. Cells were harvested and the phosphodiesterase protein was purified by metal chelate chromatography on Ni-sepharose 6FF.

The affinity of the compounds of Formula (I) for phophodiesterases (PDE) was measured by a scintillation proximity assay (SPA). PDE Yttrium Silicate SPA beads allow PDE activity to be measured by direct binding of the primary phosphate groups of non-cyclic AMP or GMP to the beads via a complex iron chelation mechanism. The amount of bound tritiated product ([ ³ H]-AMP) is measured by liquid scintillation counting.

The compounds were dissolved and diluted in 100% DMSO in polystyrene plates to a concentration of 100-fold the final concentration in the assay. Human PDE10A enzyme solution ( 10 μ,Ε) was added to 20 μΕ of incubation buffer (50 mM Tris pH 7.8, 8.3 mM MgCl?, 1.7 mM EGTA), 10 μΐ, substrate solution consisting of a mixture of non-tritiated and tritiated substrate (60 nM cAMP, 0.008 \iCi ^" 'H-cAMP), and 0.4 μΙ_ compound in 100% DMSO in a 384-weil plate, and incubated for 60 min at room temperature. After incubation, the reaction was stopped with 20 μΕ of stop solution, consisting of PDE SPA beads ( 17.8 mg beads/mL in 18 mM zinc sulphate). After sedimentation of the beads for 30 min, the radioactivity was measured in a Perkin Elmer Topcount scintillation counter and results were expressed as cpm. To measure the low control, no enzyme was added to the reaction mixture.

Data were calculated as the percentage of inhibition of total activity measured in the absence of test compound (% control). A. best-fit curve was fitted by a minimum sum of squares method to the plot of %Comrol vs compound concentration, from which an IC ₅₀ value (inhibitory concentration causing 50 % inhibition of hydrolysis) was obtained. Resultant data is shown in Table 3. For compounds tested more than the data points were aggregated.

Table 3. rPDE10a2 hPDE10a2

CpcL No. IC50 (nM) ICSO (nM)

1 46 1 15

2 141 245

3 676 759

4 200 155

5 457 126

6 25 20

7 447 692

8 813 603

9 132 427

10 17 43

11 25 55

12 1

13 14 20

14 776 955

IS 269 676

16 6 6

17 2

18 6

19 3 2

20 2 18

22 4 6

23 6 8

24 1 1

25 <: 7

27 2 J

28 1 1

29 49 39

30 2 1

31 < 1 1

32 1 J

34 2 3

35 7 5

36 2

37 < 1 1

38 4

39 5

40 2 rPDE10a2 hPDE10a2

Cpd. No. iC50 (nM) IC50 (nM)

41 1 1

42 1 1

43 1

44 1 4

45 5 8

46 1 3

47 1 1 14

48 6 9

49 4 4

50 3 8

51 4 6

52 41

53 33 41

54 1 1 7

56 7 4

57 1 1

58 4 2

59 6 5

60 <1 <1

61 <1 <1

62 9 4

63 3

64 2 1

65 8 10

66 <: 9

67 5 22

68 6 5

69 4 6

70 T 4

71 8 6

8 6

73 7 8

74 13 13

75 T 4

76 η 5

77 <1 <1

78 20 15

79 8 3

80 2 <1

81 4 1

82 2 <1

83 1 1 rPDE10a2 hPDE10a2

Cpd. No. iCSO (nM) ICSO (nM)

84 <1 <1

85 <1 <1

86 2

87 1 1

88 <1 <i

89 62 89

90 17 19

91 <1 <i

92 5 4

93 3

94 82 53

96 31 22

97 20 22

98 3

99 12 10

100 6 _^

101 5 4

102 5 4

103 3

104 8 3

105 5 4

107 16 12

108 <1 <i

109 <1 <1

110 2

111 17 -18

113 2 2

IIS 1 1

116 1 1

118 1 < 1

119 6 6

120 2 3

121 1 < 1

122 T 4

124 9 4

125 2. 2

126 1 2.

127 16 < 1

128 5 5

129 6 2

130 30 19

131 5 rPDE10a2 hPDE10a2

Cpd. No. 1C50 (nM) ICSi) (nM)

132 15 1 1

133 70 62

134 T 4

135 10 6

137 1

138 2 5

139 2 1

140 2

141 23 58

143 < 1 1

144 < 1 < 1

145 4

147 4 η

148 1 1

149 1 1

ISO 6 6

152 15 7

1S3 4

154 28 72

155 5

1S6 7 -7

157 9 2

158 5

159 9

160 1

161 4

162 9

163 12

164 <1

165 12

166 93

167 13

168 2

169

170 1

171 2

172 1

174 1

175

176 6 6

177 10 21

178 1 1 rPDE10a2 hPDE10a2

Cpd. No. iCSO (nM) ICSO (nM)

179 5

180 5

181 6

Example 3

PDElOa-Brain Permeability Assay

A. PDE I 0a- Perfused Brain Permeability Study Protocol

The purpose of the perfused blood brain barrier acute PK studies was to determine whether a compound post-administration was able to cross the blood brain barrier, and to then quantitate the drug levels in plasma relative to brain. Whole body perfusion of saline after plasma blood collection improved estimate errors due to drug remaining in the capillaries of the brain, It has been suggested in the scientific literature that compounds that do not accumulate in the brain tissue may possess fewer potential CNS side effects. Therefore, it is an objective of the present invention to ideniify compounds of Formula (I) that do not accuniuiaie in the brain tissue where they may exert CNS effects.

Drug administration by oral gavage, subcutaneous injection or intravenous was carried out using male Sprague Dawley rats under IACUC protocol (SH-MET3010). Male Sprague Dawley rats (Charles River) -300-350 g were maintained on a. 4% standard rodent diet (Test Diet 5001 ). They are allowed ad libitum access to water and food. Room temperature was maintained at 64 °F and humidity at 30-70%.

Three animals per compound were provided a dose of 2 mg/mL in 20% HpbCD/Tris pH 8 by tail i.v. or 30 mpk p.o. or s.c. in 20% HpbCD/Tris pH 8, with PDEl Oa antagonists. A first blood sample was collected at 30 min via retro-orbital sinus (anesthetic by 70% Ci)2/'30% (¾) into heparirtzed plasma separator rubes. The blood was centrifuged and 100 ^iL plasma was placed into a 96 well plate and saved on dry ice.

After the 120 min, the final blood sample was collected via retro-orbital sinus under anesthesia by IP 0.5cc injection of a 4/1 mixture of Ketaset: AnaSed [(prepared 10 mL Ketaset ( 100 mg/mL Ketam ne) + 2.5 mL AnaSed (20 mg/mL Xylazine)] . The rats were then perfused with 400 mL heparinized saline (10,000 units/L) through the left ventricle of the heart; the brains were then removed (not including the medulla), weighed and homogenized in PBS (4 niL/g tissue). The samples were stored at -80 °C and submitted for chemical analysis of blood and brain concentrations. Endpotnts of sample analysis consists of the plasma concentrations at 30 and 120 min, plus brain concentrations at 120 min. Resultant data is shown in Table 4.

B, PDE10a-Non-Petfused Brain Permeability Study Protocol

The purpose of the acute PK/ Brain Permeability Studies was to determine whether a compound post-administration was able to cross the the blood brain barrier, and then to quantitate the drug levels in plasma relative to brain. It has been suggested in the scientific literature that compounds that do not accumulate in the brain tissue may possess fewer potential C S side effects. Single dose 2 mg/ kg (i.v.) PK/ brain permeability studies using male Sprague Dawley rats were carried out under ACUC protocol (SH-MET3010). Male Sprague Dawley rats (Charles River) weighing -300- 350 g were maintained on a 4% standard rodent diet (Test Diet 5001). They were allowed ad libitum access to water and food. The room temperature was maintained at 64 °F and humidity at 30-70 %. Compounds were prepared 2 mg/niL in 20%

HpbCD/Tris ρϊί 8 for tail intravenous dosing at a dose volume for each rat at 1 mL/kg.

Three animals per compound were injected at a dose of 2 mg/kg tail i.v. with a PDElOa antagonist compound of the instant invention. Blood samples were collected at 30 and 120 min via retro-orbital sinus (anesthetic by 70% CO?/30% 0 ₂ ) into heparinzed plasma separator tubes. The blood was centrifuged and 100 mL plasma was placed into a 96 well plate and saved on dry ice. After the 12.0 min blood samples were collected, each rat was euthanized in a 100%> C0 ₂ chamber, the brain (not including the medulla) and pancreas were removed, rinsed with PBS, weighed, and homogenized in PBS (4 mL/ g tissue). 100 uL samples of tissue homogenates and 100 uL of compounds formulation were also placed in polyethylene tubes. The samples were stored at -80 °C and submitted for chemical analysis of blood and brain concentrations.

Endpoints of sample analysis consist of the plasma concentrations at 30 and 120 min, plus brain and pancreas concentrations at 120 min. Resultant data is shown in Table 4. Table 4.

Brain/ Plasma ratios ^' * ofPDEIOa compounds Ratio Plasma Brain

Br/PI cone cone

Mean 2 h 2 h

Cpd No. 2 h (ng mL) (ng/g)

65 0.01 1614 14.5

67 0.02 725 16.9

76 0.02 568 9.3

83 0 205 0

74 0.04 857 34.7

100 0.02 2838 60.7

102 0 155.3 0

125 0 283.8 0

128 o 314.4 0

134 o 925.7 0

103 o 198.6 0

124 0 86.6 0

164 0 162 0

169 0 106 0

168 0.02 1 198 30.1

* Perfused or non-perfused brain

While the foregoing specification teaches the principles of the present invention, with examples provided for the puipose of illustration, it will be understood that the practice of the invention encompasses all of the usual variations, adaptations and/or modifications as come within the scope of the following claims and their equivalents.