Jaybe. Interesting When you google. Acetylenic heteroaryl compounds
01/17/13 | Class 514 Monitor | RSS | Prev - Next | Industry/Agents/Inventors
Acetylenic heteroaryl compounds
Abstract: in which the variable groups are as defined herein, and to their preparation and use. This invention relates to compounds of the general formula:
USPTO Applicaton #: #20130018046 - Class: 514218 (USPTO) - 01/17/13 - Class 514
The Patent Description & Claims data below is from USPTO Patent Application 20130018046, Acetylenic heteroaryl compounds.
BACKGROUND OF THE INVENTION
The protein kinases represent a large family of proteins, which play a central role in the regulation of a wide variety of cellular processes and maintaining control over cellular function. A partial, non limiting, list of such kinases includes abl, Akt, bcr-abl, Blk, Brk, c-kit, c-met, c-src, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, cRaf1, CSK, EGFR, ErbB2, ErbB3, ErbB4, Erk, Pak, fes, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, flt-1, Fps, Frk, Fyn, Hck, IGF-1R, INS-R, Jak, KDR, Lck, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, ros, tie, tie2, TRK and Zap70. Abnormal protein kinase activity has been related to several disorders, ranging from non-life threatening diseases such as psoriasis to extremely serious diseases such as cancers.
In view of this large number of protein kinases and the multitude of protein kinase related diseases, there is an ever-existing need to provide new classes of compounds with increased selectivity that are useful as protein kinase inhibitors and therefore useful in the treatment of protein tyrosine kinase related diseases.
This invention concerns a new family of acetylenic heteroaryl compounds and their use in treating cancers, bone disorders, metabolic disorders, inflammatory disorders and other diseases.
DESCRIPTION OF THE INVENTION 1. General Description of Compounds of the Invention
The compounds of this invention have a broad range of useful biological and pharmacological activities, permitting their use in pharmaceutical compositions and methods for treating metabolic disorders, bone diseases (e.g., osteoporosis, Paget\'s Disease, etc.), inflammation (including rheumatoid arthritis, among other inflammatory disorders) and cancer (including solid tumors and leukemias, especially those mediated by one or more kinases such as Src or kdr, or by dysregulation of a kinase such as Abl and mutant variants thereof), including, among others, advanced cases and cases which are resistant or refractory to one or more other treatments.
Included are compounds of Formula I, tautomers thereof, or a pharmaceutically acceptable salt, hydrate or other solvate thereof:
wherein:
Ring T represents a substituted or unsubstituted 6-membered heteroaryl ring, comprising 1-4 nitrogens;
Ring A represents a 5- or 6-membered aryl or heteroaryl ring and is optionally substituted with 1-4 Ra groups;
Ring B represents a 5- or 6-membered aryl or heteroaryl ring and is optionally substituted with 1-5 Rb goups;
L1 is selected from NR1C(O) and C(O)NR1;
At each occurrence, Ra and Rb are independently selected from the group consisting of halo, —CN, —NO2, —R4, —OR2, —NR2R3, —C(O)YR2, —OC(O)YR2, —NR2C(O)YR2, —SC(O)YR2, —NR2C(-S)YR2, —OC(-S)YR2, —C(-S)YR2, —YC(-NR3)YR2, —YP(-O)(YR4)(YR4), —Si(R4)3, —NR2SO2R2, —S(O)rR2, —SO2NR2R3 and —NR2SO2NR2R3, wherein Y is independently a bond, —O—, —S— or —NR3—;
R1, R2 and R3 are independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalynyl, aryl, heterocyclyt and heteroaryl;
alternatively, NR2R3 may be a 5- or 6-membered saturated, partially saturated or unsaturated ring, which can be optionally substituted and which contains 0-2 additional heteroatoms selected from N, O and S(O)r;
each occurrence of R4 is independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl, heteroaryl;
(a) X1 is CH or CRt1 wherein Rt1 is halo, OR5, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, carbon linked heteroaryl, carbon linked heterocyclyl; wherein R5 is H, alkyl, alkenyl alkynyl; and; (a)-1: X2 is ce and X3 is N; or (a)-2: X2 is CRt2 and X3 is CRt3 wherein Rt2 and Rt3 are independently selected from H or Ra, with the proviso that when X1 is CH and Rt3 is H, Rt2 is not —C(O)OCH3, —C(O)OH or H; or (a)-3: X2 is N and X3 is CRt4 or N; wherein Rt4 is H, halo, —CN, —NO2, —R2, —OR2, —C(O)YR2, —OC(O)YR2, —SC(O)YR2, —NR2C(-S)YR2, —OC(-S)YR2, —C(-S)YR2, —YC(-NR3)YR2, —YP(-O)(YR2)(YR2), —Si(R4)3, —S(O)rR2, —SO2NR2R3; or,
(b) X1 is N, X2 is N or CRt2 and X3 is CRt3 or N; and
in (a) or (b), alternatively e and e can form together with the atoms to which they are attached, a saturated, partially saturated or unsaturated 5- or 6-membered ring, comprising carbon atoms and 0-3 heteroatoms selected from O, N, S(O), and C(O) and the said ring is optionally substituted; with the proviso that when X1 is CH, Rt2 and Rt3 do not form an unsubstituted phenyl;
or,
(c) X1 is CRt, X2 is N or CRt2 and X3 is N or CRt3, wherein Rt is selected from —CN, —NO2, —OR6, —NR2R3, —C(O)YR2, —OC(O)YR2, —NR2C(O)YR2, —SC(O)YR2, —NR2C(-S)YR2, —OC(-S)YR2, —C(-S)YR2, —YC(-NR3)YR2, —YP(-O)(YR4)(YR4), —Si(R4)3, —NR2SO2R2, —S(O)rR2, —SO2NR2R3 and —NR2SO2NR2R3, wherein R6 is cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, or heterocyclyl and;
(c)-1: at least one of Rt, Rt2, Rt3, Ra and Rb is or contains a YP(-O)(YR4)(YR4), a Si(R4)3 or —YC(-NR3)YR2 substituent; or
(c)-2: at least one of Ra and Rt is or contains a —NR2C(-S)OR2, —OC(-S)YR2, or —C(-S)OR2 substituent; or
(c)-3: at least one of Rb, Rt2 and Rt3 is or contains a —NR2C(-S)YR2, —OC(-S)YR2, or —C(-S)YR2 substituent; or
c)-4: Rt2 and Rt3 form together with the atoms to which they are attached, a saturated, partially saturated or unsaturated 5- or 6-membered ring, comprising carbon atoms and 0-3 heteroatoms selected from O, N, S(O), and C(O); which ring is optionally substituted; and,
alternatively Rt and Rt2 can form together with the atoms to which they are attached, a saturated, partially saturated or unsaturated 5- or 6-membered ring, comprising carbon atoms and 0-3 heteroatoms selected from O, N, S(O)r and C(O), the ring being optionally substituted;
each of the foregoing alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and heterocyclyl moieties are optionally substituted;
m is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3, 4 or 5; r is 0, 1 or 2.
The foregoing definitions are further elaborated upon and exemplified below and apply to all subsequent occurrences except to the extent otherwise specified.
2. Featured Classes of Compounds and their Use, Generally
This invention includes compounds of Formula I, tautomers thereof, or a pharmaceutically acceptable salt, hydrate or other solvate thereof:
wherein:
Ring T represents a substituted or unsubstituted 6-membered heteroaryl ring, comprising 1-4 nitrogens;
Ring A represents a 5- or 6-membered aryl or heteroaryl ring and is optionally substituted with 1-4 Ra groups;
Ring B represents a 5- or 6-membered aryl or heteroaryl ring and is optionally substituted with 1-5 Rb goups;
L1 is selected from NR1C(O) and C(O)NR1;
At each occurrence, Ra and are independently selected from the group consisting of halo, —CN, —NO2, —R4, —OR2, —NR2R3, —C(O)YR2, —OC(O)YR2, —NR2C(O)YR2, —SC(O)YR2, —NR2C(-S)YR2, —OC(-S)YR2, —C(-S)YR2, —YC(-NR3)YR2, —YP(-O)(YR4)(YR4), YP(-O)(YR4)(YR4), —Si(R4)3, —NR2SO2R2, —S(O)rR2, —SO2NR2R3 and —NR2SO2NR2R3, wherein Y is independently a bond, —O—, —S— or —NR3—;
R1, R2 and R3 are independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalynyl, aryl, heterocyclyl and heteroaryl;
Alternatively, a NR2R3 moiety may be a 5- or 6-membered saturated, partially saturated or unsaturated ring, which can be optionally substituted and which contains 0-2 additional heteroatoms selected from N, O and S(O)r;
each occurrence of R4 is independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclyl, heteroaryl;
(a) X1 is CH or CRt1 wherein Rt1 is halo, OR5, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, carbon linked heteroaryl, carbon linked heterocyclyl; wherein R5 is H, alkyl, alkenyl alkynyl;
and; (a)-1: X2 is CRt2 and X3 is N; or (a)-2: X2 is CRt2 and X3 is Ce wherein Fe and Rt3 are independently selected from H or Ra; or (a)-3: X2 is N and X3 is CRt4 or N; wherein Rt4 is H, halo, —CN, —NO2, —R2, —OR2, —C(O)YR2, —OC(O)YR2, —SC(O)YR2, —NR2C(-S)YR2, —OC(-S)YR2, —C(-S)YR2, —YC(-NR3)YR2, —YP(-O)(YR2(YR2), —Si(R4)3, —S(O)rR2, —SO2NR2R3; or,
(b) X1 is N, X2 is N or CRt2 and X3 is CRt3 or N; and
in (a) or (b), alternatively Rt2 and Rt3 can form together with the atoms they are attached, a saturated, partially saturated or unsaturated 5- or 6-membered ring, comprising carbon atoms and 0-3 heteroatoms selected from O, N, S(O)r and C(O) and the said ring is optionally substituted; with the proviso that when X1 is CH, Rt2 and Rt3 do not form an unsubstituted phenyl; or
or
(c) X1 is CRt, X2 is N or CRt2 and X3 is N or CRt3, wherein Rt is selected from —CN, NO2, —OR6, —NR2R3, —C(O)YR2, —OC(O)YR2, —NR2C(O)YR2, —SC(O)YR2, —NR2C(-S)YR2, —OC(-S)YR2, —C(-S)YR2, —YC(-NR3)YR2, —YP(-O)(YR4(YR4), —Si(R4)3, —NR2SO2R2, —S(O)rR2, —SO2NR2R3 and —NR2SO2NR2R3, wherein R6 is cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, or heterocyclyl and;
(c)-1: at least one of Rt, Rt2, Rt3, Ra and Rb is or contains a YP(-O)(YR4)(YR4), a Si(R4)3 or —YC(-NR3)YR2 substituent; or
(c)-2: at least one of Ra and Rt is or contains a —NR2C(-S)OR2, —OC(-S)YR2, or —C(-S)OR2 substituent; or
(c)-3: at least one of Rb, Rt2 and Rt3 is or contains a —NR2C(-S)YR2, —OC(-S)YR2, or —C(-S)YR2 substituent; or
c)-4: Rt2 and Rt3 form together with the atoms to which they are attached, a saturated, partially saturated or unsaturated 5- or 6-membered ring, comprising carbon atoms and 0-3 heteroatoms selected from O, N, S(O)r and C(O), wherein the ring is optionally substituted; and,
alternatively Rt and Rt2 can form together with the atoms to which they are attached, a saturated, partially saturated or unsaturated 5- or 6-membered ring, comprising carbon atoms and 0-3 heteroatoms selected from O, N, S(O)r and C(O), the ring being optionally substituted;
each of the foregoing alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and heterocyclyl moieties are optionally substituted;
m is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3, 4 or 5; r is 0, 1 or 2; with the proviso that the compound is not one of the following:
One class of compounds which is of special interest for use in this invention are compounds of Formula I, as described above in Part 1, in which X1 is CH or CRt1; X3 is N; and X2 is CRt2.
This class is illustrated by compounds of Formula I in which Ring T is a pyrazine of one of the following types:
wherein Rt2 is selected from the group consisting of H, halo, —CN, —NO2, —R2, —OR2, —NR2R3, —C(O)YR2, —OC(O)YR2, —NR2C(O)YR2, —SC(O)YR2, —NR2C(-S)YR2, —OC(-S)YR2, —C(-S)YR2, —YC(-NR3)YR2, —YP(-O)(YR4)(YR4), —Si(R4)3, —NR2SO2R2, —S(O)rR2, —SO2NR2R3 and —NR2SO2NR2R3, wherein Y and Rt1 are as previously defined.
Illustrative examples of such compounds include those in which ring T is any of:
Of special interest is a subclass of the foregoing where X1 is CH, X3 is N; and X2 is CRt2.
Of special interest is another class of compounds of formula I as described above in Part 1, in which X1 is CH or CRt1; X2 is CRt2 and X3 is CRt3 with the proviso that the corn pound is not one of the following:
or with the proviso that when X1 is CH and Rt3 is H, Rt2 is not —C(O)OCH3 or —C(O)OH and when X1 is CH, Rt3 and Rt2 do not form an unsubstituted phenyl ring.
This class is illustrated by compounds of Formula I in which Ring T is a pyridine of one of the following types:
wherein Rt1, RL2 and Rt3 are as defined above in part 1.
Illustrative examples of such compounds include those in which ring T is any of:
In another class of interest are compounds of formula I in which X1 is CH or CRt1; X2 is N and X3 is CRt4 or N.
This class is illustrated by compounds of Formula I in which Ring T is a pyrimidine or a triazine of the following types:
wherein Rt4 and Rt1 are as previously defined.
Illustrative examples of such compounds include those in which Ring T is any of:
Also of special interest also include a class of compounds of formula I in which X1 is N; X2 is N or CRt2; and X3 is CRt3 or N.
This class is illustrated by compounds of Formula I in which Ring T is selected from the following types:
in which Rt2 and Rt3 are as defined in part 1.
Illustrative examples of such compounds include those in which Ring T is:
Another class of interest includes compounds of formula I in which X1 is CRt, X2 is N or CRt2, X3 is N or CRt3; in which Rt, Rt2 and Rt3 are as defined previously in part 1 and;
1. at least one of Rt, Rt2, Rt3, Ra and Rb is or contains YP(-O)(YR4)(YR4), Si(R4)3 or —YC(-NR3)YR2; or
2. at least one of Ra and Rt is or contains —NR2C(-S)OR2, —OC(-S)YR2, or —C(-S)OR2; or
3. at least one of Rb, Rt2 and Rt3 is or contains —NR2C(-S)YR2, —OC(-S)YR2, or —C(-S)YR2.
For this class of compounds, preferably at least one of Rt, Rt2, Rt3, Ra and Rb is or contains YP(-O)(YR4)(YR4), Si(R4)3 or —YC(-NR3)YR2.
Illustrative examples of this class include the following compounds:
Of special interest is a subclass of the foregoing in which X' is CRt, X2 is CRt2 and X3 is CRt3; in which Rt is as defined previously in part 1 and in which Rt2 and Rt3 can form together with the atoms to which they are attached, a saturated, partially saturated or unsaturated 5- or 6-membered ring, comprising carbon atoms and 0-3 heteroatoms selected from O, N, S(O)r and C(O), the ring being optionally substituted.
Illustrative examples of this subclass include the following compounds:
In various embodiments of this class and subclass, the following can also apply:
1. at least one of Rt, Rt2, Rt3, Ra and Rb is or contains YP(-O)(YR4)(YR4), Si(R4)3 or —YC(-NR3)YR2; or
2. at least one of Ra and Rt is or contains —NR2C(-S)OR2, —OC(-S)YR2, or —C(-S)OR2; or
3. at least one of Rb, Rt2 and Rt3 is or contains —NR2C(-S)YR2, —OC(-S)YR2, or —C(-S)YR2.
An illustrative example is:
Of particular interest is an interesting subclass of compounds of Formula I and of all classes and subclasses described above which contain Rt2 and Rt3, in which Rt2 and Rt3, together with the atoms to which they are attached, form a saturated, partially saturated or unsaturated 5- or 6-membered ring (Ring E), containing 0-3 heteroatoms selected from O, N, S(O)r and C(O), C(S), Ring E being optionally substituted with 1-4 Re moities, where each Re is independently selected from halo, -O, -S, —CN, —NO2, —R4, —C(O)YR2, —OC(O)YR2, —NR2C(O)YR2, —SC(O)YR2, —NR2C(-S)YR2, —OC(-S)YR2, —C(-S)YR2, —YC(-NR3)YR2, —YP(-O)(YR4)(YR4), —Si(R4)3, —NR2SO2R2, —S(O)rR2, —SO2NR2R3 and —NR2SO2NR2R3, wherein Y, r, R2 and R3 are as previously defined in Part 1; with the proviso that the compound is not:
and with the proviso that when X1 is CH, Rt1 and Rt2 do not form an unsubstituted phenyl.
This subclass is illustrated by compounds of formula II:
in which X1 is CRt1, CRt, CH or N.
Illustrative examples of such compounds include but are not limited to those in which the fused bicyclic heteroaryl system formed by Ring T and Ring E is one of the following types:
in which s is 0, 1, 2, 3 or 4. As in all cases, it is understood that the total number of substituents Re does not exceed the normal available valencies. Thus, for example, when Ring E is a phenyl ring fused with Ring T, it can optionally be substituted with 1 to 4 substituents (i.e. s is 0, 1, 2, 3 or 4), whereas when Ring E is a pyrazole or an imidazole fused with Ring T, it can optionally be substituted with a maximum of 2 substituents (i.e. s is 0, 1 or 2). It is also understood that when Ring E is unsubstituted, hydrogen atoms otherwise not depicted are present to meet the desire valency.
Compounds of current interest include among others, compounds of Formula II in which X1 is CH.
Another class on interest includes compounds of Formula II in which X1 is N or CRt1.
For the previously described classes and subclasses of compounds, as in all compounds of the invention, Ring A and Ring B are defined as in part 1:
Illustrative examples of substituted Ring A are:
Ring B represents a 5 or 6-membered aryl or heteroaryl ring as defined previously in Part 1. Illustrative examples of substituted Ring B are:
Of special interest is another class of compounds of Formula I as described above in Part 1, in which one of the Rb substituents is a 5- or 6-membered ring (Ring C), which may be heteroaryl or heterocyclic, comprising carbon atoms and 1-3 heteroatoms independently selected from O, N and S(O)r, Ring C being optionally substituted on carbon or heteroatom(s) with 1 to 5 substituents Rc.
This class is represented by compounds of Formula III:
in which X1, X2, X3, Ra, Rb, L1, A and B are as defined above in part 1; and Rc, at each occurrence, is selected from halo, —CN, -O, -S, —NO2, —R4, —OR2, —NR2R3, —C(O)YR2, —OC(O)YR2, —NR2C(O)YR2, —Si(R4)3, —SC(O)YR2, —NR2C(-S)YR2, —OC(-S)YR2, —C(-S)YR2, —YC(-NR3)YR2, —YP(-O)(YR4)(YR4), —NR2SO2R2, —S(O)rR2, —SO2NR2R3 and —NR2SO2NR2R3, wherein Y, r, R2, R3 and R4 are defined as previously in Part 1; t is 0, 1, 2, 3 or 4 and v is 0, 1, 2, 3, 4, or 5.
Illustrative examples of Ring C systems include but are not limited to the following types:
in which v and Rc are as defined above and in which the total number of substituents Rc does not exceed the normal valencies.
For this subclass of compounds of formula III and for all compounds of this invention, Ring T can be selected from all the classes and subclasses previously described.
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